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The current World Health Organization (WHO) Hepatitis Elimination Strategy suffers from lack of a target for diagnosing or expunging occult HBV infection. A sizable segment of the global population has an undetected HBV infection, particularly the high‐risk populations and those residing in countries like India with intermediate endemicity. There is growing proof that people with hidden HBV infection can infect others, and that these infections are linked to serious chronic hepatic complications, especially hepatocellular carcinoma. Given the current diagnostic infrastructure in low‐resource settings, the WHO 2030 objective of obliterating hepatitis B appears to be undeniably challenging to accomplish. Given the molecular basis of occult HBV infection strongly linked to intrahepatic persistence, patients may inexplicably harbour HBV genomes for a prolonged duration without displaying any pronounced clinical or biochemical signs of liver disease, and present histological signs of moderate degree necro‐inflammation, diffuse fibrosis, and hence the international strategy to eradicate viral hepatitis warrants inclusion of occult HBV infection. [ABSTRACT FROM AUTHOR]

In light of the COVID-19 pandemic, researchers across the world hastened to develop vaccines that would aid in bolstering herd immunity. Utilizing mRNA coding and viral vector technology, the currently approved vaccines were required to undergo extensive testing to confirm their safety for mass usage in the general population. However, clinical trials failed to test the safety and efficacy of the COVID-19 vaccines in groups with weakened immune systems, especially pregnant women. Lack of information on the effects of vaccinations in pregnancy and the safety of fetuses are among the topmost reasons preventing pregnant women from receiving immunization. Thus, the lack of data examining the effects of COVID-19 vaccinations on pregnant women must be addressed. This review focused on the safety and efficacy of the approved COVID-19 vaccinations in pregnancy and their impact on both maternal and fetal immune responses. For that, we took the approach of combined systematic review/meta-analysis and compiled the available data from the original literature from PubMed, Web of Science, EMBASE and Medline databases. All articles analyzed presented no adverse effects of vaccination in pregnancy, with varying conclusions on the degree of effectiveness. The majority of the findings described robust immune responses in vaccinated pregnant women, successful transplacental antibody transfer, and implications for neonatal immunity. Hence, findings from the cumulative data available can be helpful in achieving COVID-19 herd immunization, including pregnant women. [ABSTRACT FROM AUTHOR]

The lethal combination involving TB and HIV, known as "syndemic" diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS. [ABSTRACT FROM AUTHOR]

HIV-1 infection gives rise to a multi-layered immune impairment in most infected individuals. The chronic presence of HIV-1 during the priming and activation of T cells by dendritic cells (DCs) promotes the expansion of suppressive T cells in a contact-dependent manner. The mechanism behind the T cell side of this HIV-induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs. Herein we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The HIV exposed DCs from cocultures between DCs and T cells resulted in a more tolerogenic phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by interaction with T cells. Transcriptomic analysis of the DCs separated from the DC-T cell coculture revealed a type I IFN response profile as well as an activation of pathways involved in T cell exhaustion. Taken together, our data indicate that the prolonged and strong type I IFN signaling in DCs, induced by the presence of HIV during DC-T cell cross talk, could play an important role in the induction of tolerogenic DCs and suppressed immune responses seen in HIV-1 infected individuals. [ABSTRACT FROM AUTHOR]

COVID-19 is being extensively studied, and much remains unknown regarding the long-term consequences of the disease on immune cells. The different arms of the immune system are interlinked, with humoral responses and the production of high-affinity antibodies being largely dependent on T cell immunity. Here, we longitudinally explored the effect COVID-19 has on T cell populations and the virus-specific T cells, as well as neutralizing antibody responses, for 6-7 months following hospitalization. The CD8+ TEMRA and exhausted CD57+ CD8+ T cells were markedly affected with elevated levels that lasted long into convalescence. Further, markers associated with T cell activation were upregulated at inclusion, and in the case of CD69+ CD4+ T cells this lasted all through the study duration. The levels of T cells expressing negative immune checkpoint molecules were increased in COVID-19 patients and sustained for a prolonged duration following recovery. Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19. Our study revealed significant and long-term alterations in T cell populations and key events associated with COVID-19 pathogenesis. [ABSTRACT FROM AUTHOR]

