Tariq Najar, PhD
PhD Molecular Biophysics, Indian Institute of Science, Bangalore, 2016
The major focus of my Ph.D. thesis work was to rationally design and stabilize the stem-fragment immunogens of HA from both group-1 and group-2 influenza A viruses, which mimic the native-HA stem conformation. To further improve upon these designed fragments in order to increase their immunogenicity and breadth of neutralizing activity against different strains of influenza viruses, I used a random mutagenesis library coupled to yeast surface display to isolate well folded, more native-like HA-stem immunogens using conformation specific bnAbs. These affinity-matured immunogens bound with very high affinity to various bnAbs. When tested in animal models, these immunogens were indeed able to protect mice against lethal virus challenge and elicited high titers of cross-reactive antibodies.
The second part of my Ph.D. thesis work was focused on developing a novel method to map antibody epitopes for the rational design of epitope specific vaccines and other antibody therapeutics. Using cysteine labeling and yeast surface display, I developed a simple, rapid and reliable method giving in-depth information about antigenic epitopes and protein:ligand binding sites down to single-residue level.
In the Littman lab, my principal focus is to study the mechanistic details of how diverse microbiota-regulated T cell responses influence tumor growth and checkpoint immunotherapy under different conditions. I will try to examine how commensal antigen-specific polarized T cell responses (Th17 versus Treg) influence the growth of transplanted and spontaneous tumors engineered to express either the microbial antigens, serum amyloid A proteins, or both. We will also investigate the effect of the commensal dependent responses on the efficacy of anti-CTLA-4 and anti-PD-1 checkpoint immunotherapy. Results from these experiments will provide insights into how microbiota can be manipulated to achieve improved outcomes in treating autoimmune diseases and in cancer therapy.
Publications:
1. Ng, C., Aichinger, M., Nguyen, T.*, Au, C.*, Najar, T., Wu,L., Mesa, K.R., Liao, W., Quivy, J.P., Hubert, B., Almouzni, G., Zuber, J., Littman, D.R. (2019). The histone chaperone CAF-1 cooperates with the DNA methyltransferases to maintain Cd4 silencing in cytotoxic T cells. Genes & Dev. 2019 Apr 11. doi: 10.1101/gad.322024.118. PMID: 30975723
2. Bommakanti, G., Citron, M.P., Hepler, R.W., Callahan, C., Heidecker, G.J., Najar, T.A., Lu, X., Joyce, J.G., Shiver, J.W., Casimiro, D.R., et al. (2010). Design of an HA2-based Escherichia coli expressed influenza immunogen that protects mice from pathogenic challenge. PNAS 107, 13701-13706.
3. Bommakanti, G., Lu, X., Citron, M.P., Najar, T.A., Heidecker, G.J., ter Meulen, J., Varadarajan, R., and Liang, X. (2012). Design of Escherichia coli-expressed stalk domain immunogens of H1N1 hemagglutinin that protect mice from lethal challenge. J. Virology 86, 13434-13444.
4. Najar, T.A., Varadarajan R. An affinity matured “Headless” HA-stem fragment binds broadly neutralizing antibodies with very high affinity (Manuscript under revision).
5. Najar, T.A., Khare, S., Pandey, R., Gupta, S.K., Varadarajan, R. (2017). Mapping protein binding sites and conformational epitopes using cysteine labeling and yeast surface display Structure 25(3) : 395-406.
6. Najar, T.A., Khare, S., Varadarajan, R. (2018). Mapping protein binding sites and conformational epitopes using cysteine labeling and yeast surface display (Methods in Molecular Biology, Vol. 1785, in press).
7. Najar, T.A., Das, M., Asok, A., Varadarajan. R. Determination of ΔG of folding using CcdA-CcdB as a model system. (Manuscript in preparation).