Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and the World Health Organization estimates that in 2012 there were 8.6 million new cases and more than one million deaths. Mtb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. One way in which it does this is by impairing key cellular functions of macrophages and dendritic cells (DCs), undermining degradation of the bacilli and presentation of antigens to T cells. Antigen presentation is critical both for priming nave T cells and for recognition of infected macrophages by effector T cells. Thus, by inhibiting antigen presentation, Mtb prevents effective clearance and promotes persistent infection. Despite its clear importance in Mtb pathogenesis and implications for vaccine development, we lack a comprehensive understanding of how Mtb inhibits antigen presentation. Our group recently found that to promote its intracellular survival, Mtb secretes EsxH, which inhibits the endosomal sorting complex required for transport (ESCRT), a cellular machinery of the host involved in protein trafficking. We hypothesize that by targeting ESCRT, EsxH also impairs MHC-II antigen presentation. Consistent with this idea, my preliminary data demonstrates that ESCRT is required for Mtb-infected macrophages to activate effector CD4+ T cells. Correspondingly, macrophages infected with an Mtb strain lacking EsxH elicited better activation of CD4+ T cells than macrophages infected with wild type Mtb, whereas overexpression of EsxH impairs T cell activation. In this application, I seek to extend these preliminary studies.
My aims are to: 1) to define the mechanism by which EsxH and ESCRT modulate antigen presentation in both macrophages and DCs, and 2) to determine their contribution to T cell evasion in vivo. These studies will significantly augment our understanding of the mechanisms employed by Mtb to evade the immune response. Our findings may provide an explanation for the delay in the initiation of an adaptive immune response seen during Mtb infection. In addition, our studies may provide a molecular explanation for how Mtb prevents effector CD4+ T cells from directly recognizing infected cells. Thus, targeting this host-pathogen interaction might promote host clearance of Mtb by restoring macrophage function and T cell activation.

Public Health Relevance

Tuberculosis (TB) is a disease that kills more than one million people every year, and the World Health Organization estimates that one third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the bacteria that cause this disease. We aim to understand how Mtb prevents efficient recognition by CD4+ T cells to elucidate mechanisms employed by the pathogen to establish a persistent infection. Our findings will ultimately enable the development of novel therapies to improve TB treatment and change the face of the global epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI119150-03
Application #
9282608
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID-B)
Program Officer
Eichelberg, Katrin
Project Start
2015-06-15
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$201,420
Indirect Cost
$14,920
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Köster, Stefan; Klevorn, Thais; Papavinasasundaram, Kadamba et al. (2018) Consequence of enhanced LC3-trafficking for a live, attenuated M. tuberculosis vaccine. Vaccine 36:939-944
Portal-Celhay, Cynthia; Tufariello, JoAnn M; Srivastava, Smita et al. (2016) Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation. Nat Microbiol 2:16232
Tinaztepe, Emir; Wei, Jun-Rong; Raynowska, Jenelle et al. (2016) Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis. Infect Immun 84:2255-2263