364 results on '"Neuropathogenesis"'
Search Results
2. Co-receptor signaling in the pathogenesis of neuroHIV
- Author
-
E. A. Nickoloff-Bybel, Olimpia Meucci, L. Festa, and P. J. Gaskill
- Subjects
Receptors, CXCR4 ,Co-receptor ,Receptors, CCR5 ,Context (language use) ,HIV Infections ,CCR5 receptor antagonist ,Review ,Biology ,chemistry.chemical_compound ,Mice ,Receptors, HIV ,Virology ,Animals ,Humans ,Neuroinflammation ,Maraviroc ,NeuroHIV ,CXCR4 ,Clinical Trials as Topic ,virus diseases ,HIV ,HIV envelope protein ,RC581-607 ,Signaling ,Infectious Diseases ,chemistry ,CCR5 Receptor Antagonists ,Neuroinflammatory Diseases ,HIV-1 ,Neuropathogenesis ,Signal transduction ,Immunologic diseases. Allergy ,Neuroscience ,CCR5 ,Signal Transduction - Abstract
The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.
- Published
- 2021
3. Neuropathogenesis caused by Trypanosoma brucei, still an enigma to be unveiled
- Author
-
Katherine Figarella
- Subjects
Trypanosoma ,Two-Photon Microscopy ,Anti-Trypanosomatid Drugs ,Disease ,Trypanosoma brucei ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Microbiology ,Applied Microbiology and Biotechnology ,Plasmodium ,Meningoencephalitis ,Virology ,parasitic diseases ,Genetics ,lcsh:QH301-705.5 ,Molecular Biology ,Tropism ,biology ,Cell Biology ,biology.organism_classification ,Leishmania ,Editorial ,lcsh:Biology (General) ,Protozoa ,Neuropathogenesis ,Parasitology - Abstract
Trypanosoma brucei is one of the protozoa parasites that can enter the brain and cause injury associated with toxic effects of parasite-derived molecules or with immune responses against infection. Other protozoa parasites with brain tropism include Toxoplasma, Plasmodium, Amoeba, and, eventually, other Trypano-somatids such as T. cruzi and Leishmania. Together, these parasites affect billions of people worldwide and are responsible for more than 500.000 deaths annually. Factors determining brain tropism, mechanisms of in-vasion as well as processes ongoing inside the brain are not well understood. But, they depend on the par-asite involved. The pathogenesis caused by T. brucei initiates locally in the area of parasite inoculation, soon trypanosomes rich the blood, and the disease enters in the so-called early stage. The pathomecha-nisms in this phase have been described, even mole-cules used to combat the disease are effective during this period. Later, the disease evolves towards a late-stage, characterized by the presence of parasites in the central nervous system (CNS), the so-called meningo-encephalitic stage. This phase of the disease has not been sufficiently examined and remains a matter of investigation. Here, I stress the importance of delve into the study of the neuropathogenesis caused by T. brucei, which will enable the identification of path-ways that may be targeted to overcome parasites that reached the CNS. Finally, I highlight the impact that the application of tools developed in the last years in the field of neuroscience will have on the study of neglect-ed tropical diseases.
- Published
- 2021
4. Environmental epidemiology and neurological manifestations of dengue serotypes with special inference on molecular trends, virus detection, and pathogenicity
- Author
-
Embalil Mathachan Aneesh and A. N. Anoopkumar
- Subjects
Serotype ,Economics and Econometrics ,education.field_of_study ,medicine.medical_specialty ,Transmission (medicine) ,Public health ,Geography, Planning and Development ,Population ,0211 other engineering and technologies ,02 engineering and technology ,010501 environmental sciences ,Management, Monitoring, Policy and Law ,Dengue virus ,Biology ,medicine.disease_cause ,medicine.disease ,01 natural sciences ,Genome ,Virology ,Dengue fever ,medicine ,Neuropathogenesis ,021108 energy ,education ,0105 earth and related environmental sciences - Abstract
The emergence of new viruses is a matter of significant concern in the current decade. It has dazed the indigenous healthcare systems in various parts of the world. Consequently, the resources for fighting the rapid spread of the DENV are ineffectual, insufficient, and incompetent. Several environmental factors have been allied with dengue fever transmission. High documentation of neuropathogenesis in dengue-infected individuals in recent years reflects the significance of our study, and the information discussed in this review can be used to enhance clinical awareness along with advances in diagnostic approaches. The replication of the DENV genome is usually engaged in a membrane-linked replication complex; the virion budding and morphogenesis have been found to take place in the modified endoplasmic reticulum membranes. Most of these non-structural proteins are believed to be responsible for RNA replication and polyprotein processing. The nucleic acid-based strategies have provided high sensitivity and progressively replacing conventional techniques. Advanced technologies like PCR have offered timely serotyping of dengue viruses, which illustrates the early warning of dengue epidemics. The molecular methods help to characterize the key factors responsible for the rapid spread of viruses and thereby update the vector control programmes targeted at extenuating their adverse impacts on public health. The vast diversity of dengue virus strains worldwide with special inference on their clinical manifestations and genetic characteristics was also analyzed in this study. As dengue threatens one third of the world's population, practical applications of advanced molecular strategies from an environmental and phylogenetic perspective are critical for disease control.
- Published
- 2021
5. Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis and poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets
- Author
-
David Moraga Amador, Mattia Prosperi, Shannan N Rich, Kenneth C Williams, Andrea S Ramirez-Mata, Marco Salemi, Melanie N. Cash, James Jarad Dollar, Alberto Riva, David J. Nolan, Kevin White, Brittany Rife Magalis, Simone Marini, and Carla Mavian
- Subjects
Male ,0301 basic medicine ,Poly ADP ribose polymerase ,Simian Acquired Immunodeficiency Syndrome ,Neuropathology ,Biology ,medicine.disease_cause ,Article ,Virus ,Transcriptome ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Virology ,Gene expression ,medicine ,Animals ,Parps ,Transcriptomics ,HIV ,Brain ,Simian immunodeficiency virus ,Macaca mulatta ,Frontal Lobe ,030104 developmental biology ,SIV ,Neurology ,Immunology ,Neuropathogenesis ,Neurology (clinical) ,Poly(ADP-ribose) Polymerases ,Cognition Disorders ,030217 neurology & neurosurgery ,CD8 - Abstract
Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.
- Published
- 2021
6. Neuropathogenesis of Neurotropic Viruses
- Author
-
Abba Musa Abdullahi
- Subjects
viruses ,Neuropathogenesis ,Biology ,Virology - Abstract
Neuropathogenesis can simply be defined as the mechanisms of the origin, development and progression of the CNS disease which comprises both neuroinvasion and neurovirulence. Viruses that have the ability to induce neuropathogenesis are called neurotropic pathogens. The exact mechanisms of neuropathogenesis is still unknown, however, the following pathways have been proposed and include retrograde axonal transport, hematogenous spread from the peripheral blood to the cerebral blood vessesls across blood brain barrier, direct invasion of the endothelial cells and endocytosis across the viral receptors. The main neurotropic viral families are picornaviruses, arboviruses, paramixoviruses, arenaviruses and herpes family viruses. In this review, the main mechanisms of neuropathogenesis of the neurotropic members of these viral families was discussed
- Published
- 2020
7. Unraveling neuroHIV in the Presence of Substance Use Disorders
- Author
-
Roger G. Sorensen, Johnny J. He, Linda Chang, and Yu Lin
- Subjects
0301 basic medicine ,medicine.medical_specialty ,HIV Proteins ,media_common.quotation_subject ,Immunology ,Neuroscience (miscellaneous) ,Human immunodeficiency virus (HIV) ,Disease ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Psychiatry ,media_common ,Pharmacology ,biology ,business.industry ,Addiction ,biology.organism_classification ,030104 developmental biology ,Neuropathogenesis ,Cannabis ,Substance use ,business ,030217 neurology & neurosurgery - Abstract
This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions.
- Published
- 2020
8. SARS-CoV-2: Should We Be Concerned about the Nervous System?
- Author
-
Marco A. Lima, Marcus Tulius T. Silva, and Abelardo Q.C. Araújo
- Subjects
2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,030231 tropical medicine ,Review Article ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Pandemic ,medicine ,Humans ,Intensive care medicine ,Pandemics ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,biology.organism_classification ,medicine.disease ,Infectious Diseases ,Middle East respiratory syndrome ,Parasitology ,Neuropathogenesis ,Nervous System Diseases ,Coronavirus Infections ,business - Abstract
The COVID-19 pandemic has proved to be an enormous challenge to the health of the world population with tremendous consequences for the world economy. New knowledge about COVID-19 is being acquired continuously. Although the main manifestation of COVID-19 is SARS, dysfunction in other organs has been described in the last months. Neurological aspects of COVID-19 are still an underreported subject. However, a plethora of previous studies has shown that human CoVs might be neurotropic, neuroinvasive, and neurovirulent, highlighting the importance of this knowledge by physicians. Besides, several neurological manifestations had been described as complications of two other previous outbreaks of CoV diseases (SARS ad Middle East respiratory syndrome). Therefore, we should be watchful, searching for early evidence of neurological insults and promoting clinical protocols to investigate them. Our objectives are to review the potential neuropathogenesis of this new CoV and the neurological profile of COVID-19 patients described so far.
- Published
- 2020
9. Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia
- Author
-
Hannah Keeney, Roberta S Dos Reis, Shilpa Sant, Velpandi Ayyavoo, and Marc Wagner
- Subjects
Models, Anatomic ,0301 basic medicine ,Cell type ,Interleukin-1beta ,Neurocognitive Disorders ,lcsh:Medicine ,Biology ,Virus Replication ,Virus-host interactions ,Article ,03 medical and health sciences ,Organ Culture Techniques ,0302 clinical medicine ,Neural Stem Cells ,Neurological models ,medicine ,Humans ,Neurodegeneration ,lcsh:Science ,Neuroinflammation ,Multidisciplinary ,Microglia ,Tumor Necrosis Factor-alpha ,lcsh:R ,Brain ,Cell Differentiation ,Human brain ,medicine.disease ,Culture Media ,Organoids ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,HIV-1 ,Increased inflammatory response ,Tumor necrosis factor alpha ,Neuropathogenesis ,lcsh:Q ,Neuroscience ,030217 neurology & neurosurgery ,HIV infections - Abstract
HIV-1 associated neurocognitive disorder (HAND) is characterized by neuroinflammation and glial activation that, together with the release of viral proteins, trigger a pathogenic cascade resulting in synaptodendritic damage and neurodegeneration that lead to cognitive impairment. However, the molecular events underlying HIV neuropathogenesis remain elusive, mainly due to lack of brain-representative experimental systems to study HIV-CNS pathology. To fill this gap, we developed a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; neurons and astrocytes along with incorporation of HIV-infected microglia. Both infected and uninfected microglia infiltrated into hBORGs resulting in a triculture system (MG-hBORG) that mirrors the multicellular network observed in HIV-infected human brain. Moreover, the MG-hBORG model supported productive viral infection and exhibited increased inflammatory response by HIV-infected MG-hBORGs, releasing tumor necrosis factor (TNF-α) and interleukin-1 (IL-1β) and thereby mimicking the chronic neuroinflammatory environment observed in HIV-infected individuals. This model offers great promise for basic understanding of how HIV-1 infection alters the CNS compartment and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.
