Wednesday, February 21, 2018
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Research

Faculty Designation Areas of Interest
Dr. V. Ravi Professor Japanese encephalitis, Acute encephalitis syndrome, Development of indigenous kits, antiretroviral therapy, immunology and pathogenesis of viral infections of CNS, psychoneuroimmunology
Dr S. N Madhusudana Professor Development of diagnostic kits for Rabies, clinical trials on vaccines and anti-viral agents for Rabies, Immunopathogenesis of Rabies
Dr Anita Desai Additional Professor Laboratory diagnosis of viral infections of the nervous system, molecular epidemiology and molecular virology of neurotropic viruses to understand pathogenesis.
Dr Reeta Mani Assistant Professor Molecular diagnosis of infections of central nervous system, Diagnostic and preventive aspects of Rabies, Acute encephalitis syndrome, Pandemic (H1N1) Influenza, Emerging viral infections

Summary of research projects ongoing/recently completed

Strengthening Surveillance for Japanese encephalitis in India

This project funded by the Centers for Disease Control (CDC, Atlanta) has the following objectives (i) Evaluate the designated JE sentinel laboratories in India using a standardized tool (ii) identification of the gaps if any in the effective functioning of the designated laboratories and suggest measures to fill the gaps, (iii) Conducting training workshops for staff from the designated laboratories (State , District and NCDC) on standardized procedures for laboratory diagnosis of JE, (iv) Identify laboratories within the network which have capacity for testing other bacterial/viral pathogens of AES and prepare a training module for providing hands on training for other bacterial pathogens, (v) Develop and put in place a protocol to ensure the quality of the laboratory network through an external quality assurance program involving JE proficiency testing and cross checking a proportion of positive and negative samples, (vi) Provide onsite support to the laboratories whenever problems arise and (vii) In consultation with CDC, India office, arrange shipment of all samples of unknown etiology to Center for Disease Control And Prevention, Fort Collins /Atlanta, USA, for further testing.  

Immune signatures in Dengue virus infection

This is a collaborative investigation between Yale University School of Medicine’s U19 and NIMHANS to examine immune mechanisms prevailing in the Indian population against Dengue virus (DENV). DENV has been a serious public health problem in India since the first widespread epidemic in 1996 and currently causes more than 10,000 cases per year. We propose to investigate individual immune responses to DENV with a systems immunology focus and taking advantage of recent technical advances. From DENV patients and asymptomatic DENV-exposed subjects we will quantify functional responses of all major arms of the immune system (the innate cells, T cells and B cells), gene expression profiles in response to DENV, and genetic determinants that have been implicated in defining the outcome of response to DENV infection. Results of these investigations will be analyzed, integrated, and combined with clinical history and results from other flaviviral immune responses to gain insights into the architecture of the immunological response to DENV and to provide insight into host immune and genetic parameters that define the course of Dengue pathogenesis in humans.

Immunopathogenesis of rabies: experimental studies in Mice

The immune responses that occur after natural infection to fixed and street rabies viruses were investigated in terms of cytokines and chemokines produced; phenotyping of different T cells in infected mouse brain and antibody response in peripheral blood. It was found that all the immune parameters were exaggerated in mice who succumbed to rabies following delayed vaccination in contrast to mice which were not vaccinated. Marked increase in CD4, CD8 and double negative cells were found in the brain of these mice. Also, levels of cytokines such as IFN gamma, IL 6 and IL4 and chemokines such as RANTES and IP-10 were drastically elevated in mice which got delayed vaccination. These observations show that immune responses play a dual role in rabies encephalitis. They offer complete protection against encephalitis if given soon after the exposure but may exaggerate the disease process if given late after the exposure has occurred. The study is ongoing to further understand the critical role played by innate and adaptive immune responses in rabies encephalitis.

To Investigate the antiviral property of an herbal extract against rabies virus by in vitro and in vivo studies

The herbal extract formulated by Dr. Rajesh Ghanju was provided by ICMR. The crude extract and its fractions were tested for antiviral property against rabies virus (CVS) and street viruses both by in vitro testing by infection of BHK 21 cells and Neuro 2 a cells as well as challenging experiments in Swiss Albino mice. Though the original herbal extract and its fraction C13 and F4 had strong ability to inhibit viral replication for up to 8 hours post- infection, they failed to protect mice with intramuscular, intra-peritoneal and oral routes of inoculation. It was concluded that the bioavailability of the active ingredient in mice may not be sufficient to clear the virus from the brain of mice.  

To study the neutralizing efficacy of 5 human rabies monoclonal antibodies produced by Celltrion , Korea

Passive immunization is one of the most important parameter of post-exposure prophylaxis. In recent times, several multinational companies have developed human rabies monoclonal antibodies for passive immunization. The Celltrion Company, South Korea has requested to test 5 of their human Mabs against different antigenic sites of rabies G protein to test their efficacy for neutralization of 6 different street viruses prevalent in India. We are now undertaking in vitro studies in Neuro 2 a Cell line. The initial screening is promising and the study is in progress.

