Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global infectious disease emergency. Each year an estimated 8 million people develop, and about two million people die of TB. Synergy with AIDS, the emergence of drug-resistance and the lack of effective anti-TB drugs and vaccines has worsened this situation. New drugs and vaccines are urgently needed to effectively control TB. This requires a better understanding of how Mtb adapts to a wide-variety of environmental conditions, inevitably faced by it during the various stages of infection. Nonhuman Primates (NHPs), arguably, best model critical aspects of TB. Analysis of the mechanisms employed by Mtb to successfully infect and persist in NHP lungs would therefore be very useful. We studied genes essential for growth/survival of Mtb in the NHP lungs experimentally exposed to high doses of aerosols of an Mtb transposon mutant library. In this acute model of TB, 33.13% of all tested mutants were attenuated for in-vivo growth compared to the mouse model where only ~6% of all mutants are attenuated. The Mtb mutants attenuated for in-vivo survival in primates were involved in the transport of lipid virulence factors;biosynthesis of cell-wall arabinan and peptidoglycan, fatty-acids and polyketides;DNA repair;sterol metabolism and mammalian cell-entry (mce). Our study highlights the various virulence-mechanisms employed by Mtb for infection and to overcome the hostile environment encountered during infection of NHP lungs. We would like to leverage our ability to model the various clinical phases of human TB - acute, pulmonary TB, chronic-progressive TB and latent, asymptomatic TB in NHPs - to study the growth/survival phenotype profiles of Mtb mutants. Further, we would like to better understand the role of two Mtb pathways crucial for virulence and pathogenesis, using the NHP model. These include the mce1/mce4 operons, whose members were among mutants that were attenuated for growth in NHP lungs;and members of the dos regulon, which were surprisingly not attenuated in NHP lungs, in-spite of their well-defined roles in latency, persistence and defense against hypoxia.

Public Health Relevance

Tuberculosis (TB) is a global emergency, responsible for the death of an estimated 2 million people annually. Monkeys, due to their genetic and physiological similarities to humans, are a very good animal system to model TB. Out of the several hundreds of genes present in the chromosome of the tubercle bacillus, we have determined which ones are needed to establish a successful infection in the lungs of monkeys. These results will be compared to those obtained from animals with TB/AIDS co-infection. Genes from the mce (mammalian cell entry) family were among those which were attenuated in the NHP lungs. We will perform functional studies using Mycobacterium tuberculosis (Mtb) and defined mutants in mce genes, using our monkey model, to better understand their role in disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089323-04
Application #
8473655
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Lacourciere, Karen A
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$730,427
Indirect Cost
$287,744
Name
Tulane University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Foreman, Taylor W; Mehra, Smriti; LoBato, Denae N et al. (2016) CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection. Proc Natl Acad Sci U S A 113:E5636-44
Kaushal, Deepak; Foreman, Taylor W; Gautam, Uma S et al. (2015) Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis. Nat Commun 6:8533
Phillips, Bonnie L; Mehra, Smriti; Ahsan, Muhammad H et al. (2015) LAG3 expression in active Mycobacterium tuberculosis infections. Am J Pathol 185:820-33
Gautam, Uma S; McGillivray, Amanda; Mehra, Smriti et al. (2015) DosS Is required for the complete virulence of mycobacterium tuberculosis in mice with classical granulomatous lesions. Am J Respir Cell Mol Biol 52:708-16
McGillivray, Amanda; Golden, Nadia A; Kaushal, Deepak (2015) The Mycobacterium tuberculosis Clp gene regulator is required for in vitro reactivation from hypoxia-induced dormancy. J Biol Chem 290:2351-67
Mothé, Bianca R; Lindestam Arlehamn, Cecilia S; Dow, Courtney et al. (2015) The TB-specific CD4(+) T cell immune repertoire in both cynomolgus and rhesus macaques largely overlap with humans. Tuberculosis (Edinb) 95:722-35
Gautam, Uma Shankar; Mehra, Smriti; Kaushal, Deepak (2015) In-Vivo Gene Signatures of Mycobacterium tuberculosis in C3HeB/FeJ Mice. PLoS One 10:e0135208
Mehra, Smriti; Foreman, Taylor W; Didier, Peter J et al. (2015) The DosR Regulon Modulates Adaptive Immunity and Is Essential for Mycobacterium tuberculosis Persistence. Am J Respir Crit Care Med 191:1185-96
Dutta, Noton K; McLachlan, James; Mehra, Smriti et al. (2014) Humoral and lung immune responses to Mycobacterium tuberculosis infection in a primate model of protection (.) Trials Vaccinol 3:47-51
Gautam, Uma S; Mehra, Smriti; Ahsan, Muhammad H et al. (2014) Role of TNF in the altered interaction of dormant Mycobacterium tuberculosis with host macrophages. PLoS One 9:e95220

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