Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global infectious disease emergency. A major hurdle in combating TB is the fact Mtb is able to persist for long periods of time in host tissues, in a quiescent state. These bacilli are able to reactivate and cause pulmonary TB, when the immune system is compromised. Hence, a complete understanding of TB latency and reactivation is required for the effective control of TB. The research models and tools necessary to perform these studies are now available. Nonhuman Primates (NHPs) are excellent models of TB, especially to study the progression of experimental infection to latency, and to study the pathology and biology of granulomatous lesions - the hallmarks of TB infections. We have established a model of human TB, by exposing NHPs to true Mtb aerosols. While many research groups focus on the bacterial factors of latency and reactivation, we would like to leverage our highly tractable model to identify host signatures and mediators of this process. We show that pro-inflammatory immune signaling pathways, initially induced in NHP TB lesions, are overwhelmingly silenced over the course of next several weeks. This transcriptional reprogramming could be a host response to changes in bacterial replication and physiology. Further, these responses could reflect the efforts of the pathogen to prevent excessive immunopathology during the infection of lungs. The central hypothesis of our proposal is that host granuloma responses can be used to predict latent and reactivation TB. We propose to perform a systematic study of the "transcriptome" and the "miRNAome" of NHP lung lesions. Temporal profiles will be obtained from NHPs infected with a low-dose of Mtb aerosols, accurately modeling long-term latent infection. Profiles will also be obtained from NHPs in which latent TB is reactivated by simian AIDS. These system-wide profiles, in conjugation with the clinical, microbiological and immunological data obtained from infected NHPs will generate statistical learning algorithms and mixed effects computational models of latent and reactivation TB. The relevance of some of the most informative set of genetic predictors available from the data collected will be tested back in both the NHP model, as well as in human patients. The expression profiles of CCL24, CCL25 and CCL27 show negative correlation with all other chemokine ligands and receptors in primate TB granulomas. The expression of these three chemokines is significantly increased in late, rather than early lesions. We hypothesize that these chemokines are important for the long-term maintenance of primate lesions harboring latent Mtb bacilli. The expression of LAG3 was induced more than 40-fold in early primate lesions relative to late ones. LAG3 is a novel marker of Treg cells. We hypothesize that LAG3 is responsible for negatively regulating protective immune responses generated by effector T cells in primate TB lesions. The expression of "latency" specific genes CCL24/25/27 and the "active-TB: specific gene LAG3 will be silenced in NHPs using a novel lipidated-siRNA nanoparticle based approach. The progression of latent disease and its immunological and molecular correlates will then be studied in these animals. Finally, the expression of an immune response to these and other "latency" and "reactivation"- specific profiles will be determined in human patients of latent and active TB, as well as TB/AIDS co- infected patients. These systems-biology studies will likely exponentially enhance our understanding of TB latency and reactivation in a host that mimics both TB and AIDS in the closest possible manner to humans. Eventually, these advances may empower clinicians better to detect and treat latent TB.

Public Health Relevance

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global infectious disease emergency. A major hurdle in combating TB is the fact Mtb is able to persist for long periods of time in host tissues, reactivating when the immune system is compromised. Hence, effective and long-term control of TB requires a better understanding of TB latency and reactivation. Nonhuman Primates (NHPs) are excellent models of TB. We have recently established a model of human TB, by exposing NHPs to Mtb aerosols. Pro-inflammatory immune signaling pathways are initially induced in NHP TB lesions, but silence over the course of several weeks. This could be a response to the progression of Mtb to a latent phase of growth within these NHP granulomas. We will employ a systems biology approach to study the host granulomatous response to Mtb latency and reactivation, using our NHP model. Towards this, we have assembled a highly diverse and collaborative team including microbiologists, aerobiologists, bioinformaticians, mathematicians/statisticians, veterinarians, veterinary pathologists, as well as infectious disease and critical respiratory care clinicians/clinician-researchers.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-Z (S1))
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Peavy, Hannah H
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Tulane University
Schools of Medicine
New Orleans
United States
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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
Levine, David M; Dutta, Noton K; Eckels, Josh et al. (2015) A tuberculosis ontology for host systems biology. Tuberculosis (Edinb) 95:570-4
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
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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