The dynamics of host-virus interactions, and impairment of the host's immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue. [ABSTRACT FROM AUTHOR]

Burkholderia pseudomallei (B. pseudomallei) causes melioidosis, a potentially fatal disease for which no licensed vaccine is available thus far. The host-pathogen interactions in B. pseudomallei infection largely remain the tip of the iceberg. The pathological manifestations are protean ranging from acute to chronic involving one or more visceral organs leading to septic shock, especially in individuals with underlying conditions similar to COVID-19. Pathogenesis is attributed to the intracellular ability of the bacterium to 'step into' the host cell's cytoplasm from the endocytotic vacuole, where it appears to polymerize actin filaments to spread across cells in the closer vicinity. B. pseudomallei effectively evades the host's surveillance armory to remain latent for prolonged duration also causing relapses despite antimicrobial therapy. Therefore, eradication of intracellular B. pseudomallei is highly dependent on robust cellular immune responses. However, it remains ambiguous why certain individuals in endemic areas experience asymptomatic seroconversion, whereas others succumb to sepsis-associated sequelae. Here, we propose key insights on how the host's surveillance radars get commandeered by B. pseudomallei. [ABSTRACT FROM AUTHOR]

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis. [ABSTRACT FROM AUTHOR]

The pathogenesis involving non-alcoholic fatty liver disease (NAFLD) in the context of chronic HBV (CHB) virus infection requires to be understood for developing improved modalities of diagnosis and treatment. We retrospectively investigated the association between NAFLD and CHB virus infection in the context of liver fibrosis. Among the 522 consecutive CHB patients who underwent transient elastography between years 2013 and 2016, we studied 455 subjects in the current investigation. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) scores were generally higher in patients with steatosis and fibrosis or cirrhosis. Antiviral treatment had significantly reduced the hepatitis B virus (HBV) viral load. Other liver function markers showed a significant positive correlation with both CAP and LSM scores. Plasma IL-13 was independently associated with increased CAP score where every increase of 1 unit of IL-13 was associated with an increase in CAP score by 0.98 unit. CCL11 was independently associated with LSM with every increase of CCL11 by a unit that, in turn, was associated with an increase of LSM score. We found that there was a high concurrence of NAFLD among patients with CHB virus infection. The presence of metabolic syndrome and chronic inflammation in CHB virus-infected patients were two independent factors that led to the progression of liver cirrhosis, with IL-13 playing the key role in linking the metabolic with the inflammatory components. [ABSTRACT FROM AUTHOR]

Gut microbiome alterations may play a paramount role in determining the clinical outcome of clinical COVID-19 with underlying comorbid conditions like T2D, cardiovascular disorders, obesity, etc. Research is warranted to manipulate the profile of gut microbiota in COVID-19 by employing combinatorial approaches such as the use of prebiotics, probiotics and symbiotics. Prediction of gut microbiome alterations in SARS-CoV-2 infection may likely permit the development of effective therapeutic strategies. Novel and targeted interventions by manipulating gut microbiota indeed represent a promising therapeutic approach against COVID-19 immunopathogenesis and associated co-morbidities. The impact of SARS-CoV-2 on host innate immune responses associated with gut microbiome profiling is likely to contribute to the development of key strategies for application and has seldom been attempted, especially in the context of symptomatic as well as asymptomatic COVID-19 disease. [ABSTRACT FROM AUTHOR]

A vast proportion of coronavirus disease 2019 (COVID-19) individuals remain asymptomatic and can shed severe acute respiratory syndrome (SARS-CoV) type 2 virus to transmit the infection, which also explains the exponential increase in the number of COVID-19 cases globally. Furthermore, the rate of recovery from clinical COVID-19 in certain pockets of the globe is surprisingly high. Based on published reports and available literature, here, we speculated a few immunovirological mechanisms as to why a vast majority of individuals remain asymptomatic similar to exotic animal (bats and pangolins) reservoirs that remain refractile to disease development despite carrying a huge load of diverse insidious viral species, and whether such evolutionary advantage would unveil therapeutic strategies against COVID-19 infection in humans. Understanding the unique mechanisms that exotic animal species employ to achieve viral control, as well as inflammatory regulation, appears to hold key clues to the development of therapeutic versatility against COVID-19. [ABSTRACT FROM AUTHOR]

