Research

Understanding and unraveling HUMAN IMMUNOLOGY through the lenses of GENOMICS.

Human immunology research is intrinsically challenging because of extensive biological heterogeneity and the limited availability of quality patient samples. In contrast to well-controlled animal models such as mice, data generated from human studies are multifaceted and demand rigorous interpretation and integration across diverse parameters. To address these challenges, we have established a comprehensive human immunology program that applies genomic and systems-level approaches to decipher immune responses in infection, cancer, and autoimmune disease. Central to this effort are longitudinal cohorts of healthy and diseased individuals, coupled with the development of innovative microscale genomic technologies that enable high-resolution investigation from scarce clinical material.

Research in our lab is aimed at dissecting the fundamental processes of immunobiology as well as dissecting the immunobiology of diseases and disorders to augment the therapeutics in humans, by studying the regulation of global gene expression patterns uniquely associated with a pathogen, immune cell-type, disease stage, vaccination status by seamlessly integrating multi-omics and immunological tools. One fundamental immunological process we strive to address is how the T cell memory is formed during the primary infection/vaccination and maintained over the years to defend the subsequent secondary infection, so that the knowledgebase can inform better vaccine designs and vaccination strategies. The other part of the lab is focused on translational immunology where the aim is to understand and identify the dynamic changes in the immune cell profiles during the course of diseases such as cancer, autoimmune disorders and neonatal sepsis through building and studying the longitudinal cohorts. Through these efforts we aim to identify prognostic and diagnostic markers to treat the disease better.

             Working towards these goals, in the last 6-7 years, we have been addressing a variety of questions relating to human immuno-biology. A brief summary of ongoing work and the direction we want to take forward are described in the following sections. 

I.  T cell Biology

1.  T cell memory development.

The acquisition of immunological memory to infections is the hallmark of protective immune response. The naive T cells that have not previously encountered antigen, differentiate during the primary infection in to memory T cells that have specialized functions in immune defense to a subsequent infection with the same pathogen. However, the T cell memory is highly diverse and heterogeneous and has only been categorized into few subtypes based on limited known markers. This limited knowledge has restricted the researchers in fully exploring the potential of protective role of T cells in designing vaccines. Hence, our focus has been to dissect the developmental lineage, diversity, specificity and heterogeneity of peripheral CD4, CD8 and Double negative (DN) T cell memory subtypes by identifying their unique gene expression profile, epigenetic landscape and T Cell Receptor repertoire using multi-omics approaches. Our integrated multi-omics data analysis highlights the difference between gene-expression profiles and the regulatory patterns defining the gene-expression across the T cell memory subsets. Furthermore, through development of in vitro differentiation models, we have built capabilities to generate T cells of a specific desired characteristics that can be explored for cell therapies in a variety of diseases.

2.   Natural and hybrid immunity.

Using single-cell transcriptomics and TCR-repertoire analysis of over 150,000 rare antigen-specific memory T cells across some common viruses we have identified commonalities and differences between the CMV-, DENV-, Influenza-, and SARS-CoV2-specific memory T cells in humans. Further, the analysis of single-cell transcriptomic analysis of T cell memory subsets from patients recovered from different disease severity in COVID-19, identified T cell memory correlates of protection and susceptibility. Further, our data also emphasise how these individual with different disease outcome to natural infection, behaved after the vaccination. Overall, the knowledge base developed here can serve as a resource for vaccine designs as well as testing the vaccine efficacy. The common signatures also indicate a potential for common vaccine design for multiple viruses.

We continue to understand T cell subsets and their development and plasticity in various other diseases such as Tuberculosis, Lupus, Rheumatoid Arthritis and a variety of cancers, thus enabling us to investigate unique characteristics of a specific T cell subtype across diseases and health.

II. Immune response to infections

1.   Neonatal immune response to sepsis

With nearly 24% of global deaths due to severe infections, sepsis is one of the major contributors of neonatal deaths worldwide, especially those born pre-term. The treatments plans that heavily target the broad-spectrum pathogens have yielded limited success and have also contributed significantly to the Anti-Microbial Resistance (AMR) burden, especially in low- and middle-income countries. A lack of understanding about the overall immune response to sepsis in pre-term neonates has limited us in tackling the multifaceted disease like sepsis from immunological perspectives. Thus, through establishing a longitudinal cohort of pre-term neonates of culture positive sepsis with different disease outcomes, in comparison to no-sepsis or healthy controls, we examined the dynamic changes in immune cell profiles in an unbiased way using single-cell multi-omics. The knowledge base that will be a useful resource in not just understanding the immunobiology of neonatal sepsis but also treating the disease from immunological perspectives, thus controling AMR (Anti-Microbial Resistance), the much dredful silent pandemic. 

2.  Dynamic changes in Immune response to diseases and disorder

To understand dynamic changes in immune response in a variety of diseases such as Tuberculosis, Cancer and Lupus we have and are building longitudinal cohorts of adult human subjects through collaborations with clinicians across hospital in India. Through these studies we are generating an atlas of gene expression and immune repertoire patterns of immune cell at various stages of the disease across disease spectrum. The efforts will genearte knowledgebase that can be utilized in developing diagnostic and prognostic panel of markers, customised therapgy leading to precision medicine, and vaccine development.