Mycobacterium tuberculosis (Mtb) causes more adult deaths worldwide than any other bacterium, and many strains are resistant to all first-line drugs. These properties contribute to the potential of Mtb as a major public health problem, as well as a potential agent of bioterrorism. In order to develop more effective means of prevention and control of tuberculosis, it is essential to better understand the mechanisms of protective immunity to Mtb. We have used a murine model to discover an essential role for type I interferons (IFNalphabeta) in control of virulent Mtb in vivo. We found that IFNlphabeta contributes to control of Mtb infection, revealed in mice that cannot respond to IFNalphabeta or to IFNgamma: STAT1-/- and IFNalphabetagammaR-/- mice exhibit a more rapid progression of infection and higher bacterial loads than IFNgammaR-/- mice. Moreover, we found that IFNalphabeta and IFNalphabeta-responsive genes are induced by infection with Mtb in vivo. We propose to test three (nonmutually exclusive) hypotheses of the roles of IFNalphabeta in control of Mtb. First, we will characterize the microbiologic and pathologic course of Mtb infection in mice that lack the ability to respond to IFNalphabeta, IFNgamma, or both, compared to wild-type mice. We will then test the hypothesis that IFNaa contributes to control of Mtb by regulating the same genes, or a subset of genes, regulated by IFNgamma, using microarray and real-time RT-PCR of RNA from lungs of specific mutant mice. Next, we will test the hypothesis that IFNaa regulates priming, differentiation, and trafficking ofCD4+and CD8+ T lymphocytes during Mtb infection. If this indicates that IFNaa promotes the development of the adaptive immune response to Mtb, we will determine whether IFNalphabeta acts indirectly by promoting the maturation and/or trafficking of dendritic cells. Finally, we will test the hypothesis that IFNalphabeta contributes to control of Mtb through natural killer (NK) cells, by characterizing the rate and extent of development, differentiation, and trafficking of NK cells in Mtb-infected mutant mice. If this implies that IFNalphabeta regulates NK cells during Mtb infection, we will determine whether Mtb infection of macrophages induces expression of ligands for stimulatory NK cell receptors. The proposed experiments will provide improved understanding of innate and adaptive immunity to Mtb, and may guide development of new means of prevention and treatment of tuberculosis, including drug-resistant tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BM-1 (02))
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Jacobs, Gail G
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Wiens, Kirsten E; Ernst, Joel D (2016) The Mechanism for Type I Interferon Induction by Mycobacterium tuberculosis is Bacterial Strain-Dependent. PLoS Pathog 12:e1005809
Wiens, Kirsten E; Ernst, Joel D (2016) Type I Interferon is Pathogenic During Chronic Mycobacterium africanum Infection. J Infect Dis 214:1893-1896
Desvignes, Ludovic; Weidinger, Carl; Shaw, Patrick et al. (2015) STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. J Clin Invest 125:2347-62
Desvignes, Ludovic; Wolf, Andrea J; Ernst, Joel D (2012) Dynamic roles of type I and type II IFNs in early infection with Mycobacterium tuberculosis. J Immunol 188:6205-15
Desvignes, Ludovic; Ernst, Joel D (2009) Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis. Immunity 31:974-85
Ernst, Joel D; Lewinsohn, David M; Behar, Samuel et al. (2008) Meeting Report: NIH Workshop on the Tuberculosis Immune Epitope Database. Tuberculosis (Edinb) 88:366-70
Kincaid, Eleanor Z; Wolf, Andrea J; Desvignes, Ludovic et al. (2007) Codominance of TLR2-dependent and TLR2-independent modulation of MHC class II in Mycobacterium tuberculosis infection in vivo. J Immunol 179:3187-95
Ernst, Joel D; Trevejo-Nunez, Giraldina; Banaiee, Niaz (2007) Genomics and the evolution, pathogenesis, and diagnosis of tuberculosis. J Clin Invest 117:1738-45