10 results on '"Anita K. McElroy"'
Search Results
2. Rift Valley Fever Virus Infection Causes Acute Encephalitis in the Ferret
- Author
-
Dominique J. Barbeau, Joseph R. Albe, Sham Nambulli, Natasha L. Tilston-Lunel, Amy L. Hartman, Seema S. Lakdawala, Ed Klein, W. Paul Duprex, and Anita K. McElroy
- Subjects
Rift Valley fever virus ,encephalitis ,ferret ,animal model ,pathogenesis ,Microbiology ,QR1-502 - Abstract
ABSTRACT Rift Valley fever virus (RVFV) is a pathogen of both humans and livestock in Africa and the Middle East. Severe human disease is associated with hepatitis and/or encephalitis. Current pathogenesis studies rely on rodents and nonhuman primates, which have advantages and disadvantages. We evaluated disease progression in Mustela putorius furo (the ferret) following intradermal (i.d.) or intranasal (i.n.) infection. Infected ferrets developed hyperpyrexia, weight loss, lymphopenia, and hypoalbuminemia. Three of four ferrets inoculated intranasally with RVFV developed central nervous system (CNS) disease that manifested as seizure, ataxia, and/or hind limb weakness at 8 to 11 days postinfection (dpi). Animals with clinical CNS disease had transient viral RNAemia, high viral RNA loads in the brain, and histopathological evidence of encephalitis. The ferret model will facilitate our understanding of how RVFV accesses the CNS and has utility for the evaluation of vaccines and/or therapeutics in preventing RVFV CNS disease. IMPORTANCE Animal models of viral disease are very important for understanding how viruses make people sick and for testing out drugs and vaccines to see if they can prevent disease. In this study, we identify the ferret as a model of encephalitis caused by Rift Valley fever virus (RVFV). This novel model will allow researchers to evaluate ways to prevent RVFV encephalitis.
- Published
- 2020
- Full Text
- View/download PDF
3. Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
- Author
-
Punya Shrivastava-Ranjan, Mike Flint, Éric Bergeron, Anita K. McElroy, Payel Chatterjee, César G. Albariño, Stuart T. Nichol, and Christina F. Spiropoulou
- Subjects
Ebola virus ,Filoviridae ,antiviral ,hemorrhagic fever ,Microbiology ,QR1-502 - Abstract
ABSTRACT Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD. IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.
- Published
- 2018
- Full Text
- View/download PDF
4. Identification and Characterization of Rift Valley Fever Virus-Specific T Cells Reveals a Dependence on CD40/CD40L Interactions for Prevention of Encephalitis
- Author
-
John Sidney, Haley N. Cartwright, Jessica R. Harmon, Christina F. Spiropoulou, Dominique J. Barbeau, Anita K. McElroy, Alessandro Sette, and Jessica R. Spengler
- Subjects
Rift Valley Fever ,T-Lymphocytes ,CD40 Ligand ,Immunology ,Spleen ,CD8-Positive T-Lymphocytes ,Microbiology ,Arbovirus ,Epitope ,Epitopes ,Mice ,Virology ,medicine ,Animals ,Cytotoxic T cell ,Encephalitis, Viral ,CD40 Antigens ,B cell ,Mice, Knockout ,B-Lymphocytes ,CD40 ,biology ,Brain ,Rift Valley fever virus ,medicine.disease ,Acquired immune system ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Liver ,Insect Science ,Africa ,Antibody Formation ,biology.protein ,Pathogenesis and Immunity ,Female ,Encephalitis - Abstract
Rift Valley fever virus (RVFV) is an arbovirus found throughout Africa. It causes disease that is typically mild and self-limiting; however, some infected individuals experience severe manifestations, including hepatitis, encephalitis, or even death. Reports of RVFV encephalitis are notable among immunosuppressed individuals, suggesting a role for adaptive immunity in preventing this severe complication. This phenomenon has been modeled in C57BL/6 mice depleted of CD4 T cells prior to infection with DelNSs RVFV (RVFV containing a deletion of nonstructural protein NSs), resulting in late-onset encephalitis accompanied by high levels of viral RNA in the brain in 30% of animals. In this study, we sought to define the specific type(s) of CD4 T cells that mediate protection from RVFV encephalitis. The viral epitopes targeted by CD4 and CD8 T cells were defined in C57BL/6 mice, and tetramers for both CD4 and CD8 T cells were generated. RVFV-specific CD8 T cells were expanded and of a cytotoxic and proliferating phenotype in the liver following infection. RVFV-specific CD4 T cells were identified in the liver and spleen following infection and phenotyped as largely Th1 or Tfh subtypes. Knockout mice lacking various aspects of pathways important in Th1 and Tfh development and function were used to demonstrate that T-bet, CD40, CD40L, and major histocompatibility complex class II (MHC-II) mediated protection from RVFV encephalitis, while gamma interferon (IFN-γ) and interleukin-12 (IL-12) were dispensable. Virus-specific antibody responses correlated with protection from encephalitis in all mouse strains, suggesting that Tfh/B cell interactions modulate clinical outcome in this model. IMPORTANCE The prevention of RVFV encephalitis requires intact adaptive immunity. In this study, we developed reagents to detect RVFV-specific T cells and provide evidence for Tfh cells and CD40/CD40L interactions as critical mediators of this protection.