- Published
- 2020
10. Cerebrospinal Fluid Features in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reverse Transcription Polymerase Chain Reaction (RT-PCR) Positive Patients
- Author
-
Manuel Schibler, Cecilia Schweblin, Patrice H. Lalive, Nathalie Lambeng, Pascal Cherpillod, Christine Deffert, Jessica Vazquez, and Mathilde Bellon
- Subjects
0301 basic medicine ,Microbiology (medical) ,viruses ,ddc:616.07 ,Blood–brain barrier ,medicine.disease_cause ,Immunoglobulin G ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,medicine ,Blood-brain barrier ,Coronavirus ,ddc:616 ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,virus diseases ,Intrathecal synthesis ,Virology ,Reverse transcriptase ,ddc:616.8 ,Reverse transcription polymerase chain reaction ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Real-time polymerase chain reaction ,Neurological manifestations ,biology.protein ,Neuropathogenesis ,business ,030217 neurology & neurosurgery - Abstract
This study analyzed the cerebrospinal fluid features of 31 coronavirus disease 2019 (COVID-19) patients with neurological complications. We observed neither severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the cerebrospinal fluid, nor intrathecal immunoglobulin G (IgG) synthesis but did observe signs of blood-brain barrier disruption. These results might serve as a basis for a better understanding of SARS-CoV-2 related neuropathogenesis.
- Published
- 2020
11. TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71
- Author
-
Xiaoyan Zhong, Lexun Lin, Yao Wang, Wenran Zhao, Xiaoman Wo, Shuoxuan Zhao, Yan Wang, Yong Xu, Yang Chen, Zhaohua Zhong, and Yuan Yuan
- Subjects
0301 basic medicine ,medicine.medical_treatment ,030106 microbiology ,Immunology ,TAR DNA-Binding Protein 43 ,Cleavage (embryo) ,Pathogenesis ,03 medical and health sciences ,Virology ,mental disorders ,Enterovirus Infections ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Caspase ,Enterovirus ,Protease ,biology ,Chemistry ,nutritional and metabolic diseases ,medicine.disease ,Enterovirus A, Human ,nervous system diseases ,DNA-Binding Proteins ,030104 developmental biology ,Cytoplasm ,biology.protein ,Molecular Medicine ,Neuropathogenesis ,Research Article ,Peptide Hydrolases - Abstract
Enterovirus A71 (EV-A71) is one of the etiological pathogens leading to hand, foot, and mouth disease (HFMD), which can cause severe neurological complications. The neuropathogenesis of EV-A71 infection is not well understood. The mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, whether TDP-43 was impacted by EV-A71 infection is unknown. This study demonstrated that TDP-43 was cleaved during EV-A71 infection. The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection. TDP-43 is cleaved by viral protease 3C between the residues 331Q and 332S, while mutated TDP-43 (Q331A) was not cleaved. In addition, mutated 3C which lacks the protease activity failed to induce TDP-43 cleavage. We also found that TDP-43 was translocated from the nucleus to the cytoplasm, and the mislocalization of TDP-43 was induced by viral protease 2A rather than 3C. Taken together, we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection, implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-020-00262-x) contains supplementary material, which is available to authorized users.
- Published
- 2020
12. Coronaviruses and the central nervous system
- Author
-
Morgello, Susan
- Subjects
0301 basic medicine ,Clinical Review ,Neurologic disease ,Coronaviridae ,Coronaviridae Infections ,Neurotropism ,viruses ,Central nervous system ,Pneumonia, Viral ,Clinical Neurology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Betacoronavirus ,0302 clinical medicine ,Immune system ,Viral entry ,Virology ,medicine ,Animals ,Humans ,Pandemics ,Coronavirus ,biology ,business.industry ,SARS-CoV-2 ,Meningoencephalitis ,virus diseases ,COVID-19 ,medicine.disease ,biology.organism_classification ,Meningitis, Viral ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Immunology ,Neuropathogenesis ,Neurology (clinical) ,business ,Coronavirus Infections ,030217 neurology & neurosurgery - Abstract
Seven coronavirus (CoV) species are known human pathogens: the epidemic viruses SARS-CoV, SARS-CoV-2, and MERS-CoV and those continuously circulating in human populations since initial isolation: HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63. All have associations with human central nervous system (CNS) dysfunction. In infants and young children, the most common CNS phenomena are febrile seizures; in adults, non-focal abnormalities that may be either neurologic or constitutional. Neurotropism and neurovirulence are dependent in part on CNS expression of cell surface receptors mediating viral entry, and host immune response. In adults, CNS receptors for epidemic viruses are largely expressed on brain vasculature, whereas receptors for less pathogenic viruses are present in vasculature, brain parenchyma, and olfactory neuroepithelium, dependent upon viral species. Human coronaviruses can infect circulating mononuclear cells, but meningoencephalitis is rare. Well-documented human neuropathologies are infrequent and, for SARS, MERS, and COVID-19, can entail cerebrovascular accidents originating extrinsically to brain. There is evidence of neuronal infection in the absence of inflammatory infiltrates with SARS-CoV, and CSF studies of rare patients with seizures have demonstrated virus but no pleocytosis. In contrast to human disease, animal models of neuropathogenesis are well developed, and pathologies including demyelination, neuronal necrosis, and meningoencephalitis are seen with both native CoVs as well as human CoVs inoculated into nasal cavities or brain. This review covers basic CoV biology pertinent to CNS disease; the spectrum of clinical abnormalities encountered in infants, children, and adults; and the evidence for CoV infection of human brain, with reference to pertinent animal models of neuropathogenesis.
- Published
- 2020
13. Reciprocal Influences of HIV and Cannabinoids on the Brain and Cognitive Function
- Author
-
Sheri L. Towe, Christine C. Cloak, Ryan P. Bell, Linda Chang, Christina S. Meade, and Julian Baptiste
- Subjects
0301 basic medicine ,Exacerbation ,Immunology ,Neuroscience (miscellaneous) ,HIV Infections ,Article ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Neuroimaging ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Effects of cannabis ,Pharmacology ,biology ,Cannabinoids ,business.industry ,Brain ,biology.organism_classification ,030104 developmental biology ,Clinical research ,Marijuana Use ,Neuropathogenesis ,Cannabis ,business ,Neurocognitive ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Globally, cannabis is the most commonly used illicit drug, with disproportionately high use among persons with HIV. Despite advances in HIV care, nearly half of persons living with HIV continue to experience neurocognitive deficits or impairments that may have negative impacts on their daily function. Chronic cannabis use may play a role in the development or exacerbation of these impairments. Here we present a review summarizing existing research detailing the effect of cannabis use associated with the neuropathogenesis of HIV. We examine evidence for possible additive or synergistic effects of HIV infection and cannabis use on neuroHIV in both the preclinical and adult human literatures, including in vitro studies, animal models, clinical neuroimaging research, and studies examining the cognitive effects of cannabis. We discuss the limitations of existing research, including methodological challenges involved with clinical research with human subjects. We identify gaps in the field and propose critical research questions to advance our understanding of how cannabis use affects neuroHIV. Graphical Abstract.
- Published
- 2020
14. The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside
- Author
-
Frasia Oosthuizen, Thabisile Mpofana, Suvira Ramlall, and Henry Ukachukwu Michael
- Subjects
Brain-derived neurotrophic factor ,biology ,business.industry ,Neuropathology ,HIV-associated neurocognitive disorder ,medicine.disease ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Neurotrophic factors ,Neuroplasticity ,medicine ,biology.protein ,Neuropathogenesis ,business ,Neurocognitive ,Neuroscience ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains prevalent in the anti-retroviral (ART) era. While there is a complex interplay of many factors in the neuropathogenesis of HAND, decreased neurotrophic synthesis has been shown to contribute to synaptic degeneration which is a hallmark of HAND neuropathology. Brain derived neurotrophic factor (BDNF) is the most abundant and synaptic-promoting neurotrophic factor in the brain and plays a critical role in both learning and memory. Reduced BDNF levels can worsen neurocognitive impairment in HIV-positive individuals across several domains. In this paper, we review the evidence from pre-clinical and clinical studies showing the neuroprotective roles of BDNF against viral proteins, effect on co-morbid mental health disorders, altered human microbiome and ART in HAND management. Potential applications of BDNF modulation in pharmacotherapeutic, cognitive and behavioral interventions in HAND are also discussed. Finally, research gaps and future research direction are identified with the aim of helping researchers to direct efforts to make these BDNF driven interventions improve the quality of life of patients living with HAND.