Inflammation is a universal response mechanism existing as inter-communicator of biological systems. Uncontrolled or dysregulated inflammation addresses chronic low-grade effects eventually resulting in multimorbidity. Active solute transport across the membrane establishes varying osmotic gradients. Aquaporins (AQPs) are a class of critical ubiquitously expressed transmembrane proteins that aid in fluid and small solute transport via facilitated diffusion over established osmotic gradients. Numerous significant data features the biological functions of AQPs rendering them as an appropriate biomarker of health and diseases. Besides their physiological role in well-balanced inflammatory responses, it is worth noting the dysregulation of AQPs during any undesirable inflammatory event. Most literature to date clearly sets out AQPs as potential drug targets instigating AQP-based therapies. In light of this conception, the current review provides a compendious overview on the propitious and portentous out-turns of AQPs under inflammation. [ABSTRACT FROM AUTHOR]

Burkholderia cepacia complex (Bcc) are opportunistic pathogens implicated with nosocomial infections, and high rates of morbidity and mortality, especially in individuals with cystic fibrosis (CF). B. cepacia are naturally resistant to different classes of antibiotics, and can subvert the host innate immune responses by producing quorum sensing (QS) controlled virulence factors and biofilms. It still remains a conundrum as to how exactly the bacterium survives the intracellular environment within the host cells of CF patients and immunocompromised individuals although the bacterium can invade human lung epithelial cells, neutrophils, and murine macrophages. The mechanisms associated with intracellular survival in the airway epithelial cells and the role of QS and virulence factors in B. cepacia infections in cystic fibrosis remain largely unclear. The current review focuses on understanding the role of QS‐controlled virulence factors and biofilms, and provides additional impetus to understanding the potentials of QS‐inhibitory strategies against B. cepacia. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) treatment monitoring is paramount to clinical decision-making and the host biomarkers appears to play a significant role. The currently available diagnostic technology for TB detection is inadequate. Although GeneXpert detects total DNA present in the sample regardless live or dead bacilli present in clinical samples, all the commercial tests available thus far have low sensitivity. Humoral responses against Mycobacterium tuberculosis (Mtb) antigens are generally low, which precludes the use of serological tests for TB diagnosis, prognosis, and treatment monitoring. Mtb-specific CD4+ T cells correlate with Mtb antigen/bacilli burden and hence might serve as good biomarkers for monitoring treatment progress. Omics-based techniques are capable of providing a more holistic picture for disease mechanisms and are more accurate in predicting TB disease outcomes. The current review aims to discuss some of the recent advances on TB biomarkers, particularly host biomarkers that have the potential to diagnose and differentiate active TB and LTBI as well as their use in disease prognosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Background: Whether the portal/superior mesenteric vein (PV) should be resected during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) based on preoperative CT or intraoperative findings is controversial. Methods: This was a retrospective study with data of patients who had undergone pancreatoduodenectomy for PDAC between 2002 and 2016 in a tertiary referral centre. Based on the extent of contact between the PV and tumour on CT, patients were categorized into: group 1, no contact; group 2, contact 180° or less; group 3, contact greater than 180°. Extent of pathological PV invasion (pPV) (no invasion, pv0; invasion to tunica adventitia, pv1; invasion to media, pv2; invasion to intima, pv3) was compared with patient survival. To assess the feasibility of performing PV resection (PVR) based on intraoperative findings, the prognosis of patients in groups 1 and 2 with pv0 and no PVR (PVR(−)pv0) was compared with that of patients who had PVR (PVR(+)pv0), selected using propensity score matching. Results: Groups 1, 2 and 3 comprised 230, 232 and 38 patients respectively, and PVR was performed in 10·9, 73·3 and 95 per cent of them (P < 0·001). Extent of pPV differed significantly (P < 0·001). The positive predictive value of radiological tumour contact with PV in predicting positive pPV was 42·6 per cent. In 64 patients with PVR(−)pv0 and 64 matched patients with PVR(+)pv0, the R0 resection rate (66 versus 73 per cent respectively; P = 0·337) and survival (median 32·4 versus 32·1 months; P = 0·780) were not significantly different. Conclusion: PVR is needed only when the tumour is in clear contact with the PV and cannot be detached during surgery. [ABSTRACT FROM AUTHOR]