- Published
- 2021
5. Rift Valley Fever Virus Infection Causes Acute Encephalitis in the Ferret
- Author
-
Seema S. Lakdawala, Joseph R. Albe, Sham Nambulli, W. Paul Duprex, Anita K. McElroy, Dominique J. Barbeau, Amy L. Hartman, Ed Klein, and Natasha L. Tilston-Lunel
- Subjects
Male ,0301 basic medicine ,Ataxia ,Rift Valley Fever ,viruses ,encephalitis ,030106 microbiology ,Central nervous system ,Disease ,Microbiology ,Host-Microbe Biology ,Pathogenesis ,03 medical and health sciences ,medicine ,Animals ,Encephalitis, Viral ,ferret ,Molecular Biology ,Pathogen ,Hepatitis ,business.industry ,animal model ,pathogenesis ,Ferrets ,Brain ,Rift Valley fever virus ,medicine.disease ,Virology ,QR1-502 ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Acute Disease ,Viral disease ,medicine.symptom ,business ,Encephalitis ,Research Article - Abstract
Animal models of viral disease are very important for understanding how viruses make people sick and for testing out drugs and vaccines to see if they can prevent disease. In this study, we identify the ferret as a model of encephalitis caused by Rift Valley fever virus (RVFV). This novel model will allow researchers to evaluate ways to prevent RVFV encephalitis., Rift Valley fever virus (RVFV) is a pathogen of both humans and livestock in Africa and the Middle East. Severe human disease is associated with hepatitis and/or encephalitis. Current pathogenesis studies rely on rodents and nonhuman primates, which have advantages and disadvantages. We evaluated disease progression in Mustela putorius furo (the ferret) following intradermal (i.d.) or intranasal (i.n.) infection. Infected ferrets developed hyperpyrexia, weight loss, lymphopenia, and hypoalbuminemia. Three of four ferrets inoculated intranasally with RVFV developed central nervous system (CNS) disease that manifested as seizure, ataxia, and/or hind limb weakness at 8 to 11 days postinfection (dpi). Animals with clinical CNS disease had transient viral RNAemia, high viral RNA loads in the brain, and histopathological evidence of encephalitis. The ferret model will facilitate our understanding of how RVFV accesses the CNS and has utility for the evaluation of vaccines and/or therapeutics in preventing RVFV CNS disease. IMPORTANCE Animal models of viral disease are very important for understanding how viruses make people sick and for testing out drugs and vaccines to see if they can prevent disease. In this study, we identify the ferret as a model of encephalitis caused by Rift Valley fever virus (RVFV). This novel model will allow researchers to evaluate ways to prevent RVFV encephalitis.