- Published
- 2020
15. Establishment of Human-Induced Pluripotent Stem Cell-Derived Neurons—A Promising In Vitro Model for a Molecular Study of Rabies Virus and Host Interaction
- Author
-
Penpicha Chankeeree, Kantinan Leetanasaksakul, Boonlert Lumlertdacha, Wanapinun Nawae, Nanchaya Wanasen, Porntippa Lekcharoensuk, Sira Sriswasdi, Sithichoke Tangphatsornruang, Thanakorn Jaemthaworn, Thanathom Chailangkarn, Yuparat Jantraphakorn, Challika Kaewborisuth, and Nathiphat Tanwattana
- Subjects
Cell type ,Cytoskeleton organization ,Proteome ,Rabies ,QH301-705.5 ,Induced Pluripotent Stem Cells ,neurons ,virus–host interaction ,Biology ,medicine.disease_cause ,Article ,Catalysis ,Inorganic Chemistry ,medicine ,human-induced pluripotent stem cells ,Humans ,rabies virus ,Physical and Theoretical Chemistry ,Biology (General) ,Induced pluripotent stem cell ,Molecular Biology ,QD1-999 ,Spectroscopy ,Cells, Cultured ,Organic Chemistry ,Rabies virus ,proteomics analysis ,General Medicine ,medicine.disease ,Synaptic vesicle cycle ,Computer Science Applications ,Chemistry ,in vitro model ,Host-Pathogen Interactions ,Neuropathogenesis ,Neurotransmitter transport ,Neuroscience - Abstract
Rabies is a deadly viral disease caused by the rabies virus (RABV), transmitted through a bite of an infected host, resulting in irreversible neurological symptoms and a 100% fatality rate in humans. Despite many aspects describing rabies neuropathogenesis, numerous hypotheses remain unanswered and concealed. Observations obtained from infected primary neurons or mouse brain samples are more relevant to human clinical rabies than permissive cell lines, however, limitations regarding the ethical issue and sample accessibility become a hurdle for discovering new insights into virus–host interplays. To better understand RABV pathogenesis in humans, we generated human-induced pluripotent stem cell (hiPSC)-derived neurons to offer the opportunity for an inimitable study of RABV infection at a molecular level in a pathologically relevant cell type. This study describes the characteristics and detailed proteomic changes of hiPSC-derived neurons in response to RABV infection using LC-MS/MS quantitative analysis. Gene ontology (GO) enrichment of differentially expressed proteins (DEPs) reveals temporal changes of proteins related to metabolic process, immune response, neurotransmitter transport/synaptic vesicle cycle, cytoskeleton organization, and cell stress response, demonstrating fundamental underlying mechanisms of neuropathogenesis in a time-course dependence. Lastly, we highlighted plausible functions of heat shock cognate protein 70 (HSC70 or HSPA8) that might play a pivotal role in regulating RABV replication and pathogenesis. Our findings acquired from this hiPSC-derived neuron platform help to define novel cellular mechanisms during RABV infection, which could be applicable to further studies to widen views of RABV-host interaction.
- Published
- 2021
16. Locust as an in Vivo Model
- Author
-
Naveed Ahmed Khan, Jibran Sualeh Muhammad, and Ruqaiyyah Siddiqui
- Subjects
Whole genome sequencing ,0303 health sciences ,animal structures ,Physiology ,Cognitive Neuroscience ,Genomics ,Cell Biology ,General Medicine ,Computational biology ,Biology ,biology.organism_classification ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Neuropathogenesis ,Throughput (business) ,030217 neurology & neurosurgery ,Large size ,Locust ,030304 developmental biology - Abstract
The combination of newly available genome sequence information on locusts together with high throughput genomics capabilities, novel approaches for genetic traceability, and their large size for easier handling makes locusts a valuable in vivo tool to study brain formation, functional adaptations, and neuropathogenesis during embryonic development in various environmental niches.
- Published
- 2021
17. Zika Virus and Neuropathogenesis: The Unanswered Question of Which Strain Is More Prone to Causing Microcephaly and Other Neurological Defects
- Author
-
Emily Louise King, Nerea Irigoyen, Apollo - University of Cambridge Repository, and Irigoyen, Nerea [0000-0001-6346-3369]
- Subjects
Microcephaly ,Neurosciences. Biological psychiatry. Neuropsychiatry ,neural progenitor cells ,Review ,Biology ,Virus ,Zika virus ,Cellular and Molecular Neuroscience ,viral lineages ,Cellular neuroscience ,neuropathogenesis ,medicine ,premature differentiation ,apoptosis ,unfolded protein response ,medicine.disease ,biology.organism_classification ,Virology ,Neural stem cell ,medicine.anatomical_structure ,Macular scarring ,Cerebral cortex ,Cellular Neuroscience ,Neuropathogenesis ,RC321-571 - Abstract
Despite being perceived to be a relatively innocuous pathogen during its circulation in Africa in the 20th century, consequent outbreaks in French Polynesia and Latin America revealed the Zika virus (ZIKV) to be capable of causing severe neurological defects. Foetuses infected with the virus during pregnancy developed a range of pathologies including microcephaly, cerebral calcifications and macular scarring. These are now collectively known as Congenital Zika syndrome (CZS). It has been established that the neuropathogenesis of ZIKV results from infection of neural progenitor cells in the developing cerebral cortex. Following this, two main hypotheses have emerged: the virus causes either apoptosis or premature differentiation of neural progenitor cells, reducing the final number of mature neurons in the cerebral cortex. This review describes the cellular processes which could potentially cause virus induced apoptosis or premature differentiation, leading to speculation that a combination of the two may be responsible for the pathologies associated with ZIKV. The review also discusses which specific lineages of the ZIKV can employ these mechanisms. It has been unclear in the past whether the virus evolved its neurotropic capability following circulation in Africa, or if the virus has always caused microcephaly but public health surveillance in Africa had failed to detect it. Understanding the true neuropathogenesis of ZIKV is key to being prepared for further outbreaks in the future, and it will also provide insight into how neurotropic viruses can cause profound and life-long neurological defects.
- Published
- 2021
18. Coronin 1A facilitates calcium mobilization and promotes astrocyte reactivity in HIV-1 neuropathogenesis
- Author
-
Hriday Shanker Pandey, Bindu, Pankaj Seth, and Rishabh Kapoor
- Subjects
Cancer Research ,biology ,Physiology ,Chemistry ,Human immunodeficiency virus (HIV) ,Coronin ,Calcium mobilization ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cell biology ,medicine.anatomical_structure ,medicine ,biology.protein ,Molecular Medicine ,Neuropathogenesis ,Reactivity (chemistry) ,Astrocyte - Abstract
BackgroundIn most neurodegenerative disorders, including neuroAIDS, reactive astrocytes are detrimental to the neuronal population. Calcium and its downstream regulators play a central role in mediating astrocyte reactivity. Coronin 1A, an actin binding protein, majorly reported in hematopoietic cells, regulates cell activity in a calcium-dependent manner, but its role in astrocyte physiology and reactivity is largely unknown. We explored the roles of Coronin 1A in astrocyte physiology and its involvement in facilitating astrocyte reactivity. MethodsCoronin 1A expression was assessed in astrocytes and human brain autopsy sections using western blotting, immunocytochemistry, and immunohistochemistry. siRNA-mediated downregulation was performed to assess its loss of function. To assess the cell activity, live-cell calcium imaging was performed on ATP-stimulated astrocytes using a confocal microscope. HIV-1 Tat B expression vector was used to induce astrocyte reactivity, after which gene and protein expressions were assessed using qPCR and western blotting; cytokine release was measured using flow cytometry and glutamate release was assessed using enzymatic activity. TUNEL assay was performed on neurons treated with the astrocyte-conditioned media. Small RNA-sequencing and qPCR assays were performed to list miRNAs differentially regulated as a result of HIV-1 Tat transfection. Transfection with mimic and inhibitor against selected miRNA and luciferase assay was performed to confirm the miRNA regulation.ResultsWe report Coronin 1A expression in human primary astrocytes and autopsy brain sections, and that it plays activity-dependent roles by facilitating Calcium mobilization from the intracellular stores. HIV-1 Tat, a potent neurotoxicant that turns astrocytes reactive, augments Coronin 1A expression, apart from affecting GFAP and pro-inflammatory molecules. Also, the autopsy brain tissue of HIV-1 infected individuals has higher Coronin 1A expression. Downregulation of Coronin 1A attenuated the HIV-1 Tat-induced deleterious effects of reactive astrocytes, measured as upregulated GFAP expression, enhanced release of IL-6, and Glutamate and hence reduced astrocyte-mediated neuroinflammation. Our findings also suggest that out of a pool of dysregulated miRNAs studied by us, hsa-miR-92b-5p regulates Coronin 1A expression under the effect of HIV-1 Tat. ConclusionThese findings highlight the novel roles of Coronin 1A in regulating astrocyte activity in stimulated conditions and astrocyte reactivity observed in HIV-1 neuropathogenesis.
- Published
- 2021
19. Molecular Mechanism(s) of Zika virus infection and associated neuropathogenesis
- Author
-
Chet Raj Ojha
- Subjects
Microcephaly ,biology ,Autophagy ,medicine ,Unfolded protein response ,Molecular mechanism ,Neuropathogenesis ,medicine.disease ,biology.organism_classification ,Virology ,Zika virus - Published
- 2021
20. Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS
- Author
-
Stefania Farcomeni, Maria Teresa Maggiorella, Alessandra Borsetti, Leonardo Sernicola, Sara Virtuoso, and Sonia Moretti
- Subjects
Microbiology (medical) ,viruses ,neuroAIDS ,markers ,Review ,Biology ,medicine.disease_cause ,Macaque ,Virus ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,biology.animal ,medicine ,Genetic predisposition ,Immunology and Allergy ,Molecular Biology ,General Immunology and Microbiology ,macaque ,virus diseases ,Simian immunodeficiency virus ,medicine.disease ,Virology ,macrophages ,Infectious Diseases ,inflammation ,Medicine ,Neuropathogenesis ,Simian Immunodeficiency Virus ,Encephalitis - Abstract
Non-human primates (NHPs) are the most relevant model of Acquired Immunodeficiency Syndrome (AIDS) and neuroAIDS, being of great importance in explaining the pathogenesis of HIV-induced nervous system damage. Simian Immunodeficiency Virus (SIV)/ Simian-Human Immunodeficiency Virus (SHIV)-infected monkeys have provided evidence of complex interactions between the virus and host that include host immune response, viral genetic diversity, and genetic susceptibility, which may explain virus-associated central nervous system (CNS) pathology and HIV-associated neurocognitive disorders (HAND). In this article, we review the recent progress contributions obtained using monkey models of HIV infection of the CNS, neuropathogenesis and SIV encephalitis (SIVE), with an emphasis on pharmacologic therapies and dependable markers that predict development of CNS AIDS.
- Published
- 2021
21. Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease
- Author
-
Marc S. Penn, Peter L. Nara, W. Sue T. Griffin, Jan Potempa, and Daniel Sindelar
- Subjects
0301 basic medicine ,Iron ,Cholinergic Agents ,Virulence ,Disease ,Biology ,cholinergic hypothesis ,Pathogenesis ,03 medical and health sciences ,Extremophiles ,0302 clinical medicine ,Anti-Infective Agents ,Alzheimer Disease ,Bacteroidaceae Infections ,Humans ,Saliva ,Porphyromonas gingivalis ,Pathogen ,systemic inflammation ,Lactoferrin ,General Neuroscience ,Brain ,General Medicine ,Hypothesis ,biology.organism_classification ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,biological extremophile ,Immunology ,biology.protein ,Neuropathogenesis ,Geriatrics and Gerontology ,Bacterial outer membrane ,Alzheimer’s disease ,030217 neurology & neurosurgery ,outer membrane vesicles ,Bacterial Outer Membrane Proteins ,dementia - Abstract
Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.
