I am inspired by an interest in the translational application of research, accompanied by a broad curiosity for science that is fundamental yet cross-disciplinary in nature. My research interests took shape during my graduate studies on Mycobacterium tuberculosis (Mtb). Under the guidance of Dr. Carl Nathan, I studied the endogenous checkpoints employed by Mtb that modulate the host immune response to be sub-optimal in clearing infection.
As a postdoctoral scholar in Dr. David Schneider's lab, I’m attempting to address a question relevant for all infection systems: how has the body evolved to induce an immune response in response to infections? In particular, I’m studying the antimicrobial response using Drosophila as a model system. I'm interested in understanding how we can define an optimal immune response that is overall beneficial and least damaging for the host. At the Schneider lab, our overarching goal is to find ways to limit the impact of infections, by improving disease-tolerance as well as recovery.
Boards, Advisory Committees, Professional Organizations
Member, The New York Academy of Sciences (2007 - Present)
Member, Bengal Tuberculosis Association, India (2006 - Present)
Doctor of Philosophy, Cornell University (2013)
MSc, Calcutta University, India (2007)
David Schneider, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
Host-pathogen interactions, infectious diseases, protective immune responses, disease-tolerance, recovery
Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (49): E4790-E4797
Mycobacterium tuberculosis (Mtb) restrains immune responses well enough to escape eradication but elicits enough immunopathology to ensure its transmission. Here we provide evidence that this host-pathogen relationship is regulated in part by a cytosolic, membrane-associated protein with a unique structural fold, encoded by the Mtb gene rv0431. The protein acts by regulating the quantity of Mtb-derived membrane vesicles bearing Toll-like receptor 2 ligands, including the lipoproteins LpqH and SodC. We propose that rv0431 be named "vesiculogenesis and immune response regulator."
View details for DOI 10.1073/pnas.1320118110
View details for Web of Science ID 000327744900011
View details for PubMedID 24248369
Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (40): 16004-16011
Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb's replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB's 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb's replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.
View details for DOI 10.1073/pnas.1214188109
View details for Web of Science ID 000309611400020
View details for PubMedID 23012453
Virulence of Mycobacterium tuberculosis Depends on Lipoamide Dehydrogenase, a Member of Three Multienzyme Complexes
CELL HOST & MICROBE
2011; 9 (1): 21-31
Mycobacterium tuberculosis (Mtb) adapts to persist in a nutritionally limited macrophage compartment. Lipoamide dehydrogenase (Lpd), the third enzyme (E3) in Mtb's pyruvate dehydrogenase complex (PDH), also serves as E1 of peroxynitrite reductase/peroxidase (PNR/P), which helps Mtb resist host-reactive nitrogen intermediates. In contrast to Mtb lacking dihydrolipoamide acyltransferase (DlaT), the E2 of PDH and PNR/P, Lpd-deficient Mtb is severely attenuated in wild-type and immunodeficient mice. This suggests that Lpd has a function that DlaT does not share. When DlaT is absent, Mtb upregulates an Lpd-dependent branched-chain keto acid dehydrogenase (BCKADH) encoded by pdhA, pdhB, pdhC, and lpdC. Without Lpd, Mtb cannot metabolize branched-chain amino acids and potentially toxic branched-chain intermediates accumulate. Mtb deficient in both DlaT and PdhC phenocopies Lpd-deficient Mtb. Thus, Mtb critically requires BCKADH along with PDH and PNR/P for pathogenesis. These findings position Lpd as a potential target for anti-infectives against Mtb.
View details for DOI 10.1016/j.chom.2010.12.004
View details for Web of Science ID 000287344500005
View details for PubMedID 21238944
Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity
2010; 5 (12)
In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain.
View details for DOI 10.1371/journal.pone.0015120
View details for Web of Science ID 000285181400016
View details for PubMedID 21170273
Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils
2009; 10 (8): 889-U121
Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells express together with IgM through alternative RNA splicing. Here we report active T cell-dependent and T cell-independent IgM-to-IgD class switching in B cells of the human upper respiratory mucosa. This process required activation-induced cytidine deaminase (AID) and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell-stimulating factors, including cathelicidin, interleukin 1 (IL-1), IL-4 and B cell-activating factor (BAFF), after IgD crosslinking. By showing dysregulation of IgD class-switched B cells and 'IgD-armed' basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.
View details for DOI 10.1038/ni.1748
View details for Web of Science ID 000268141400019
View details for PubMedID 19561614