Th1 and Th2 Immune responses to different schedules of rabies vaccination

For the first time, a systematic evaluation of Th1 and Th2 immune responses to Intradermal and intramuscular rabies vaccination was done in people who have taken pre and post exposure rabies vaccination. The levels of interferon gamma (Th1) and IL 4 ( Th2) was determined by ELISPOT assay. It was found that both types of vaccination induced a strong Th1 and Th2 arms of immune responses which last for 1 year. There was significant elevation following a booster dose of vaccination. Further the levels of both IFN gamma and IL 4 significantly correlated with levels of rabies virus neutralizing antibodies.  Further studies are ongoing to determine each response in prevention of rabies in humans.

Understanding the biology of Chikungunya virus infection  in permissive cell lines and mosquito  vectors

Indirect immunofluorescence assay using a polyclonal Chikungunya antibody confirmed successful infection in cell lines C6/36 and C2C12. Identification of the cellular components involves intermediate steps like growing cells to extract cell membrane proteins, resolving the proteins on a SDS-PAGE, Western Blotting and probing with antibodies to detect a “band” corresponding to a protein/(s) that bind to CHIKV. These steps were standardised to give the best results with optimal use of resources. The more sensitive silver staining method was utilized to detect the same. The excised protein from the gel for C6/36, has been submitted to the Molecular Biophysics Department, IISc Bangalore for MALDI-TOF to characterise the protein, followed by MASCOT SEARCH to identify it. 

Three mosquito species Aedes aegypti, Aedes albopictus and Culex quinquefaciatus are being reared at CRME, Madurai. Mosquito midguts from all the three species were dissected and collected in order to prepare mosquito midgut membrane proteins for SDS-PAGE and VOPBA experiments. Mosquito midgut brush border membrane fraction (BBMF) proteins have been isolated and resolved on a SDS-PAGE.

Translational Research on the Neuroimmuno-pathology of Schizophrenia" 

Schizophrenia is perhaps one of the most puzzling mental disorders whose etiopathogenesis is yet to be ascertained.  Substantial research evidence from various lines of studies argues towards a compelling role for gene-environment interaction as a promising causal model for schizophrenia. genetic, immunological as well as epidemiological studies implicate a robust role for immune-mediated pathogenesis in schizophrenia.  Indeed, immune disturbances mediated pathogenesis is among the most comprehensive & integrative models to understand the pathogenesis of schizophrenia.  Immune mediated pathogenesis has also been described in bipolar disorder.  This research on one of the component projects on DBT-Center of Excellence for Translational Research on the Neuroimmunopathology of Schizophrenia seeks to evaluate diagnostic utility of immune markers in psychoses to differentiate schizophrenia patients from those of bipolar disorder and healthy controls.

 Structural & Functional Connectivity of Hippocampus in Schizophrenia: Evaluation of Neuroimmunological & Neurotrophic Factors Interactions using Diffusion Tensor Imaging & functional Magnetic Resonance Imaging Studies

Schizophrenia is complex neuropsychiatric disorder is characterized by delusions, hallucinations, disorganized behaviour and progressive cognitive deficits, whose pathophysiology remains unclear. It is ranked among the top ten disabling disorders by the World Health Organization. A compelling hypothesis with translational potential, investigated in the senior fellowship research, is that “complex interactions between neuroimmunological / neutrophic factors and hippocampus might underlie the pathogenesis of schizophrenia”.  Ascertaining evidence for these pathogenetic interactions will enhance our understanding of this intriguing disorder and can potentially open novel therapeutic targets for schizophrenia.  Interim findings of this research project has demonstrated deficient serum BDNF in antipsychotic-naïve schizophrenia patients and as well as trend level significant deficiency in HR subjects partially support the postulated endophenotypes basis of BDNF in schizophrenia.  In subjects at high risk for schizophrenia, there was a pathophysiologically relevant & significant correlation between plasma IL-6 and hippocampus activation during the performance of learned irrelevance task.

Neuroimmunogenetic & Functional MRI Correlates of Smooth Pursuit Eye Movement Deficits: An Imaging Genomics Study of   a Novel Composite Biomarker for Schizophrenia

This project proposal seeks to explore the possibility of a novel composite biomarker for schizophrenia phenotype involving nicotinergic abnormalities and eye movement abnormalities by examining their clinical, immunopathogenetic as well as endophenotypical correlates. Preliminary observations have revealed significantly greater eye movement deficits in schizophrenia patients that correlate with DLPFC volume deficit.  Ongoing analyses attempt to examine the relationship between the eye movement deficits and immunological abnormalities in schizophrenia involving plasma interleukin-6 levels / lymphocyte gene expression as well as other cytokines.