Objectives: Eradication of Helicobacter pylori is influenced by susceptibility to antimicrobial agents, elevated bacterial load and degree of acid inhibition, which can be affected by genotypes of drug-metabolizing enzymes [cytochrome P450 (CYP) 2C19 polymorphism]. Theoretically, the choice and dose of proton pump inhibitor may also influence the suppression of H. pylori infection. The CYP2C19 genotype has recently been found to have an impact on peptic ulcer healing, H. pylori eradication and therapeutic efficacy of proton pump inhibitors.Methods: Here, we investigated the impact of the CYP2C19 genotype polymorphism and the success of triple therapy (fluoroquinolones/metronidazole/clarithromycin) on antibiotic-resistant strains in eradicating H. pylori in human subjects with non-ulcer dyspepsia (NUD), in human subjects with peptic ulcer disease (PUD) and in asymptomatic human subjects (positive and negative for H. pylori infection).Results: Based on the CYP2C19 genotypes, determined by Droplet Digital PCR (ddPCR) analysis, we found 11.2%, 62.5% and 26.3% corresponding to rapid metabolizers, intermediate metabolizers and poor metabolizers, respectively. However, we did not find any significant effect for homozygous ABCB1 or CYP2C19*2 and CYP2C19*3 alleles. We detected several participants heterozygous for both ABCB1 and CYP2C19*2, CYP2C19*3 and CYP2C19*17 loci. The participants heterozygous for both ABCB1 and CYP2C19*2 and *3 loci should be defined as intermediate and poor metabolizers according to the haplotype analysis in the NUD, PUD and asymptomatic subjects.Conclusions: Consequently, fluoroquinolones/metronidazole/clarithromycin-based triple therapies can be used to eradicate H. pylori infection, if one does not know the CYP2C19 genotype of the patient. [ABSTRACT FROM AUTHOR]

Background: Definitions of regional lymph nodes for gallbladder cancer differ according to staging system. Hence, the appropriate extent of lymph node dissection has not yet been standardized. Methods: Pathological stages and disease‐specific survival (DSS) of patients who had undergone surgical resection of gallbladder cancer between 1990 and 2016 were reviewed. Patients with nodal metastases limited to the hepatoduodenal ligament or common hepatic artery, extending to the posterosuperior pancreatic head lymph nodes (PSPLNs), or in nodes along the coeliac axis or superior mesenteric vessels were grouped as having Na, Nb and Nc disease respectively. Metastases beyond these regions were defined as distant metastases (M1). Absence of distant metastasis was expressed as M0. Results: A total of 259 patients were evaluated. There were 74, 31 and nine patients respectively in the Na, Nb and Nc groups. Twenty‐five, nine and four patients in the respective groups had M1 disease (P = 0·682). The 5‐year DSS rate was comparable between patients with Na M0 and those with Nb M0 disease (36 versus 34 per cent respectively; P = 0·950), whereas the rate in patients with Nc M0 status (0 per cent) was worse than that of patients with Nb M0 (P = 0·017) and comparable to that of patients with M1 disease (14 per cent; P = 0·590). Among 22 patients with Nb M0 disease, the 5‐year DSS rate did not differ between those who had undergone pancreatoduodenectomy and those who had had dissection of PSPLNs without pancreatoduodenectomy (50 versus 30 per cent respectively; P = 0·499). Conclusion: PSPLNs and nodes along the hepatoduodenal ligament and hepatic artery should be considered regional nodes for gallbladder cancer, and should be resected. Standardized lymphadenectomy is important [ABSTRACT FROM AUTHOR]