- Published
- 2021
22. The Potential Roles of Glial Cells in the Neuropathogenesis of Cerebral Malaria
- Author
-
Nana Efua Andoh and Ben Gyan
- Subjects
Microbiology (medical) ,Plasmodium ,Immunology ,Plasmodium falciparum ,Malaria, Cerebral ,microglia ,Review ,Blood–brain barrier ,Microbiology ,Pathogenesis ,Cellular and Infection Microbiology ,parasitic diseases ,medicine ,Humans ,biology ,Microglia ,business.industry ,astrocytes ,blood-brain barrier ,biology.organism_classification ,medicine.disease ,QR1-502 ,glial cells ,Infectious Diseases ,medicine.anatomical_structure ,Cerebral Malaria ,Child, Preschool ,Neuropathogenesis ,cerebral malaria ,Nervous System Diseases ,business ,Malaria - Abstract
Cerebral malaria (CM) is a severe neurological complication of malaria caused by the Plasmodium falciparum parasite. It is one of the leading causes of death in children under 5 years of age in Sub-Saharan Africa. CM is associated with blood-brain barrier disruption and long-term neurological sequelae in survivors of CM. Despite the vast amount of research on cerebral malaria, the cause of neurological sequelae observed in CM patients is poorly understood. In this article, the potential roles of glial cells, astrocytes, and microglia, in cerebral malaria pathogenesis are reviewed. The possible mechanisms by which glial cells contribute to neurological damage in CM patients are also examined.
- Published
- 2021
23. Tick-borne encephalitis virus: molecular determinants of neuropathogenesis of an emerging pathogen
- Author
-
Morgane Solis, Marlène Cesbron, Samira Fafi-Kremer, Eric Soulier, Yves Hansmann, Magali Paz, Aurélie Velay, Martin Martinot, Xavier Argemi, and Pierre Gantner
- Subjects
0301 basic medicine ,Virulence Factors ,viruses ,030106 microbiology ,Applied Microbiology and Biotechnology ,Microbiology ,Virus ,Encephalitis Viruses, Tick-Borne ,03 medical and health sciences ,Emerging pathogen ,medicine ,Animals ,Humans ,biology ,Transmission cycle ,General Medicine ,medicine.disease ,biology.organism_classification ,Tick vector ,Virology ,Disease Models, Animal ,Tick-borne encephalitis virus ,030104 developmental biology ,Host-Pathogen Interactions ,Ixodes ,Neuropathogenesis ,Encephalitis, Tick-Borne ,Encephalitis - Abstract
Tick-borne encephalitis virus (TBEV) is a zoonotic agent causing severe encephalitis. The transmission cycle involves the virus, the Ixodes tick vector, and a vertebrate reservoir, such as ...
- Published
- 2019
24. Friends Turn Foe—Astrocytes Contribute to Neuronal Damage in NeuroAIDS
- Author
-
Pankaj Seth and Hriday Shanker Pandey
- Subjects
0301 basic medicine ,Cell type ,medicine.medical_specialty ,Neurology ,Central nervous system ,HIV Infections ,Biology ,Indirect pathway of movement ,Synaptic Transmission ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Animals ,Humans ,Neurons ,Neurodegeneration ,Neurodegenerative Diseases ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Astrocytes ,Neuropathogenesis ,Astrocytosis ,Neuroscience ,030217 neurology & neurosurgery ,Astrocyte - Abstract
Astrocytes play a wide variety of roles in the central nervous system (CNS). Various facets of astrocyte-neuron interplay, investigated for the past few decades, have placed these most abundant and important glial cell types to be of supreme importance for the maintenance of the healthy CNS. Interestingly, glial dysfunctions have proven to be the major contributor to neuronal loss in several CNS disorders and pathologies. Specifically, in the field of neuroAIDS, glial dysfunction-mediated neuronal stress is a major factor contributing to the HIV-1 neuropathogenesis. As there is increasing evidence that astrocytes harbor HIV-1 and serve as "safe haven" for the dormant virus in the brain, the indirect pathway of neuronal damage has taken over the direct neuronal damage in its contribution to HIV-1 neuropathogenesis. In this review, we provide a brief insight into the astrocyte functions and dysfunctions in different CNS conditions with an elaborated insight into neuroAIDS. Detailed understanding of the role of astrocytes in neuroAIDS will help in the better therapeutic management of the neurological problems associated with HIV-1 patients.
- Published
- 2019
25. Differences in Neuropathogenesis of Encephalitic California Serogroup Viruses
- Author
-
Alyssa B. Evans, Clayton W. Winkler, and Karin E. Peterson
- Subjects
Genes, Viral ,Epidemiology ,encephalitis ,viruses ,vector-borne infections ,C57BL/6 ,lcsh:Medicine ,neurons ,California serogroup viruses ,Global Health ,Inkoo virus ,susceptibility ,Pathogenesis ,Mice ,0302 clinical medicine ,La Crosse virus ,Cluster Analysis ,pathogenicity ,Public Health Surveillance ,030212 general & internal medicine ,Geography, Medical ,Cells, Cultured ,virus replication ,Jamestown Canyon virus ,Incidence ,Age Factors ,Titer ,snowshoe hare virus ,Infectious Diseases ,Neuropathogenesis ,orthobunyaviruses ,Encephalitis ,Microbiology (medical) ,brain ,mouse model ,030231 tropical medicine ,Encephalitis Virus, California ,Tahyna virus ,Biology ,Serogroup ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Encephalitis, California ,neuropathogenesis ,medicine ,Animals ,Humans ,lcsh:RC109-216 ,mosquitoborne viruses ,disease ,Research ,lcsh:R ,Sequence Analysis, DNA ,medicine.disease ,Virology ,United States ,Differences in Neuropathogenesis of Encephalitic California Serogroup Viruses ,Disease Models, Animal ,Viral replication - Abstract
The California serogroup of orthobunyaviruses comprises a group of mosquitoborne viruses, including La Crosse (LACV), snowshoe hare (SSHV), Tahyna (TAHV), Jamestown Canyon (JCV), and Inkoo (INKV) viruses, that cause neurologic disease in humans of differing ages with varying incidences. To determine how the pathogenesis of these viruses differs, we compared their ability to induce disease in mice and replicate and induce cell death in vitro. In mice, LACV, TAHV, and SSHV induced neurologic disease after intraperitoneal and intranasal inoculation, and JCV induced disease only after intranasal inoculation. INKV rarely induced disease, which correlated with less viral antigen in the brain than the other viruses. In vitro, all viruses replicated to high titers; however, LACV, SSHV, and TAHV induced high cell death, whereas JCV and INKV did not. Results demonstrated that CSG viruses differ in neuropathogenesis in vitro and in vivo, which correlates with the differences in pathogenesis reported in humans.
- Published
- 2019
26. Use of induced pluripotent stem cells (iPSCs) and cerebral organoids in modeling the congenital infection and neuropathogenesis induced by Zika virus
- Author
-
Adriana Ávila Moura, Denise Cantarelli Machado, Daniel Rodrigo Marinowic, Fernanda Majolo, and Jaderson Costa da Costa
- Subjects
Microcephaly ,Induced Pluripotent Stem Cells ,Central nervous system ,Virus ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,Virology ,medicine ,Global health ,Humans ,030212 general & internal medicine ,Induced pluripotent stem cell ,Subclinical infection ,biology ,Zika Virus Infection ,business.industry ,Brain ,Zika Virus ,Models, Theoretical ,biology.organism_classification ,medicine.disease ,Organoids ,Infectious Diseases ,medicine.anatomical_structure ,030211 gastroenterology & hepatology ,Neuropathogenesis ,business - Abstract
Infection with Zika virus (ZIKV) was recently demonstrated to be associated with damage to the central nervous system, especially microcephaly and the Guillain-Barré syndrome. This finding had alarmed public health agencies and mobilized institutions around the world to search for more information about the virus, its effects, pathophysiological mechanisms, and potential immunizations and treatments. Given the increasing interest in using iPSCs and cerebral organoids to model the congenital infection and neuropathogenesis induced by ZIKV, the aim of this review was to present an up-to-date summary of the publications on the association of ZIKV with microcephaly, using iPSCs and organoids. According to our review, the number of studies has decreased concomitantly with a decrease in the number of cases. The presence of subclinical lesions at birth, which may eventually present cognitive or behavioral problems in the future, suggests that persistent research efforts on the virus should be undertaken by the global health community till the threat is completely wiped out.
- Published
- 2018
27. Fatal neuroinvasion and SARS-CoV-2 tropism in K18-hACE2 mice is partially independent on hACE2 expression
- Author
-
Hans Gertje, Alexander D. Klose, Mariano Carossino, Mohsan Saeed, Joel R. Walker, Maria Ericsson, Bertrand R. Huber, Saravanan Subramaniam, Paige Montanaro, Udeni B. R. Balasuriya, Susanna Kurnick, Neal Paragas, Nicholas A. Crossland, Aoife O'Connell, Florian Douam, Kyle Grosz, Markus Bosmann, Kevin P. Francis, Devin Kenney, and Thomas A. Kirkland
- Subjects
Genetically modified mouse ,viruses ,Mice, Transgenic ,Viremia ,Biology ,Article ,Virus ,Pathogenesis ,Mice ,Virology ,medicine ,Animals ,Humans ,Melphalan ,Tropism ,Keratin-18 ,SARS-CoV-2 ,COVID-19 ,medicine.disease ,Olfactory bulb ,Viral Tropism ,Infectious Diseases ,Viral replication ,translational animal model ,comparative pathology ,immunohistochemistry ,in situ hybridization ,viral pathogenesis ,transmission electron microscopy ,in vivo imaging ,Immunology ,Neuropathogenesis ,Angiotensin-Converting Enzyme 2 ,gamma-Globulins - Abstract
Animal models recapitulating distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. The precise mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate pneumonia, rapid clinical decline or death of mice was invariably associated with viral neuroinvasion and direct neuronal injury (including brain and spinal neurons). Neuroinvasion was observed as early as 4 dpi, with virus initially restricted to the olfactory bulb supporting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. No evidence of viremia was detected suggesting neuroinvasion occurs independently of entry across the blood brain barrier. SARS-CoV-2 tropism was not restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), and some ACE2-positive lineages were not associated with the presence of viral antigen (e.g., bronchiolar epithelium and brain capillaries). Detectable ACE2 expression was not observed in neurons, supporting overexpression of ACE2 in the nasal passages and neuroepithelium as more likely determinants of neuroinvasion in the K18-hACE2 model. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis that may have clinical relevance acknowledging the growing body of evidence that suggests COVID-19 may result in long-standing neurologic consequences.IMPORTANCECOVID-19 is predominantly a respiratory disease caused by SARS-CoV-2 that has infected more than 191 million people with over 4 million fatalities (2021-07-20). The development of animal models recapitulating distinctive features of severe COVID-19 is critical to enhancing our understanding of SARS-CoV-2 pathogenesis and in the evaluation of vaccine and therapeutic efficacy. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. Here, we show lethality of this model is invariably associated with viral neuroinvasion linked with viral replication and assembly. Importantly, pneumonia albeit invariably present was generally moderate with the absence of culturable infectious virus at peak neuroinvasion. The dynamics of viral neuroinvasion and pneumonia were only partially dependent on hACE2. Overall, this study provides an in-depth sequential characterization of the K18-hACE2 model following SARS-CoV-2 infection, highlighting its significance to further study the mechanisms of SARS-CoV-2 neuropathogenesis.
