High Profile Diseases - Tuberculosis

Deepak Kaushal (TNPRC, SNPRC)

Tuberculosis (TB) is an age-old disease of mankind. Despite the availability of chemotherapy for ~50 years and vaccination for more than a century, infections with Mycobacterium tuberculosis (Mtb) continue to result in ~10 million cases of TB every year, of which ~ 1.3 million people die (1). Similarly, the global TB situation is highly affected by AIDS, since Mtb/HIV co-infections often result in reactivation of clinically latent TB infection (LTBI) into clinically active TB (2). Therefore new drugs and vaccines are urgently needed to control this global epidemic. We also need to make advances in diagnostics.

A major hurdle to better understanding TB has been a lack of faithful experimental model systems (1, 2, 3), which can be leveraged to understand both bacterial and host determinants of disease progression, or protection from it. In the last few decades it has become clear that commonly used rodent studies are insufficient to recapitulate key aspects of Mtb infection and TB disease, including granulomatous pathology and LTBI. Thus, in response to Mtb infection, rodents do not form classical lung granulomas. Further, while 90% of humans are resistant to TB, 100% of rodents develop disease and fail to survive (3). In addition, there is ample experimental evidence to suggest that Mtb pathogenesis and the host response is faithfully reproduced in macaques. Thus, in a comparative assessment of a library of transposon mutants in Mtb, in both rhesus macaques and mice, as many as one-third of all mutants tested were required for virulence in macaques, while only 6-8% were necessary for virulence in mice. Furthermore, the Mtb Dos Rregulon has long been a mystery, since it is strongly induced in response to hypoxia in-vitro (a model of a Mtb granuloma) but exhibits no phenotype in-vivo in mice (4), even in ones where lesions do develop hypoxia (5). On the other hand, this mutant exhibits a profound growth defect phenotype in macaques (6). Lastly, a mutant in the key Mtb stress response regulator SigH (Δ-sigH) was able to grow to comparable levels as wild-type Mtb in mice (7), but was completely attenuated for survival in macaques (8). These studies along with others has elegantly elucidated the macaque model of TB and described its use in both understanding bacterial pathogenesis (6, 8, 9) as well as immunity to TB and vaccine development (10, 11, 12). These datahave also been used to suggest that studies of the pathogenesis of Mtb in mice are fundamentally flawed (13).

It is widely believed that the application of the macaque model to TB will be critical to ongoing efforts to develop effective drugs and vaccines against TB, which will be needed to stem the tide of this pandemic. This is particularly true when considering the interplay between HIV and Mtb in vivo, which can only be assessed in nonhuman primates.

Article References

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2. Mehra S, Golden NA, Dutta NK, Midkiff CC, Alvarez X, Doyle LA, Asher M, Russell-Lodrigue K, Monjure C, Roy CJ, Blanchard JL, Didier PJ, Veazey RS, Lackner AA, Kaushal D. Reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus. Journal of medical primatology. 2011;40(4):233-43. Epub 2011/07/26. doi: 10.1111/j.1600-0684.2011.00485.x. PubMed PMID: 21781131; PMCID: 3227019.

3. Kaushal D, Mehra S, Didier PJ, Lackner AA. The non-human primate model of tuberculosis. J Med Primatol. 2012;41(3):191-201. Epub 2012/03/21. doi: 10.1111/j.1600-0684.2012.00536.x. PubMed PMID: 22429048; PMCID: 3961469.

4. Rustad TR, Harrell MI, Liao R, Sherman DR. The enduring hypoxic response of Mycobacterium tuberculosis. PloS one. 2008;3(1):e1502. Epub 2008/01/31. doi: 10.1371/journal.pone.0001502. PubMed PMID: 18231589; PMCID: 2198943.

5. Gautam US, McGillivray A, Mehra S, Didier PJ, Midkiff CC, Kissee RS, Golden NA, Alvarez X, Niu T, Rengarajan J, Sherman DR, Kaushal D. DosS is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions. American journal of respiratory cell and molecular biology. 2014. doi: 10.1165/rcmb.2014-0230OC. PubMed PMID: 25322074.

6. Mehra S, Foreman TW, Didier PJ, Ahsan MH, Hudock TA, Kissee R, Golden NA, Gautam US, Johnson AM, Alvarez X, Russell-Lodrigue KE, Doyle LA, Roy CJ, Niu T, Blanchard JL, Khader SA, Lackner AA, Sherman DR, Kaushal D. The DosR Regulon Modulates Adaptive Immunity and is Essential for M. tuberculosis Persistence. Am J Respir Crit Care Med. 2015. doi: 10.1164/rccm.201408-1502OC. PubMed PMID: 25730547.

7. Kaushal D, Schroeder BG, Tyagi S, Yoshimatsu T, Scott C, Ko C, Carpenter L, Mehrotra J, Manabe YC, Fleischmann RD, Bishai WR. Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH. Proc Natl Acad Sci U S A. 2002;99(12):8330-5. PubMed PMID: 12060776.

8. Mehra S, Golden NA, Stuckey K, Didier PJ, Doyle LA, Russell-Lodrigue KE, Sugimoto C, Hasegawa A, Sivasubramani SK, Roy CJ, Alvarez X, Kuroda MJ, Blanchard JL, Lackner AA, Kaushal D. The Mycobacterium tuberculosis stress response factor SigH is required for bacterial burden as well as immunopathology in primate lungs. J Infect Dis. 2012;205(8):1203-13. Epub 2012/03/10. doi: 10.1093/infdis/jis102. PubMed PMID: 22402035; PMCID: 3308902.

9. Dutta NK, Mehra S, Didier PJ, Roy CJ, Doyle LA, Alvarez X, Ratterree M, Be NA, Lamichhane G, Jain SK, Lacey MR, Lackner AA, Kaushal D. Genetic requirements for the survival of tubercle bacilli in primates. J Infect Dis. 2010;201(11):1743-52. Epub 2010/04/17. doi: 10.1086/652497. PubMed PMID: 20394526; PMCID: 2862080.

10. Mehra S, Alvarez X, Didier PJ, Doyle LA, Blanchard JL, Lackner AA, Kaushal D. Granuloma correlates of protection against tuberculosis and mechanisms of immune modulation by Mycobacterium tuberculosis. The Journal of infectious diseases. 2013;207(7):1115-27. Epub 2012/12/21. doi: 10.1093/infdis/jis778. PubMed PMID: 23255564; PMCID: 3633457.

11. Martinez AN, Mehra S, Kaushal D. Role of interleukin 6 in innate immunity to Mycobacterium tuberculosis infection. The Journal of infectious diseases. 2013;207(8):1253-61. Epub 2013/01/30. doi: 10.1093/infdis/jit037. PubMed PMID: 23359591; PMCID: 3693587.

12. Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, Kaushal D, Reinhart TA, Randall TD, Khader SA. CXCR5⁺ T helper cells mediate protective immunity against tuberculosis. The Journal of clinical investigation. 2013;123(2):712-26. Epub 2013/01/03. doi: 10.1172/JCI65728. PubMed PMID: 23281399; PMCID: 3561804.

13. Kaufmann SH, Cole ST, Mizrahi V, Rubin E, Nathan C. Mycobacterium tuberculosis and the host response. The Journal of experimental medicine. 2005;201(11):1693-7. Epub 2005/06/09. doi: 10.1084/jem.20050842. PubMed PMID: 15939785; PMCID: 2213264.