- Published
- 2020
6. CD4 T Cells, CD8 T Cells, and Monocytes Coordinate To Prevent Rift Valley Fever Virus Encephalitis
- Author
-
JoAnn D. Coleman-McCray, Jessica R. Spengler, Stuart T. Nichol, Jessica R. Harmon, Anita K. McElroy, and Christina F. Spiropoulou
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Rift Valley Fever ,Receptors, CCR2 ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Microbiology ,Monocytes ,Virus ,Mice ,03 medical and health sciences ,Immune system ,Immunity ,Virology ,medicine ,Animals ,Cytotoxic T cell ,Encephalitis, Viral ,Mice, Knockout ,Brain ,Rift Valley fever virus ,medicine.disease ,Acquired immune system ,Immunity, Innate ,Immunity, Humoral ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Insect Science ,Pathogenesis and Immunity ,Encephalitis ,CD8 - Abstract
Rift Valley fever virus (RVFV) is an arbovirus that causes disease in livestock and humans in Africa and the Middle East. While human disease is typically mild and self-limiting, some individuals develop severe manifestations, such as hepatitis, hemorrhagic fever, or encephalitis. Encephalitis occurs 2 to 3 weeks after acute illness; therefore, we hypothesized that it was a result of an inadequate adaptive immunity. To test this hypothesis in vivo, we used an attenuated virus (DelNSsRVFV) that does not typically cause disease in mice. We first characterized the normal immune response to infection with DelNSsRVFV in immunocompetent mice and noted expansion of natural killer cells and monocytes, as well as activation of both CD8 and CD4 T cells. Depleting C57BL/6 mice of CD4 T cells prior to DelNSsRVFV infection resulted in encephalitis in 30% of the mice; in encephalitic mice, we noted infiltration of T cells and inflammatory monocytes into the brain. CD4 and CD8 codepletion in C57BL/6 mice, as well as CD4 depletion in CCR2 knockout mice, increased the frequency of encephalitis, demonstrating that these cell types normally contributed to the prevention of disease. Encephalitic mice had similar viral RNA loads in the brain regardless of which cell types were depleted, suggesting that CD4 T cells, CD8 T cells, and inflammatory monocytes did little to control viral replication in the brain. CD4-depleted mice exhibited diminished humoral and T cell memory responses, suggesting that these immune mechanisms contributed to peripheral control of virus, thus preventing infection of the brain. IMPORTANCE RVFV is found in Africa and the Middle East and is transmitted by mosquitos or through contact with infected animals. Infected individuals can develop mild disease or more severe forms, such as hepatitis or encephalitis. In order to understand why some individuals develop encephalitis, we first need to know which immune functions protect those who do not develop this form of disease. In this study, we used a mouse model of RVFV infection to demonstrate that CD4 T cells, CD8 T cells, and monocytes all contribute to prevention of encephalitis. Their likely mechanism of action is preventing RVFV from ever reaching the brain.
- Published
- 2018
7. Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4 + T Cell and Virus-Specific Antibody Responses
- Author
-
Anita K. McElroy, Christina F. Spiropoulou, Stuart T. Nichol, Megan E. B. Jones, and Kimberly A. Dodd
- Subjects
CD4-Positive T-Lymphocytes ,Rift Valley Fever ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Viral Nonstructural Proteins ,Biology ,Antibodies, Viral ,Microbiology ,Virus ,Pathogenesis ,Mice ,Immune system ,Virology ,medicine ,Animals ,Humans ,Rift Valley fever ,Neutralizing antibody ,B-Lymphocytes ,Rift Valley fever virus ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Insect Science ,Antibody Formation ,biology.protein ,Pathogenesis and Immunity ,Female ,Nervous System Diseases ,Encephalitis ,CD8 - Abstract
Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human RVFV infections generally manifest as a self-limiting febrile illness, but in some individuals, the disease can progress to a fatal encephalitis or hemorrhagic syndrome. Little is known about the host characteristics that predispose development of more severe disease. Early in infection, interferon-mediated antiviral responses are critical for controlling RVFV replication, but the roles of downstream adaptive immune responses in determining clinical outcome have not been examined. Here, using a C57BL/6 mouse disease model, we evaluated the roles of B cells and T cells in RVFV pathogenesis. Given the profound inhibition of the innate response by the viral NSs protein and rapid course of wild-type infection, we utilized an attenuated RVFV lacking NSs to examine host responses following primary infection. Experiments utilizing B-cell-deficient mice or targeted T cell depletions of wild-type mice demonstrated that B cells and CD4 + T cells, but not CD8 + T cells, were critical for mediating viral clearance, even in the presence of a functional innate response. One-third of CD4-depleted mice developed severe neurologic disease following infection, in contrast to virus-infected mock-depleted mice that showed no clinical signs. CD4 + T cells were required for robust IgG and neutralizing antibody responses that correlated with RVFV clearance from peripheral tissues. Furthermore, CD4-depleted mice demonstrated significantly stronger proinflammatory responses relative to controls, suggesting CD4 + T cells regulate immune responses to RVFV infection. Together, these results indicate CD4 + T cells are critical determinants of RVFV pathogenesis and play an important role in preventing onset of neurologic disease.