- Published
- 2021
28. Use of human induced pluripotent stem cells (hiPSC)-derived neuronal models to study the neuropathogenesis of the protozoan parasite, Toxoplasma gondii
- Author
-
Sandra K. Halonen
- Subjects
education.field_of_study ,biology ,Intracellular parasite ,Population ,Toxoplasma gondii ,Disease ,biology.organism_classification ,medicine.disease ,Toxoplasmosis ,Chronic infection ,medicine ,Neuropathogenesis ,Cognitive decline ,education ,Neuroscience - Abstract
The use of in vitro generated neurons derived from human induced pluripotent stem cells (hiPSCs) is an important tool for neurological disease modeling. Two-dimensional (2D) monolayer cultures and three-dimensional (3D) brain organoids, which can more precisely mimic in vivo complexities and cytoarchitecture of the brain, have been used to study neurological disorders such as Parkinson’s disease, schizophrenia, autism spectrum disorder, among others. While significant progress has been made using 2D and 3D hiPSC-derived neuronal models to study neurological disorders, the use of hiPSCs in the study of neuropathogenesis of parasitic diseases has been limited. Toxoplasma gondii is an obligate intracellular parasite that infects neurons in the central nervous system causing a chronic lifelong infection in the brain with approximately one-third of the worlds’ population chronically infected. While chronic Toxoplasmosis has been thought to be asymptomatic, recent evidence indicates that the chronic infection is associated with development of neuropsychiatric disorders such as schizophrenia, neurological disorders such as cryptogenic epilepsy, and cognitive decline in the elderly. Cysts in neurons, containing the bradyzoite form of the parasite, are the dominant forms present in chronic infections and likely the cause of some neurological effects during the chronic infection, yet remain poorly understood aspects of the parasites’ life cycle. The use of 2D and 3D human neuronal models provides opportunities to address questions of host/parasite interactions of the bradyzoites and cysts in neurons and investigate mechanisms of neuropathogenesis of T. gondii. In this review, an overview of the methods of hiPSC-derived 2D and 3D neuronal models is given, followed by a discussion of potentials of these neuronal models to study T. gondii. The use of hiPSC-derived 3D organoids to study pathogenesis of other parasitic infections is also briefly addressed.
- Published
- 2021
29. Return of the Neurotropic Enteroviruses: Co-Opting Cellular Pathways for Infection
- Author
-
Jan E. Carette and Christine E. Peters
- Subjects
0301 basic medicine ,Central Nervous System ,Neurotropism ,viruses ,030106 microbiology ,lcsh:QR1-502 ,virus–host interactions ,Host factors ,Computational biology ,Genome, Viral ,Review ,Biology ,Internal Ribosome Entry Sites ,Virus Replication ,enteroviruses ,lcsh:Microbiology ,03 medical and health sciences ,Broad spectrum ,antivirals ,Viral entry ,neuropathogenesis ,EV-D68 ,Virology ,Autophagy ,Enterovirus Infections ,Animals ,Humans ,Host protein ,Phospholipids ,Enterovirus ,host-directed therapeutics ,viral tissue tropism ,Cellular pathways ,Virus Internalization ,EV-A71 ,Viral Tropism ,030104 developmental biology ,Infectious Diseases ,Protein Biosynthesis ,Host-Pathogen Interactions ,Central Nervous System Viral Diseases ,RNA, Viral ,Receptors, Virus ,picornaviruses ,Neuropathogenesis ,Organelle biogenesis ,Viral Replication Compartments ,CRISPR and haploid screens - Abstract
Enteroviruses are among the most common human infectious agents. While infections are often mild, the severe neuropathogenesis associated with recent outbreaks of emerging non-polio enteroviruses, such as EV-A71 and EV-D68, highlights their continuing threat to public health. In recent years, our understanding of how non-polio enteroviruses co-opt cellular pathways has greatly increased, revealing intricate host–virus relationships. In this review, we focus on newly identified mechanisms by which enteroviruses hijack the cellular machinery to promote their replication and spread, and address their potential for the development of host-directed therapeutics. Specifically, we discuss newly identified cellular receptors and their contribution to neurotropism and spread, host factors required for viral entry and replication, and recent insights into lipid acquisition and replication organelle biogenesis. The comprehensive knowledge of common cellular pathways required by enteroviruses could expose vulnerabilities amenable for host-directed therapeutics against a broad spectrum of enteroviruses. Since this will likely include newly arising strains, it will better prepare us for future epidemics. Moreover, identifying host proteins specific to neurovirulent strains may allow us to better understand factors contributing to the neurotropism of these viruses.
- Published
- 2021
30. Neural Infection by Oropouche Virus in Adult Human Brain Slices Induces an Inflammatory and Toxic Response
- Author
-
Glaucia M. Almeida, Juliano P. Souza, Niele D. Mendes, Marjorie C. Pontelli, Nathalia R. Pinheiro, Giovanna O. Nogueira, Ricardo S. Cardoso, Isadora M. Paiva, Gustavo D. Ferrari, Flávio P. Veras, Fernando Q. Cunha, Jose A. C. Horta-Junior, Luciane C. Alberici, Thiago M. Cunha, Guilherme G. Podolsky-Gondim, Luciano Neder, Eurico Arruda, Adriano Sebollela, Universidade de São Paulo (USP), and Universidade Estadual Paulista (UNESP)
- Subjects
Central nervous system ,viral encephalitis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Context (language use) ,Biology ,medicine.disease_cause ,neuroinflammation ,histocultures ,medicine ,human brain ,Neuroinflammation ,Original Research ,Neurotropic virus ,neuroinfection ,Microglia ,Oropouche virus ,General Neuroscience ,Human brain ,neurotropic virus ,Virology ,medicine.anatomical_structure ,arboviruses ,RNA ,Neuropathogenesis ,RC321-571 ,Neuroscience - Abstract
Made available in DSpace on 2022-04-29T08:46:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-23 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Oropouche virus (OROV) is an emerging arbovirus in South and Central Americas with high spreading potential. OROV infection has been associated with neurological complications and OROV genomic RNA has been detected in cerebrospinal fluid from patients, suggesting its neuroinvasive potential. Motivated by these findings, neurotropism and neuropathogenesis of OROV have been investigated in vivo in murine models, which do not fully recapitulate the complexity of the human brain. Here we have used slice cultures from adult human brains to investigate whether OROV is capable of infecting mature human neural cells in a context of preserved neural connections and brain cytoarchitecture. Our results demonstrate that human neural cells can be infected ex vivo by OROV and support the production of infectious viral particles. Moreover, OROV infection led to the release of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and diminished cell viability 48 h post-infection, indicating that OROV triggers an inflammatory response and tissue damage. Although OROV-positive neurons were observed, microglia were the most abundant central nervous system (CNS) cell type infected by OROV, suggesting that they play an important role in the response to CNS infection by OROV in the adult human brain. Importantly, we found no OROV-infected astrocytes. To the best of our knowledge, this is the first direct demonstration of OROV infection in human brain cells. Combined with previous data from murine models and case reports of OROV genome detection in cerebrospinal fluid from patients, our data shed light on OROV neuropathogenesis and help raising awareness about acute and possibly chronic consequences of OROV infection in the human brain. Department of Biochemistry and Immunology Ribeirão Preto Medical School University of São Paulo Center for Virus Research Ribeirão Preto Medical School University of São Paulo Department of Cell and Molecular Biology Ribeirão Preto Medical School University of São Paulo Department of Pathology and Forensic Medicine Ribeirão Preto Medical School University of São Paulo Department of Pharmacology Ribeirão Preto Medical School University of São Paulo Center for Research in Inflammatory Diseases (CRID) Ribeirão Preto Medical School University of São Paulo Department of Physics and Chemistry School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Department of Structural and Functional Biology (Anatomy) Institute of Biosciences São Paulo State University Division of Neurosurgery Department of Surgery and Anatomy Ribeirão Preto Clinics Hospital Ribeirão Preto Medical School University of São Paulo Department of Structural and Functional Biology (Anatomy) Institute of Biosciences São Paulo State University FAPESP: #2014/02438-6 FAPESP: #2014/25681-3 FAPESP: #2018/06614-4
- Published
- 2021
31. Neuropathogenesis of Multiple Sclerosis and Huntington's Disease
- Author
-
Tiziano Balzano, Nadia Zouhairi, Ismail El Moudden, Halima Gamrani, Hicham Chatoui, Hind Benammi, Omar El Hiba, Faical Isbaine, Fatima Zahra Marhoume, Abdelali Bitar, and Hamid Rguibi Idrissi
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Huntington's disease ,Multiple sclerosis ,medicine ,Neuropathogenesis ,Biology ,medicine.disease ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Substantial epidemiological studies have established a link between environmental factors and prevalence of neurodegenerative diseases. Increasingly, some studies report a direct cause-and-effect relation between environmental agents such as heavy metals and pesticides, and some neurodegenerative disorders including multiple sclerosis (MS) and Huntington's disease (HD). Interestingly, high blood level of heavy metals and pesticides has been shown in patients with MS and HD. Those agents could be involved directly or indirectly in the pathogenesis of MS and HD. The underlying mechanisms may imply an immune breaking of self-tolerance or neurodegeneration onset of several neurotransmission systems. The chapter will discuss the role of different metals and pesticides in the onset and progress of MS and HD with an overview of the possible underlying pathomechanisms.
