Host-pathogen interactions
Investigating host-pathogen interactions across various scales is imperative because it provides a comprehensive understanding of how infectious agents interact with hosts, from molecular mechanisms to organism-level responses and spread and evolution of pathogens in the population. This multi-scale perspective is crucial for identifying the dynamic processes that underlie infection, immune evasion, and disease progression. By studying these interactions at different levels, from the intricate dance of proteins and genes to the systemic impact on host physiology, we can uncover novel targets for therapeutic intervention, design more effective treatments, and ultimately, devise strategies to prevent infection.
Virus Metagenomics and Immune Response to Infections
Molecular heterogeneity is a key hallmark of the RNA viruses due to their high mutation rates. Therefore, RNA viruses like Dengue propagate as a quasispecies of closely related genotypes in the host. This helps the virus in rapid adaptation, acquiring drug resistance and enabling their immune escape. Sequence diversity and virulence of a viral species is regulated by the host selection pressures at different levels of its life cycle. Since imaging cannot capture the large number of variants, we focus on adapting next generation sequencing (NGS) to accurately quantify variants of genomic RNA (or gene) and probe the population level distributions.
Unfortunately, full genome data on Dengue viral strains prevalent in India and world-wide has been limited. As part of a multi-center team spanning several research institutions and hospitals across India working on epidemiology of Dengue, we established expertise in viral genomics and data analysis. By focusing our sequencing pipeline on recovery efficiency and small sample volume, we could sequence prevalent Dengue virus strains directly from stored serum samples from prior years (Kar, et al. IJID 2018). This led to the development of first indigenious DNA vaccine against Dengue virus tailored for the Indian sub-continent (Sankaradoss et al. Mol Therapy 2022). Through a comprehensive analysis of the Dengue virus sequences propagating in the country, we were able to demonstrate that immune selection pressure was a major driver of the dengue evolution in India (Jagtap et al. PLoS Pathogens 2023).
This study is being extended to characterize Dengue strains from multiple centers across India to understand the evolutionary dynamics of Dengue virus over the last decade. In parallel, working in collaboration with Prof. Narendra Dixit (ChemE, IISc), we are developing mathematical models of immune response dynamics that can help us connect experimental observations and develop quantitative understanding of underlying immunological phenomena in response to viral infections. For example, recently we showed how the level of T-cell exhaustion in persistent infection can determine the outcome of antiviral therapy in Hepatitis C viral infection (Baral, et al. Immun. & Cell Biol. 2018 ).
M Kar, A Nisheetha, A Kumar, S Jagtap, J Shinde, M Singla, S Marimuthu, A Pandit, A Chandele, SK Kabra, S Krishna, R Roy, R Lodha, C Pattabiraman, G Medegeshi, "Isolation and molecular characterization of Dengue virus clinical isolates from pediatric patients in New Delhi" International J of Infectious Diseases, pii:S1201-9712(18)34953-1 doi:10.1016/j.ijid.2018.12.003 (2018)
A Sankaraoss, et al., "Immune profile and responses of a novel Dengue DNA vaccine encoding EDIII-NS1 consensus design based on Indo-African sequences" Molecular Therapy, https://doi.org/10.1016/j.ymthe.2022.01.013 (2022)
S Jagtap, et al. "Evolutionary dynamics of dengue virus in India" PLoS Pathogens 19(4): e1010862. https://doi.org/10.1371/journal.ppat.1010862 (2023)
S Baral, R Roy, NM Dixit, “Modelling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct-acting antiviral agents” Immunology & Cell Biology, 96(9), 969-980, doi:10.1111/imcb.12161 (2018)
Contributors
Subhasish Baral