- Published
- 2013
8. Rift Valley Fever Virus Vaccine Lacking the NSs and NSm Genes Is Safe, Nonteratogenic, and Confers Protection from Viremia, Pyrexia, and Abortion following Challenge in Adult and Pregnant Sheep
- Author
-
Stuart T. Nichol, César G. Albariño, Marina L. Khristova, Christina F. Spiropoulou, Baltus J. Erasmus, Anita K. McElroy, Bobbie R. Erickson, Kimberly A. Dodd, Brian H. Bird, Louis H. Maartens, Shelley Campbell, Deborah Cannon, Barbara Knust, and Clifton P. Drew
- Subjects
Fever ,Rift Valley Fever ,Injections, Subcutaneous ,Immunology ,Sheep Diseases ,Viremia ,Viral Nonstructural Proteins ,Biology ,Vaccines, Attenuated ,Microbiology ,Congenital Abnormalities ,Pregnancy ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,Seroconversion ,Vaccines, Synthetic ,Sheep ,Immunogenicity ,Outbreak ,Viral Vaccines ,Rift Valley fever virus ,Vaccine efficacy ,medicine.disease ,Vaccination ,Insect Science ,Gestation ,Female ,Gene Deletion - Abstract
Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on the safety, immunogenicity, and efficacy of the ΔNSs-ΔNSm recombinant RVFV (rRVFV) vaccine (which lacks the NSs and NSm virulence factors) in a total of 41 sheep, including 29 timed-pregnant ewes. This vaccine was proven safe and immunogenic for adult animals at doses ranging from 1.0 × 10 3 to 1.0 × 10 5 PFU administered subcutaneously (s.c.). Pregnant animals were vaccinated with 1.0 × 10 4 PFU s.c. at day 42 of gestation, when fetal sensitivity to RVFV vaccine-induced teratogenesis is highest. No febrile reactions, clinical illness, or pregnancy loss was observed following vaccination. Vaccination resulted in a rapid increase in anti-RVFV IgM (day 4) and IgG (day 7) titers. No seroconversion occurred in cohoused control animals. A subset of 20 ewes progressed to full-term delivery after vaccination. All lambs were born without musculoskeletal, neurological, or histological birth defects. Vaccine efficacy was assessed in 9 pregnant animals challenged at day 122 of gestation with virulent RVFV (1.0 × 10 6 PFU intravenously). Following challenge, 100% (9/9) of the animals were protected, progressed to full term, and delivered healthy lambs. As expected, all 3 sham-vaccinated controls experienced viremia, fetal death, and abortion postchallenge. These results demonstrate that the ΔNSs-ΔNSm rRVFV vaccine is safe and nonteratogenic and confers high-level protection in sheep.