- Published
- 2021
32. Coronin 1A Expression in Human Astroglia, its Function in Physiology and Astrogliosis in HIV-1 Neuropathogenesis
- Author
-
Bindu, Pankaj Seth, Rishabh Kapoor, and Hriday Shanker Pandey
- Subjects
nervous system ,biology ,Expression (architecture) ,Human immunodeficiency virus (HIV) ,medicine ,Coronin ,biology.protein ,Neuropathogenesis ,medicine.disease_cause ,medicine.disease ,Neuroscience ,Function (biology) ,Astrogliosis - Abstract
BackgroundIn most neurodegenerative disorders, including neuroAIDS, reactive astroglia are detrimental to the neuronal population. Calcium and its downstream regulators play a central role in mediating glial activation. Coronin 1A, an acting binding protein, majorly reported in cells of hematopoietic origin, regulates cell activity in a calcium-dependent manner, but its role in astroglial physiology and astrogliosis is largely unknown. We explored the roles of Coronin 1A in astroglia physiology and the mechanisms by which it facilitates reactive astrogliosis. MethodsCoronin 1A expression was assessed in different cell types including astroglia using western blotting and immunocytochemistry. Loss of function assays were performed after siRNA-mediated knockdown of coronin 1A. Live-cell calcium imaging was performed on ATP-stimulated astroglia using confocal microscopy. To induce astrogliosis, HIV-1 Tat B expression vector was used after which gene and protein expressions were assessed using qPCR and western blotting, cytokine release was measured using flow cytometry, glutamate release was assessed using enzyme-kinetics based kit. TUNEL assay was performed to assess the glia-mediated neuronal death on neurons treated with the astrocyte-conditioned media. Small RNA-sequencing and qPCR assays were performed to get miRNAs differentially regulated a result of HIV-1 Tat transfection. Transfection with mimic and inhibitor against selected miRNA, and luciferase assay were performed to confirm the miRNA regulation.ResultsIn this study, we report for the first time, that human primary astroglia express Coronin 1A, and it plays activity-dependent roles in events such as PLCγ1 phosphorylation followed by Calcium mobilization from the intracellular stores. HIV-1 Tat, a potent neurotoxicant that induces astrogliosis, enhances the expression of Coronin 1A, apart from affecting GFAP and pro-inflammatory molecules. Downregulation of Coronin 1A ameliorated the HIV-1 Tat-induced deleterious effects of reactive astroglia, measured as enhanced GFAP expression and release of IL-6, and Glutamate and thus reduced glia-mediated neurodegeneration. Our findings also suggest that out of a pool of dysregulated miRNAs studied by us, hsa-miR-92b-5p regulates Coronin 1A expression which further facilitates reactive astrogliosis under the effect of HIV-1 Tat. ConclusionThese findings highlight the novel roles of Coronin 1A in regulating the astroglial physiology and astrogliosis observed in HIV-1 neuropathogenesis.
- Published
- 2020
33. Neuropathogenesis in COVID-19
- Author
-
Marcos Altable and Juan Moisés de la Serna
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,AcademicSubjects/MED00994 ,Clinical Neurology ,Pathology and Forensic Medicine ,Betacoronavirus ,Cellular and Molecular Neuroscience ,Central Nervous System Diseases ,Pandemic ,medicine ,Animals ,Humans ,Letters to the Editor ,Pandemics ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,General Medicine ,biology.organism_classification ,medicine.disease ,Virology ,Pneumonia ,Neurology ,Neuropathogenesis ,Neurology (clinical) ,Coronavirus Infections ,business - Published
- 2020
- Full Text
- View/download PDF
34. Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus
- Author
-
Heather A. Simmons, Jiancheng Hou, Saverio Capuano, Jennifer M. Hayes, Emma L. Mohr, Andrea M. Weiler, Laurel M. Stewart, Michael K. Fritsch, Ann Mitzey, David H. O’Connor, Andres Mejia, Mariel S. Mohns, Carol A. Rasmussen, Alex Katz, Mary L. Schneider, Sarah Kohn, Elaina Razo, Anna S. Jaeger, Kevin K. Noguchi, Matthew R Semler, Xiankun Zeng, Dawn M. Dudley, Leandro B. C. Teixeira, Thomas C. Friedrich, Michele L Schotzko, Kathryn M. Bach, Sierra Rybarczyk, Matthew T. Aliota, Michelle R Koenig, Vivek Prabhakaran, Thaddeus G. Golos, Veena A. Nair, T Michael Nork, Maria Dennis, Jens C. Eickhoff, Christina M. Newman, Meghan E. Breitbach, C. B. Y. Kim, James N. Ver Hoeve, Karla Ausderau, Kathleen M. Antony, Sallie R. Permar, Nancy Schultz-Darken, and Amy Hartman
- Subjects
Sensory Receptors ,Maternal Health ,Placenta ,Social Sciences ,Disease ,Monkeys ,Pathology and Laboratory Medicine ,Zika virus ,0302 clinical medicine ,Animal Cells ,Pregnancy ,Psychology ,Hearing Disorders ,Mammals ,Neurons ,Zika Virus Infection ,Delayed onset ,Pregnancy Outcome ,Eukaryota ,Bioassays and Physiological Analysis ,Medical Microbiology ,Viral Pathogens ,Prenatal Exposure Delayed Effects ,Medicine ,Cellular Types ,Macaque ,Primates ,medicine.medical_specialty ,Imaging Techniques ,Science ,Vision Disorders ,Neurophysiology ,Nervous System Malformations ,Microbiology ,03 medical and health sciences ,biology.animal ,Microbial Pathogens ,Flaviviruses ,Organisms ,Reproductive System ,medicine.disease ,030104 developmental biology ,Eyes ,Histopathology ,Clinical Medicine ,030217 neurology & neurosurgery ,Neuroscience ,Developmental Biology ,0301 basic medicine ,RNA viruses ,Photoreceptors ,Pediatrics ,Embryology ,Future studies ,Vision ,Physiology ,Medicine and Health Sciences ,Pregnancy Complications, Infectious ,Clinical Neurophysiology ,Brain Mapping ,Multidisciplinary ,biology ,Obstetrics and Gynecology ,Electroencephalography ,Electrophysiology ,Brain Electrophysiology ,Vertebrates ,Viruses ,Fetal Demise ,Neuropathogenesis ,Sensory Perception ,Female ,Pathogens ,Anatomy ,Research Article ,Signal Transduction ,Neuroimaging ,Research and Analysis Methods ,Ocular System ,Old World monkeys ,medicine ,Animals ,Biology and life sciences ,business.industry ,Electrophysiological Techniques ,Visual-Evoked Potentials ,Cognitive Psychology ,Afferent Neurons ,Zika Virus ,Cell Biology ,biology.organism_classification ,Macaca mulatta ,Retinal structure ,Animals, Newborn ,Cellular Neuroscience ,Amniotes ,Cognitive Science ,Women's Health ,Perception ,business ,Zoology ,Head - Abstract
Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.
- Published
- 2020
35. Effects of COVID-19 on the nervous system
- Author
-
Costantino Iadecola, Hooman Kamel, and Josef Anrather
- Subjects
Nervous system ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Neurotropism ,Pneumonia, Viral ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Olfaction Disorders ,03 medical and health sciences ,0302 clinical medicine ,Pandemic ,medicine ,Animals ,Humans ,Intensive care medicine ,Pandemics ,030304 developmental biology ,Brain Diseases ,0303 health sciences ,COVID-19 ,medicine.disease ,Cardiopulmonary Resuscitation ,Stroke ,Pneumonia ,Critical appraisal ,medicine.anatomical_structure ,Neuropathogenesis ,Coronavirus Infections ,030217 neurology & neurosurgery - Abstract
Summary Neurological complications have emerged as a significant cause of morbidity and mortality in the ongoing COVID-19 pandemic. Beside respiratory insufficiency, many hospitalized patients exhibit neurological manifestations, ranging from headache and loss of smell, to confusion and disabling strokes. COVID-19 is also anticipated to take a toll on the nervous system in the long term. Here we will provide a critical appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2, as they relate to the acute and chronic neurological consequences of the infection. Finally, we will examine potential avenues for future research and therapeutic development., Iadecola et al., review and discuss the acute and chronic neurological consequences of COVID-19, potential mechanisms for neuropathogenesis and the outstanding questions to minimize its harmful nervous system involvement.
- Published
- 2020
36. Cathelicidin bovine myeloid antimicrobial peptide (BMAP) 28 is involved in the inflammatory response against alpha-herpesviruses in the bovine nervous system
- Author
-
Maia Solange Marin, Sandra Perez, Anselmo Carlos Odeón, Mercedes María Burucúa, Eduardo R. Cobo, and Silvina Quintana
- Subjects
0301 basic medicine ,Nervous system ,medicine.medical_treatment ,Immunology ,Central nervous system ,Biology ,Cathelicidin ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,NEUROPATHOGENESIS ,Gene expression ,medicine ,Molecular Biology ,Innate immune system ,ALPHAHERPESVIRUS ,Ciencias Veterinarias ,Cathelicidins ,030104 developmental biology ,medicine.anatomical_structure ,CIENCIAS AGRÍCOLAS ,CATHELICIDINS ,INNATE IMMUNITY ,Tumor necrosis factor alpha ,030215 immunology - Abstract
The role of the local innate immune response in the neuropathogenesis of bovine herpesvirus (BoHV) type 1 and 5 remains largely unknown. This study determined the gene transcriptional expression of relevant bovine cathelicidins, TNFα and IFNβ in the nervous system of experimentally-infected cattle during the different stages of BoHV-1 and BoHV-5 infectious cycle. We studied the modulation of bovine myeloid antimicrobial peptide (BMAP) 27 and 28 by alpha-herpesviruses during acute infection of the central nervous system (CNS). However, BMAP 28 was the main cathelicidin modulated.. BoHV-5 supressed BMAP28 expression mainly in frontal cortex and cervical medulla whereas BoHV-1 slightly induced the expression of cathelicidins in the olfactory and posterior cortex. The differences in the regulation of the innate response are likely related to distinct replication rates of both alpha-herpesviruses in the CNS. During latency and reactivation, BoHV-1 and -5 decreased BMAP28 and BMAP27 expression, accompanied by high levels of TNFα and IFNβ transcripts in the posterior brain region and medulla during BoHV reactivation. In terms of cytokines, a remarkably overexpression of IFNβ was induced by BoHV-5 (133.8-fold). In trigeminal ganglion (TG) both alpha-herpesviruses induced cathelidicins gene expression at all stages of the infection cycle, while only acute BoHV-5 infection increased TNFα (129-fold) mRNA levels. This study suggests that the pronounced downregulation of BMAP28 in BoHV-5-acutely-infected CNS is due to a decreased immune stimulation during viral infection, favouring its establishment in the CNS with a low replication rate until latency. Thus, cathelicidins, together with IFNβ and TNFα, are differentially regulated by BoHV-5 and BoHV-1 infections and this regulation is dependent on the stage of virus infection in the bovine nervous system. Fil: Burucúa, Mercedes María. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; Argentina Fil: Perez, Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Odeón, Anselmo Carlos. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; Argentina Fil: Cobo, Eduardo Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Calgary; Canadá Fil: Quintana, Silvina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Marin, Maia Solange. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; Argentina
- Published
- 2020
37. Brain tissue transcriptomic analysis of SIV-infected macaques identifies Poly (ADP-ribose) polymerases (PARPs) as potential biomarkers for neuropathogenesis
- Author
-
Andrea S Ramirez-Mata, Kenneth C. Williams, Alberto Riva, Brittany Rife Magalis, David J. Nolan, James Jarad Dollar, Mattia Prosperi, Shannan N Rich, Melanie N. Cash, Carla Mavian, Simone Marini, Kevin White, Marco Salemi, and David Moraga Amador
- Subjects
Transcriptome ,Poly ADP ribose polymerase ,Gene expression ,Immunology ,medicine ,Neuropathogenesis ,Neuropathology ,Simian immunodeficiency virus ,Biology ,medicine.disease_cause ,Virus ,CD8 - Abstract
Background. Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified.Results. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n=11), with or without CD8+ lymphocyte depletion, based on detectable (n=6) or non-detectable (n=5) presence of the virus in frontal cortex tissues. S ignificant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion . In addition, transcripts of four poly (ADP-ribose) polymerases ( PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction.Conclusions. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology .
- Published
- 2020
38. Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis, and Poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets
- Author
-
Alberto Riva, David J. Nolan, Melanie N. Cash, Marco Salemi, David Moraga Amador, Simone Marini, Carla Mavian, Shannan N Rich, Brittany Rife Magalis, James Jarad Dollar, Andrea S Ramirez-Mata, Kenneth C. Williams, Mattia Prosperi, and Kevin P. White
- Subjects
Transcriptome ,Poly ADP ribose polymerase ,Immunology ,Gene expression ,medicine ,Neuropathogenesis ,Neuropathology ,Biology ,Simian immunodeficiency virus ,medicine.disease_cause ,Virus ,CD8 - Abstract
BackgroundDespite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified.ResultsWe investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n=11), with or without CD8+ lymphocyte depletion, based on detectable (n=6) or non-detectable (n=5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction.ConclusionsOur results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.
- Published
- 2020
39. Neuropathogenesis of viral infections
- Author
-
Avindra Nath and Joseph R. Berger
- Subjects
Neuropathogenesis ,Biology ,Virology - Published
- 2020
40. The neuropathic itch caused by pseudorabies virus
- Author
-
Kathlyn Laval and Lynn W. Enquist
- Subjects
Microbiology (medical) ,Nervous system ,animal diseases ,viruses ,VARICELLA-ZOSTER-VIRUS ,lcsh:Medicine ,Pseudorabies ,Disease ,Review ,medicine.disease_cause ,Virus ,Pseudorabies virus ,neuroinflammation ,Pathogenesis ,neuropathogenesis ,medicine ,Immunology and Allergy ,non-natural hosts ,PIG-OFFAL ,AUJESZKYS-DISEASE VIRUS ,Veterinary Sciences ,MOLECULAR CHARACTERIZATION ,WILD BOAR ,Molecular Biology ,neuropathic itch ,Neuroinflammation ,IN-VIVO ,General Immunology and Microbiology ,biology ,lcsh:R ,Varicella zoster virus ,immunopathogenesis ,virus diseases ,Biology and Life Sciences ,swine ,POSTHERPETIC NEURALGIA ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Virology ,NERVOUS-SYSTEM ,SUID HERPESVIRUS TYPE-1 ,Infectious Diseases ,medicine.anatomical_structure ,Herpes simplex virus ,SHANDONG PROVINCE - Abstract
Pseudorabies virus (PRV) is an alphaherpesvirus related to varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1). PRV is the causative agent of Aujeskzy’s disease in swine. PRV infects mucosal epithelium and the peripheral nervous system (PNS) of its host where it can establish a quiescent, latent infection. While the natural host of PRV is the swine, a broad spectrum of mammals, including rodents, cats, dogs, and cattle can be infected. Since the nineteenth century, PRV infection is known to cause a severe acute neuropathy, the so called “mad itch” in non-natural hosts, but surprisingly not in swine. In the past, most scientific efforts have been directed to eradicating PRV from pig farms by the use of effective marker vaccines, but little attention has been given to the processes leading to the mad itch. The main objective of this review is to provide state-of-the-art information on the mechanisms governing PRV-induced neuropathic itch in non-natural hosts. We highlight similarities and key differences in the pathogenesis of PRV infections between non-natural hosts and pigs that might explain their distinctive clinical outcomes. Current knowledge on the neurobiology and possible explanations for the unstoppable itch experienced by PRV-infected animals is also reviewed. We summarize recent findings concerning PRV-induced neuroinflammatory responses in mice and address the relevance of this animal model to study other alphaherpesvirus-induced neuropathies, such as those observed for VZV infection.
- Published
- 2020
41. Two neurotropic pathogens of concern for striped dolphins
- Author
-
Manuela Tittarelli, Giuliano Garofolo, Gabriella Di Francesco, Giovanni Di Guardo, and Ludovica Di Renzo
- Subjects
040301 veterinary sciences ,Zoology ,Brucella ,Stenella coeruleoalba ,Brucellosis ,0403 veterinary science ,Comparative neuropathology ,Brucella ceti ,Central Nervous System Infections ,Stenella ,biology.animal ,Animals ,Epidemics ,General Veterinary ,biology ,Coinfection ,0402 animal and dairy science ,Cetacean Morbillivirus ,04 agricultural and veterinary sciences ,General Medicine ,biology.organism_classification ,Bottlenose dolphin ,040201 dairy & animal science ,Italy ,Morbillivirus ,Cetacean Morbillivirus, Brucella ceti, Neurobrucellosis, Encephalitis, Infection, Coinfection, Comparative neuropathology, Neuropathogenesis ,Neuropathogenesis ,Encephalitis ,Neurobrucellosis ,Infection ,Morbillivirus Infections - Abstract
Following the first isolation of Brucella ceti from a bottlenose dolphin ( Tursiops truncatus ) fetus,1 several cases of B ceti infection were reported among free-ranging cetaceans worldwide.2 These included cases in the Mediterranean sea, where B ceti infection was first described in 2009.3 As with other Brucella genus members, B ceti displays a zoonotic capability4– prominent central nervous system (CNS) involvement in B ceti infection is commonly seen in striped dolphins ( Stenella coeruleoalba ) and in people,2, 5 but …
- Published
- 2020
42. MAGIC: Multi-scale Heterogeneity Analysis and Clustering for Brain Diseases
- Author
-
Aristeidis Sotiras, Erdem Varol, Christos Davatzikos, Ganesh B. Chand, and Junhao Wen
- Subjects
0303 health sciences ,Hippocampus ,Cognition ,Disease ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Schizophrenia ,medicine ,Neuropathogenesis ,Effects of sleep deprivation on cognitive performance ,Cluster analysis ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
There is a growing amount of clinical, anatomical and functional evidence for the heterogeneous presentation of neuropsychiatric and neurodegenerative diseases such as schizophrenia and Alzheimer’s Disease (AD). Elucidating distinct subtypes of diseases allows a better understanding of neuropathogenesis and enables the possibility of developing targeted treatment programs. Recent semi-supervised clustering techniques have provided a data-driven way to understand disease heterogeneity. However, existing methods do not take into account that subtypes of the disease might present themselves at different spatial scales across the brain. Here, we introduce a novel method, MAGIC, to uncover disease heterogeneity by leveraging multi-scale clustering. We first extract multi-scale patterns of structural covariance (PSCs) followed by a semi-supervised clustering with double cyclic block-wise optimization across different scales of PSCs. We validate MAGIC using simulated heterogeneous neuroanatomical data and demonstrate its clinical potential by exploring the heterogeneity of AD using T1 MRI scans of 228 cognitively normal (CN) and 191 patients. Our results indicate two main subtypes of AD with distinct atrophy patterns that consist of both fine-scale atrophy in the hippocampus as well as large-scale atrophy in cortical regions. The evidence for the heterogeneity is further corroborated by the clinical evaluation of two subtypes, which indicates that there is a subpopulation of AD patients that tend to be younger and decline faster in cognitive performance relative to the other subpopulation, which tends to be older and maintains a relatively steady decline in cognitive abilities.
- Published
- 2020
43. Use of Primary Human Fetal Astrocytes and Tissue Explants as Ex Vivo Models to Study Zika Virus Infection of the Developing Brain
- Author
-
William G. Branton, Cheung Pang Wong, Christopher Power, Tom C. Hobman, Daniel Limonta, and Leina Saito
- Subjects
0301 basic medicine ,Microcephaly ,030231 tropical medicine ,Tissue explants ,Human brain ,Biology ,biology.organism_classification ,medicine.disease ,Virology ,Zika virus ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Human fetal ,medicine ,ZikV Infection ,Neuropathogenesis ,Ex vivo - Abstract
Zika virus (ZIKV) infection during pregnancy can result in congenital Zika syndrome which is characterized by microcephaly and other neurodevelopmental disorders. In this chapter, we describe methods to model ex vivo ZIKV infection in astrocytes and tissue explants from human fetal brain. These cell- and tissue-based platforms have been useful to elucidate mechanisms of ZIKV persistence and might lead to important clues about virus-induced neuropathogenesis. In addition, these ex vivo model systems allow researchers to conduct drug discovery and development experiments in more representative settings of the developing human brain.
- Published
- 2020
44. Flaviviruses and the Central Nervous System: Revisiting Neuropathological Concepts
- Author
-
Alexander G. Pletnev and Olga A. Maximova
- Subjects
0301 basic medicine ,viruses ,Neurotropism ,Central nervous system ,Biology ,Encephalitis Viruses, Tick-Borne ,Disease course ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Encephalitis Viruses ,medicine ,Animals ,Humans ,Encephalitis, Viral ,Encephalitis Virus, Japanese ,virus diseases ,Pathogenicity ,Viral Tropism ,030104 developmental biology ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Tissue tropism ,Neuropathogenesis ,Tickborne encephalitis ,West Nile virus ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Flaviviruses are major emerging human pathogens on a global scale. Some flaviviruses can infect the central nervous system of the host and therefore are regarded as neurotropic. The most clinically relevant classical neurotropic flaviviruses include Japanese encephalitis virus, West Nile virus, and tick-borne encephalitis virus. In this review, we focus on these flaviviruses and revisit the concepts of flaviviral neurotropism, neuropathogenicity, neuroinvasion, and resultant neuropathogenesis. We attempt to synthesize the current knowledge about interactions between the central nervous system and flaviviruses from the neuroanatomical and neuropathological perspectives and address some misconceptions and controversies. We hope that revisiting these neuropathological concepts will improve the understanding of flaviviral neuroinfections. This, in turn, may provide further guiding foundations for relevant studies of other emerging or geographically expanding flaviviruses with neuropathogenic potential, such as Zika virus and dengue virus, and pave the way for intelligent therapeutic strategies harnessing potentially beneficial, protective host responses to interfere with disease progression and outcome.