T-cell exhaustion reportedly leads to dysfunctional immune responses of antigen-specific T cells. Investigations have revealed that T cells expand into functionally defective phenotypes with poor recall/memory abilities to parasitic antigens. The exploitation of co-inhibitory pathways represent a highly viable area of translational research that has very well been utilized against certain cancerous conditions. Malaria, at times, evolve into a sustained chronic state where T cells express several co-inhibitory molecules (negative immune checkpoints) facilitating parasite escape and sub-optimal protective responses. Experimental evidence suggests that blockade of co-inhibitory molecules on T cells in malaria could result in the sustenance of protective responses together with dramatic parasite clearance. The role of several co-inhibitory molecules in malaria infection largely remain unclear, and here we discussed the potential applicability of co-inhibitory molecules in the management of malaria with a view to harness protective host responses against chronic disease and associated consequences. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with comple- ment fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Physiological constituents in airway surface liquids (ASL) appear to impact the adherence and invasion potentials of Burkholderia pseudomallei contributing to recrudescent melioidosis. Here, we investigated the factors present in ASL that is likely to influence bacterial adhesion and invasion leading to improved understanding of bacterial pathogenesis. Six B. pseudomallei clinical isolates from different origins were used to investigate the ability of the bacteria to adhere and invade A549 human lung epithelial cells using a system that mimics the physiological ASL with different pH, NaCl, KCl, CaCl2 and glucose concentrations. These parameters resulted in markedly differential adherence and invasion abilities of B. pseudomallei to the lung epithelial cells. The concentration of 20 mM glucose dramatically increased adherence and invasion by increasing the rate of pili formation in depiliated bacteria. Glucose significantly increased adherence and invasion of B. pseudomallei to A549 cells, and presence of NaCl, KCl and CaCl2 markedly ablated the effect despite the presence of glucose. Our data established a link between glucose, enhanced adhesion and invasion potentials of B. pseudomallei, hinting increased susceptibility of individuals with diabetes mellitus to clinical melioidosis. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1. [ABSTRACT FROM AUTHOR]

Gut microbiota is established during birth and evolves with age, mostly maintaining the commensal relationship with the host. A growing body of clinical evidence suggests an intricate relationship between the gut microbiota and the immune system. With ageing, the gut microbiota develops significant imbalances in the major phyla such as the anaerobic Firmicutes and Bacteroidetes as well as a diverse range of facultative organisms, resulting in impaired immune responses. Antimicrobial therapy is commonly used for the treatment of infections; however, this may also result in the loss of normal gut flora. Advanced age, antibiotic use, underlying diseases, infections, hormonal differences, circadian rhythm, and malnutrition, either alone or in combination, contribute to the problem. This nonbeneficial gastrointestinal modulation may be reversed by judicious and controlled use of antibiotics and the appropriate use of prebiotics and probiotics. In certain persistent, recurrent settings, the option of faecal microbiota transplantation can be explored. The aim of the current review is to focus on the establishment and alteration of gut microbiota, with ageing. The review also discusses the potential role of gut microbiota in regulating the immune system, together with its function in healthy and diseased state. [ABSTRACT FROM AUTHOR]

Background Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies ( AAA) for disease outcome in Crohn's disease ( CD) patients remained unclear. Aim To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. Methods We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide ( TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. Results There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/ mL vs 5.4 ± 4.3 μg/ mL: P <.001). Adalimumab trough level of 5.0 μg/ mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 ( P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6 TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. Conclusion Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6 TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. ( UMIN Registration No. 000005146) [ABSTRACT FROM AUTHOR]

Background: Melioidosis is a neglected tropical disease endemic across South East Asia and Northern Australia. The etiological agent, Burkholderia pseudomallei (B.pseudomallei), is a Gram-negative, rod-shaped, motile bacterium residing in the soil and muddy water across endemic regions of the tropical world. The bacterium is known to cause persistent infections by remaining latent within host cells for prolonged duration. Reactivation of the recrudescent disease often occurs in elders whose immunity wanes. Moreover, recurrence rates in melioidosis patients can be up to ~13% despite appropriate antibiotic therapy, suggestive of bacterial persistence and inefficacy of antibiotic regimens. The mechanisms behind bacterial persistence in the host remain unclear, and hence understanding host immunity during persistent B. pseudomallei infections may help designing potential immunotherapy. Methodology/Principal findings: A persistent infection was generated using a small-colony variant (SCV) and a wild-type (WT) B. pseudomallei in BALB/c mice via intranasal administration. Infected mice that survived for >60 days were sacrificed. Lungs, livers, spleens, and peripheral blood mononuclear cells were harvested for experimental investigations. Histopathological changes of organs were observed in the infected mice, suggestive of successful establishment of persistent infections. Moreover, natural killer (NK) cell frequency was increased in SCV- and WT-infected mice. We observed programmed death-1 (PD-1) upregulation on B cells of SCV- and WT-infected mice. Interestingly, PD-1 upregulation was only observed on NK cells and monocytes of SCV-infected mice. In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) downregulation was seen on NK cells of WT-infected mice, and on monocytes of SCV- and WT-infected mice. Conclusions/Significance: The SCV and the WT of B. pseudomallei distinctly upregulated PD-1 expression on B cells, NK cells, and monocytes to dampen host immunity, which likely facilitates bacterial persistence. PD-1/PD-L1 pathway appears to play an important role in the persistence of B. pseudomallei in the host. [ABSTRACT FROM AUTHOR]

