Biology subjects

Tripathy, R.

Publications and source records attributed to Tripathy, R..

3 recordsLinked to original sources

bioRxiv2017

A 23bp Indel Polymorphism in TLR2 Gene Enhances Inflammation and Disease Severity in Dengue

BackgroundDengue is the most rapidly spreading viral disease transmitted by the bite of infected Aedes mosquitos. Pathogenesis of dengue is still unclear; although host genetic factors, immune responses and virus serotypes have been proposed to contribute to disease severity. The development of high-throughput methods have allowed to scale up capabilities of identifying the key markers of inflammation. Since NS1 protein of dengue virus has been reported to activate immune cells towards enhanced inflammation through TLR2, we examined the role of a polymorphism, a 23bp deletion in 5UTR region of TLR2 gene in patients with dengue (with and without warning signs) and correlated with plasma levels of inflammatory mediators with disease severity and viral serotypes.\n\nMethodsEighty nine patients classified as per WHO 2009 criteria during dengue outbreak in Odisha, India in 2016 were included in the current study. Presence of dengue virus (DENV) was demonstrated by detecting NS1 antigen, IgM capture ELISA and serotypes in circulation were discriminated by type-specific RT-PCR and/or sequencing. Sixty-one confirmed dengue cases were typed for TLR2 indel polymorphism and compared with 485 disease free controls. Plasma samples were assayed for 41-plex cytokine/ chemokines using Luminex bead based immunoassay.\n\nResultsPresence of 23bp deletion allele of TLR2 gene was significantly more in patients with severe dengue in comparison to dengue fever cases (p= 0.03; Odds ratio 4.05) although the frequency of insertion (Ins) allele of TLR2 was comparable in healthy controls and dengue cases (82.4 and 87.9 % respectively). Seventy-three (82%) samples were found to be positive by NS1/IgM capture ELISA/ RT-PCR. DENV-2 was predominant (58%) during the outbreak. Among the host inflammatory biomarkers 9 molecules were significantly altered in dengue patients when compared to healthy controls. The increased levels of IFN-{gamma}, GM-CSF, IL-10, IL-1R and MIP-1{beta} correlated significantly with severe dengue.\n\nConclusionsThe frequency of 23bp Indel mutation of TLR2 was comparable between healthy controls and dengue fever (with and without warning signs), suggesting that this indel mutation does not contribute significantly to susceptibility/ resistance to dengue; however, del allele of TLR2 gene was significantly more associated in patients with severe dengue symptoms when compared to dengue fever cases.

microbiology↗

bioRxiv2017

A primate specific loss of function polymorphism in TLR2 gene decreases inflammation and protects humans from organ dysfunction in Malaria

Polymorphisms of TLR genes could regulate and contribute functionally to innate immunity and inflammation. TLR2, a promiscous receptor recognizes Pathogen Associated Molecular Patterns from several microbes, bacterial, viral, protozoan and helminths. We demonstrate that monocytes of humans with deletion polymorphism in TLR2 gene (a 23 bp deletion in 5 UTR region) respond more vigorously in vitro to several TLR2 ligands in comparison to those with insertion allele. Lower primates such as Rhesus monkeys and Baboon display deletion genotype while insertion is found in higher primates viz., Orangutan, Chimpanzees and Gorilla. Enhanced inflammation is a hallmark of pathogenesis in human severe malaria leading to bad prognosis and odds ratio of patients prone to develop severe malaira such as multi organ failure with del/del genotype was found to be very high. Based on induction of inflammatory cytokines by normal human PBMCs in vitro and circulating cytokine levels in cohorts of patients with severe P. falciparum malaria, we propose that insertion of a 23bp sequence in 5UTR region of TLR2 gene could have led to moderated TLR2 induced inflammation thus offering survival advantage to higher primates by rendering them relatively refractory to multi-organ dysfunction in severe malaria.\n\nOne Sentence SummaryA 23bp deletion in TLR2 gene is associated with high inflammation and susceptibility to organ dysfunction in Plasmodium falciparum malaria.

immunology↗

bioRxiv2017

Sepsis: Partial least squares structural equation modelling (PLS-SEM) suggests a critical role for anti-inflammatory responses in clinical severity

BackgorundDespite major advances in medicine, Sepsis remains one of the major killers in critical care wards around the world. For several years it was widely believed that an early pro-inflammatory host response is followed by an overwhelming anti-inflammatory phase. The hypo-inflammatory status, termed as Compensatory anti-inflammatory response syndrome (CARS), was proposed to be the primary cause of sepsis-associated mortality. However, this paradiam changed in recent years since there was little evidence to support the linear model of host response and pathogenesis in sepsis. Currently held view is that both inflammatory and anti-inflammatory host responses are stimulated in an overlapping manner. In this study a robust statistical model to study the complex interplay of host cytokines in human sepsis has been developed to evaluate host responses in sepsis that contribute significantly to clinical pathology.\n\nMethodsTwentyseven cytokines/ chemokines were quantified in 139 sepsis patients and multivariate analysis of variance (MANOVA) was performed to assess differences in host responses in different categories of clinical severity. Partial least squares regression based structural equation modelling (PLS-SEM) was used to assess interactions between different groups of cytokines and their contribution to clinical pathology. An array of 23 cytokines was analysed in a mouse model of endotoxemia and a similar mathematical model was constructed.\n\nResultsThe results of MANOVA demonstrated the ability of combined cytokine response to discriminate sepsis patients according to clinical severity or outcome. Structural equation modelling revealed strong positive association between inflammatory and anti-inflammatory cytokines. In human sepsis, anti-inflammatory cytokines emerged as a significant entity associated with clinical severity as assessed by APACHE II scores.\n\nConclusionPLS-SEM modeling of cytokine responses and APACHE II score in human sepsis revealed that anti-inflammatory molecules contribute significantly towards clinical severity. More critically, the model offers emperical evidence for failures of clinical trials conducted during the last two decades in which antagonists of inflammatory host responses for human Sepsis were used for sepsis. The model also provides credence to the notion that inflammatory and anti-inflammatory host responses occur concurrently in both experimental endotoxemia and in human sepsis.

immunology↗