- Published
- 2018
45. A Zika virus primary isolate induces neuroinflammation, compromises the blood-brain barrier and upregulates CXCL12 in adult macaques
- Author
-
Antonito T. Panganiban, Diana G. Bohannon, Myrna C. Bonaldo, Nicholas J. Maness, Blake Schouest, Robert V Blair, Julian B. Hattler, and Woong-Ki Kim
- Subjects
0301 basic medicine ,Male ,Central nervous system ,Neuropathology ,Blood–brain barrier ,Virus ,Pathology and Forensic Medicine ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Medicine ,Animals ,Remyelination ,Neuroinflammation ,Research Articles ,Neurotropic virus ,biology ,business.industry ,Zika Virus Infection ,General Neuroscience ,Brain ,Zika Virus ,biology.organism_classification ,Macaca mulatta ,Chemokine CXCL12 ,Up-Regulation ,Flavivirus ,Rhesus macaque ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Blood-Brain Barrier ,Immunology ,Encephalitis ,Neuropathogenesis ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Zika virus (ZIKV) is a neurotropic virus that can cause neuropathy in adults and fetal neurologic malformation following infection of pregnant women. We used a nonhuman primate model, the Indian-origin Rhesus macaque (IRM), to gain insight into virus-associated hallmarks of ZIKV-induced adult neuropathy. We find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood-brain barrier (BBB) in adult animals. Infection results in significant, targeted, and sustained upregulation of the chemokine, CXCL12, in the central nervous system (CNS). CXCL12 plays a key role both in regulating lymphocyte trafficking through the BBB to the CNS, and in mediating repair of damaged neural tissue including remyelination. Understanding how CXCL12 expression is controlled will likely be of central importance in the definition of ZIKV-associated neuropathy in adults.Author summaryZika virus (ZIKV) is a virus that can cause neurological problems in adults and damage to the fetal brain. Nonhuman primates (NHPs) are usually superior animal models for recapitulating human neurological disease because their brain, nervous system structure and immune response to virus infection are very similar to that of humans. We have studied the effect of ZIKV infection on the adult NHP brain and made several significant observations. Infection resulted in a high incidence of mild to moderate brain inflammation that persisted for a surprisingly long period of time. We also found that the virus disrupted the blood brain barrier, which is important for controlling transport of material from blood to the brain. It appears that the central nervous system expresses a specific substance in response to virus infection called a chemokine. This specific chemokine may be involved in virus-induced inflammation and/or in repair of virus-induced brain damage. Our data are significant since they help in understanding the mechanism of brain damage caused by ZIKV in adults.
- Published
- 2019
46. Global Gene Expression Analysis of the Brainstem in EV71- and CVA16-Infected Gerbils
- Author
-
Pingping Yao, Yanjun Zhang, Jianmin Jiang, Yisheng Sun, Chen Chen, Zhang-Nv Yang, Hanping Zhu, Fang Xu, and Hang-Jing Lu
- Subjects
0301 basic medicine ,030106 microbiology ,lcsh:QR1-502 ,Coxsackievirus Infections ,Down-Regulation ,Gene Expression ,Biology ,Coxsackievirus a16 ,coxsackievirus 16 ,lcsh:Microbiology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,neuropathogenesis ,Virology ,Gene expression ,parasitic diseases ,Enterovirus 71 ,Enterovirus Infections ,Animals ,RNA-Seq ,Gene ,enterovirus 71 ,Enterovirus ,biology.organism_classification ,Molecular biology ,Enterovirus A, Human ,Up-Regulation ,030104 developmental biology ,Infectious Diseases ,Gene Expression Regulation ,CXCL9 ,Cytokines ,Neuropathogenesis ,Brainstem ,sense organs ,gerbils ,cytokine dysregulation ,Gerbillinae ,Brain Stem - Abstract
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the two most important pathogens of hand, foot, and mouth disease (HFMD). However, the neuropathogenesis of EV71 and CVA16 has not been elucidated. In our previous study, we established gerbils as a useful model for both EV71 and CVA16 infection. In this work, we used RNA-seq technology to analyze the global gene expression of the brainstem of EV71- and CVA16-infected gerbils. We found that 3434 genes were upregulated while 916 genes were downregulated in EV71-infected gerbils. In CVA16-infected gerbils, 1039 genes were upregulated, and 299 genes were downregulated. We also found significant dysregulation of cytokines, such as IP-10 and CXCL9, in the brainstem of gerbils. The expression levels of 10 of the most upregulated genes were confirmed by real-time RT-PCR, and the upregulated tendency of most genes was in accordance with the differential gene expression (DGE) results. Our work provided global gene expression analysis of virus-infected gerbils and laid a solid foundation for elucidating the neuropathogenesis mechanisms of EV71 and CVA16.
- Published
- 2019
47. Pyroptosis induced by enterovirus A71 infection in cultured human neuroblastoma cells
- Author
-
Lunbiao Cui, Ying Chi, Minjun Ji, Yiyue Ge, Fengcai Zhu, Bin Wu, Minghao Zhou, Tao Wu, and Xiaojuan Zhu
- Subjects
0301 basic medicine ,Programmed cell death ,Lysis ,Interleukin-1beta ,Caspase 1 ,DNA Fragmentation ,Biology ,Virus Replication ,Microbiology ,Neuroblastoma ,03 medical and health sciences ,Virology ,Gene expression ,Pyroptosis ,medicine ,Humans ,Secretion ,Cells, Cultured ,Inflammation ,Interleukin-18 ,Meningoencephalitis ,medicine.disease ,Enterovirus A, Human ,030104 developmental biology ,Neuropathogenesis ,Hand, Foot and Mouth Disease - Abstract
Enterovirus A71 (EV-A71) infection can cause hand, foot and mouth disease (HFMD), and even fatal meningoencephalitis. Unfortunately, there is currently no effective treatment for EV-A71 infection due to the lack of understanding of the mechanism of neurological diseases. In this study, we employed SH-SY5Y human neuroblastoma cells to explore the roles of caspase-1 in neuropathogenesis. The expression and activity of caspase-1 were analyzed. The potential immuneconsequences mediated by caspase-1 including cell death, lysis, DNA degradation, and secretion of pro-inflammatory were also examined. We found the gene expression levels of caspase-1, IL-1β, IL-18 and active caspase-1 were markedly increased in the SH-SY5Y cells at 48 h post EV-A71 infection. The cell death, lysis, and DNA degradation were also increased during infection, which could be significantly alleviated by caspase-1 inhibition. These observations provided additional experimental evidence supporting caspase-1-mediated pyroptosis as a novel pathway of inflammatory programmed cell death.
- Published
- 2018
48. West Nile Virus Induced Cell Death in the Central Nervous System
- Author
-
Bi-Hung Peng and Tian Wang
- Subjects
Microbiology (medical) ,animal diseases ,viruses ,Central nervous system ,lcsh:Medicine ,Review ,Virus ,03 medical and health sciences ,medicine ,Immunology and Allergy ,west nile virus ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,General Immunology and Microbiology ,biology ,030306 microbiology ,business.industry ,Viral encephalitis ,lcsh:R ,apoptosis ,Outbreak ,virus diseases ,medicine.disease ,biology.organism_classification ,central nervous system ,Virology ,neuronal death ,3. Good health ,nervous system diseases ,Flavivirus ,Infectious Diseases ,medicine.anatomical_structure ,Neuropathogenesis ,business ,Meningitis ,Encephalitis - Abstract
West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis.
- Published
- 2019
49. Insights from the sequence similarity of Zika virus proteins with the Human nerve proteins
- Author
-
Prasanna Marsakatla, Logeshwaran Vasudevan, Sujai Suneetha, Paari Dominic Swaminathan, Rachael Supriya, Lavanya M. Suneetha, and Joshua Lee
- Subjects
Zika V ,Bioinformatics ,Virulence ,Peptide ,Galanin ,Zika virus ,Nestin ,Nerve tissue proteins ,Calcium-binding protein ,Gap-43 protein ,BLAST ,Sequence (medicine) ,chemistry.chemical_classification ,biology ,General Medicine ,Hypothesis ,biology.organism_classification ,Virology ,Neuromodulin ,chemistry ,biology.protein ,Neuropathogenesis ,Bombesin - Abstract
Massive peptide sharing between the Zika virus polyprotein and host tissue proteins could elicit significant host-pathogen interactions and cross-reactions leading to autoimmune diseases. This study found similarities in the Zika V proteins and human nerve tissue proteins. 63 human nerve proteins were screened for similarities with the Zika V of which Neuromodulin, Nestin, Galanin, Bombesin, Calcium-binding protein were found to have similarities to the Zika V poly protein C at different sequence regions. These sequence similarities could be significant in regulating pathogenic interactions/autoimmunity, as Polyprotein C is known to be a virulent factor.
- Published
- 2018
50. Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis
- Author
-
Tracy Fischer, Stephen D. Ginsberg, Sang Han Lee, Susan Morgello, Melissa J. Alldred, Satya M. Gunnam, and Consuelo Schiroli
- Subjects
0301 basic medicine ,Microglia ,virus diseases ,Inflammation ,Biology ,medicine.disease ,Virus ,Gene expression profiling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Neurology ,Neurotrophic factors ,Immunology ,medicine ,Neuropathogenesis ,Neurology (clinical) ,medicine.symptom ,CD163 ,030217 neurology & neurosurgery ,Encephalitis - Abstract
Objective CD16+ /CD163+ macrophages (MΦs) and microglia accumulate in the brains of patients with human immunodeficiency virus (HIV) encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia. Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE and HIV/noE, and HIV- controls. Methods Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+ , CD16+ , or CD68+ MΦs/microglia per case, using terminal continuation RNA amplification and a custom-designed array platform. Results Several classes of microglial transcripts in HIVE and HIV/noE were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors were reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE. Interpretation Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as to ascertain alterations in specific pathways, genes, and potentially, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. Ann Neurol 2018;83:406-417.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.