Background Simultaneous use of proton pump inhibitors ( PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug ( NSAID)-induced small bowel injury. Aim To investigate whether polymorphisms of the cytochrome P450 2C19 gene ( CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. Methods Study participants included 55 healthy Japanese volunteers, who participated in the PPI- NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. Results In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. Conclusions The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB) and IFN-γ in the exhaustion of innate-like TCR Vα7.2+CD4+T cells, in 15 individuals with chronic HBV (CHB) infection where six were HBV DNA+ and nine were HBV DNA–. The percentage of cytokine-producing T cells and MAIT cells were significantly perturbed in HBV patients relative to healthy controls (HCs). The intracellular expression of GrB and IFN-γ was significantly reduced in MAIT cells derived from HBV-infected patients as compared to HCs, and the levels correlated with the percentage and levels [mean fluorescence intensity (MFI)] of CD69 expression. The total expression of CD69 (iMFI) was lower in CHB patients as compared to HCs. The frequency of CD69+ cells correlated with the levels of cytokine expression (MFI), particularly in CHB patients as compared to HCs. In summary, the polyfunctionality of peripheral T cells was significantly reduced among CHB patients, especially in the TCR Vα7.2+CD4+T cells, and the levels of cytokine expression correlated with functional cytokine levels. [ABSTRACT FROM AUTHOR]

Background: Currently, several assays can diagnose acute dengue infection. However, none of these assays can predict the severity of the disease. Biomarkers that predicts the likelihood that a dengue patient will develop a severe form of the disease could permit more efficient patient triage and allows better supportive care for the individual in need, especially during dengue outbreaks.Methods: We measured 20 plasma markers i.e. IFN-γ, IL-10, granzyme-B, CX3CL1, IP-10, RANTES, CXCL8, CXCL6, VCAM, ICAM, VEGF, HGF, sCD25, IL-18, LBP, sCD14, sCD163, MIF, MCP-1 and MIP-1β in 141 dengue patients in over 230 specimens and correlate the levels of these plasma markers with the development of dengue without warning signs (DWS-), dengue with warning signs (DWS+) and severe dengue (SD).Results: Our results show that the elevation of plasma levels of IL-18 at both febrile and defervescence phase was significantly associated with DWS+ and SD; whilst increase of sCD14 and LBP at febrile phase were associated with severity of dengue disease. By using receiver operating characteristic (ROC) analysis, the IL-18, LBP and sCD14 were significantly predicted the development of more severe form of dengue disease (DWS+/SD) (AUC = 0.768, P < 0.0001; AUC = 0.819, P < 0.0001 and AUC = 0.647, P = 0.014 respectively). Furthermore, we also found that the levels of VEGF were directly correlated and sCD14 was inversely correlated with platelet count, suggesting that the endothelial activation and microbial translocation may played a role in pathogenesis of dengue disease.Conclusions: Given that the elevation IL-18, LBP and sCD14 among patients with severe form of dengue disease, our findings suggest a pathogenic role for an aberrant inflammasome and monocyte activation in the development of severe form of dengue disease. [ABSTRACT FROM AUTHOR]

The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive antiretroviral therapy (ART) naïve, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-naïve individuals. In sharp contrast to CD4−iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ARTnaïve individuals were defective in their ability to produce intracellular IFN-γ. Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses. [ABSTRACT FROM AUTHOR]