- Published
- 2011
9. Cyclin-Dependent Kinase Activity Is Required at Early Times for Accurate Processing and Accumulation of the Human Cytomegalovirus UL122-123 and UL37 Immediate-Early Transcripts and at Later Times for Virus Production
- Author
-
Veronica Sanchez, Sama Tamrakar, Anita K. McElroy, Charles L. Clark, Rachel A. Schwartz, Deborah H. Spector, and Judy Y. Yen
- Subjects
Gene Expression Regulation, Viral ,Human cytomegalovirus ,Transcription, Genetic ,viruses ,Molecular Sequence Data ,Immunology ,Cytomegalovirus ,Virus Replication ,Microbiology ,Immediate early protein ,Immediate-Early Proteins ,Viral Proteins ,Cyclin-dependent kinase ,Virology ,Gene expression ,Roscovitine ,medicine ,Humans ,Kinase activity ,Cells, Cultured ,Base Sequence ,biology ,Kinase ,Fibroblasts ,medicine.disease ,Molecular biology ,Cyclin-Dependent Kinases ,Virus-Cell Interactions ,Viral replication ,Purines ,Insect Science ,Trans-Activators ,biology.protein - Abstract
Human cytomegalovirus (HCMV) infection leads to dysregulation of multiple cell cycle-regulatory proteins. In this study, we examined the effects of inhibition of cyclin-dependent kinase (cdk) activity on viral replication. With the drug Roscovitine, a specific inhibitor of cyclin-dependent kinases 1, 2, 5, 7, and 9, we have shown that during the first 6 h of infection, cyclin-dependent kinase-dependent events occurred that included the regulated processing and accumulation of the immediate-early (IE) UL122-123 transcripts and UL36-37 transcripts. Altered processing of UL122-123 led to a loss of IE1-72 and an increase in IE2-86. The ratio of spliced to unspliced UL37 transcripts also changed. These effects did not require de novo protein synthesis or degradation of proteins by the proteasome. Addition of Roscovitine at the beginning of the infection was also associated with inhibition of expression of selected viral early gene products, viral DNA replication, and late viral gene expression. When Roscovitine was added after the first 6 h of infection, the effects on IE gene expression were no longer observed and viral replication proceeded through the late phase, but viral titers were reduced. The reduction in viral titer was observed even when Roscovitine was first added at 48 h postinfection, indicating that cyclin-dependent kinase activity is required at both IE and late times. Flavopiridol, another specific inhibitor of cyclin-dependent kinases, had similar effects on IE and early gene expression. These results underscore the importance of accurate RNA processing and reiterate the significant role of cell cycle-regulatory factors in HCMV infection.
- Published
- 2004
10. Mechanisms Governing Maintenance of Cdk1/Cyclin B1Kinase Activity in Cells Infected with HumanCytomegalovirus
- Author
-
Deborah H. Spector, Veronica Sanchez, and Anita K. McElroy
- Subjects
Cyclin D ,Immunology ,Cyclin A ,Cyclin B ,Cytomegalovirus ,Fluorescent Antibody Technique ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Microbiology ,Cyclin-dependent kinase ,Virology ,CDC2 Protein Kinase ,Humans ,Cyclin B1 ,Cells, Cultured ,biology ,Membrane Proteins ,Nuclear Proteins ,Fibroblasts ,Protein-Tyrosine Kinases ,Molecular biology ,Virus-Cell Interactions ,Cell biology ,Enzyme Activation ,enzymes and coenzymes (carbohydrates) ,Gene Expression Regulation ,Insect Science ,Cytomegalovirus Infections ,biology.protein ,Cyclin-dependent kinase complex ,biological phenomena, cell phenomena, and immunity ,Cyclin A2 ,Subcellular Fractions - Abstract
Previous work has demonstrated dysregulation of key cell cycle components in human cytomegalovirus (HCMV)-infected human fibroblasts, resulting in cell cycle arrest (F. M. Jault, J.-M. Jault, F. Ruchti, E. A. Fortunato, C. L. Clark, J. Corbeil, D. D. Richman, and D. H. Spector, J. Virol. 69:6697-6704, 1995). The activation of the mitotic kinase Cdk1/cyclin B, which was detected as early as 8 h postinfection (p.i.) and maintained throughout the time course, was particularly interesting. To understand the mechanisms underlying the induction of this kinase activity, we have examined the pathways that regulate the activation of Cdk1/cyclin B1 complexes. The accumulation of the cyclin B1 subunit in HCMV-infected cells is the result of increased synthesis and reduced degradation of the protein. In addition, the catalytic subunit, Cdk1, accumulates in its active form in virus-infected cells. The decreased level of the Tyr15-phosphorylated form of Cdk1 in virus-infected fibroblasts is due in part to the down-regulation of the expression and activity of the Cdk1 inhibitory kinases Myt1 and Wee1. Increased degradation of Wee1 via the proteasome also accounts for its absence at 24 h p.i. At late times, we observed accumulation of the Cdc25 phosphatases that remove the inhibitory phosphates from Cdk1. Interestingly, biochemical fractionation studies revealed that the active form of Cdk1, a fraction of total cyclin B1, and the Cdc25 phosphatases reside predominantly in the cytoplasm of infected cells. Collectively, these data suggest that the maintenance of Cdk1/cyclin B1 activity observed in HCMV-infected cells can be explained by three mechanisms: the accumulation of cyclin B1, the inactivation of negative regulatory pathways for Cdk1, and the accumulation of positive factors that promote Cdk1 activity.
- Published
- 2003
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.