Background: During infection, successful bacterial clearance is achieved via the host immune system acting in conjunction with appropriate antibiotic therapy. However, it still remains a tip of the iceberg as to where persistent pathogens namely, Burkholderia pseudomallei (B. pseudomallei) reside/hide to escape from host immune sensors and antimicrobial pressure. Methods: We used transmission electron microscopy (TEM) to investigate post-mortem tissue sections of patients with clinical melioidosis to identify the localisation of a recently identified gut microbiome, B. pseudomallei within host cells. The intranuclear presence of B. pseudomallei was confirmed using transmission electron microscopy (TEM) of experimentally infected guinea pig spleen tissues and Live Z-stack, and ImageJ analysis of fluorescence microscopy analysis of in vitro infection of A549 human lung epithelial cells. Results: TEM investigations revealed intranuclear localization of B. pseudomallei in cells of infected human lung and guinea pig spleen tissues. We also found that B. pseudomallei induced actin polymerization following infection of A549 human lung epithelial cells. Infected A549 lung epithelial cells using 3D LSCM and immunofluorescence microscopy confirmed the intranuclear localization of B. pseudomallei. Conclusion: B. pseudomallei was found within the nuclear compartment of host cells. The nucleus may play a role as an occult or transient niche for persistence of intracellular pathogens, potentially leading to recurrrent episodes or recrudescence of infection. [ABSTRACT FROM AUTHOR]

Background: Burkholderia pseudomallei, the causative agent of melioidosis poses a serious threat to humankind. B. pseudomallei secretes numerous virulence proteins that alter host cell functions to escape from intracellular immune sensors. However, the events underlying disease pathogenesis are poorly understood. Methods: We determined the ability of B. pseudomallei to invade and survive intracellularly in A549 human lung epithelial cells, and also investigated the early transcriptional responses using an Illumina HumanHT-12 v4 microarray platform, after three hours of exposure to live B. pseudomallei (BCMS) and its secreted proteins (CCMS). Results: We found that the ability of B. pseudomallei to invade and survive intracellularly correlated with increase of multiplicity of infection and duration of contact. Activation of host carbohydrate metabolism and apoptosis as well as suppression of amino acid metabolism and innate immune responses both by live bacteria and its secreted proteins were evident. These early events might be linked to initial activation of host genes directed towards bacterial dissemination from lungs to target organs (via proposed in vivo mechanisms) or to escape potential sensing by macrophages. Conclusion: Understanding the early responses of A549 cells toward B. pseudomallei infection provide preliminary insights into the likely pathogenesis mechanisms underlying melioidosis, and could contribute to development of novel intervention strategies to combat B. pseudomallei infections. [ABSTRACT FROM AUTHOR]

Background: The 7.5 kb cryptic plasmid of Chlamydia trachomatis has been shown to be a virulence factor in animal models, but its significance in humans still remains unknown. The aim of this study was to investigate the prevalence and potential involvement of the C. trachomatis cryptic plasmid in causing various clinical manifestations; including infertility, reproductive tract disintegrity, menstrual disorder, and polycystic ovarian syndrome (PCOS) among genital C. trachomatis-infected patients. Results: A total of 180 female patients of child bearing age (mean 30.9 years old, IQR:27-35) with gynecological complications and subfertility issues, who visited Obstetrics and Gynecology clinics in Kuala Lumpur, Malaysia were recruited for the study. Prevalence of genital chlamydial infection among these patients was alarmingly high at 51.1 % (92/180). Of the 92 chlamydia-infected patients, 93.5 % (86/92) were infected with plasmid-bearing (+) C. trachomatis while the remaining 6.5 % (6/92) were caused by the plasmid-free (-) variant. Our data showed that genital C. trachomatis infection was associated with infertility issues, inflammation in the reproductive tract (mucopurulent cervicitis or endometriosis), irregular menstrual cycles and polycystic ovarian syndrome (PCOS). However, no statistical significance was detected among patients with plasmid (+) versus plasmid (-) C. trachomatis infection. Interestingly, plasmid (+) C. trachomatis was detected in all patients with PCOS, and the plasmid copy numbers were significantly higher among PCOS patients, relative to non-PCOS patients. Conclusion: Our findings show a high incidence of C. trachomatis infection among women with infertility or gynecological problems in Malaysia. However, due to the low number of plasmid (-) C. trachomatis cases, a significant role of the plasmid in causing virulence in human requires further investigation of a larger cohort. [ABSTRACT FROM AUTHOR]

Background: Burkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B. pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis. Methods: Ten-day LD50 was determined for the small-colony variant (SCV) and its parental wild-type (WT) via intranasal route in experimental BALB/c mice. Persistent B. pseudomallei infection was generated by administrating sub-lethal dose of the two strains based on previously determined LD50. After two months, peripheral blood mononuclear cells (PBMCs) and plasma were obtained to investigate host immune responses against persistent B. pseudomallei infection. Lungs, livers, and spleens were harvested and bacterial loads in these organs were determined. Results: Based on the ten-day LD50, the SCV was ~20-fold less virulent than the WT. The SCV caused higher bacterial loads in spleens compared to its WT counterparts with persistent B. pseudomallei infection. We found that the CD4+ T-cell frequencies were decreased, and the expressions of PD-1, but not CTLA-4 were significantly increased on the CD4+ and CD8+ T cells of these mice. Notably, persistent infection with the SCV led to significantly higher levels of PD-1 than the WT B. pseudomallei. Plasma IFN-γ, IL-6, and IL-17A levels were elevated only in SCV-infected mice. In addition, skewed plasma Th1 and Th17 responses were observed in SCV-infected mice relative to WT-infected and uninfected mice. Conclusion: B. pseudomallei appears to upregulate the expression of PD-1 on T cells to evade host immune responses, which likely facilitates bacterial persistence in the host. SCVs cause distinct pathology and immune responses in the host as compared to WT B. pseudomallei. [ABSTRACT FROM AUTHOR]

Background Mucosal-associated invariant T ( MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus ( HCV) infection remains unclear. Materials and methods We investigated the frequency of CD8+ CD161++ TCR Vα7.2+ MAIT cells in a cross-sectional cohort of chronic HCV-infected patients ( n = 25) and healthy controls ( n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing ( CCR5 and CD103), biomarkers of immune exhaustion ( PD-1, TIM-3 and CTLA-4), chronic immune activation ( CD38 and HLA- DR), and immunosenescence ( CD57) by flow cytometry. Results The frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA- DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. Conclusions Immune exhaustion and senescence of CD8+ CD161++ TCR Vα7.2+ MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) -induced gastric inflammation impacts the functions of leptin- and ghrelin-producing cells in the gastroduodenum. Inflammation resulting from H. pylori sensing via Toll-like receptors (TLRs) and the associated downstream signaling largely remain ambiguous. Here, we investigated the role of gut hormones, pro-inflammatory cytokines and single nucleotide polymorphisms (SNPs) associated with TLR 4p14 in H. pylori disease in 30 subjects with non-ulcer dyspepsia (NUD), 40 with peptic ulcer disease (PUD) and 15 with gastric cancer (GC) subjects positive and negative for H. pylori infection. The level of pro-inflammatory cytokines was directly proportional to the severity of gastritis, and disease status influenced the levels of gut hormones and pro-inflammatory cytokines. TLR-1 SNPs rs4833095 and TLR-10 SNPs rs10004195 and were directly associated with H. pylori disease, and were up-regulated in the presence of H. pylori in a genotype-independent manner. We concluded that TLR-1 rs4833095 and TLR10 rs10004195 confer susceptibility to development of gastroduodenal disease, especially GC in H.pylori disease. [ABSTRACT FROM AUTHOR]

Background Hepatitis C virus ( HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. Materials and methods We characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA- DR, and survival marker CD127 ( IL-7 R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. Results HCV-specific CD4+ and CD8+ T cells from chronic HCV ( CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA- DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. Conclusions Chronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection. [ABSTRACT FROM AUTHOR]

Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8+ T cells co-expressing the semi-invariant TCR Vα7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV-1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161++CD8+ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naïve HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naïve HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono- and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono- and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses. [ABSTRACT FROM AUTHOR]

Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions thatmay complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS. [ABSTRACT FROM AUTHOR]