
High Profile Diseases - Tuberculosis
“High Profile Diseases” are written by individual NPRC Core Scientists who are experts in the specific subject of each article. Before publication on the website, each article is reviewed by representatives of all seven NPRCs.
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
1. Raviglione MC. The new Stop TB Strategy and the Global Plan to Stop TB, 2006-2015. Bull World Health Organ. 2007;85(5):327. Epub 2007/07/20. PubMed PMID: 17639210; PMCID: 2636638.
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.
Recent NPRC Publications
2020
Ahmed M, Thirunavukkarasu S, Rosa BA, Thomas KA, Das S, Rangel-Moreno J, Lu L, Mehra S, Mbandi SK, Thackray LB, Diamond MS, Murphy KM, Means T, Martin J, Kaushal D, Scriba TJ, Mitreva M, Khader SA
Immune correlates of tuberculosis disease and risk translate across species.
Sci Transl Med. 2020 Jan 29;12(528). pii: 12/528/eaay0233. doi:10.1126/scitranslmed.aay0233. 2020.
Collins JM, Siddiqa A, Jones DP, Liu K, Kempker RR, Nizam A, Shah NS, Ismail N, Ouma SG, Tukvadze N, Li S, Day CL, Rengarajan J, Brust JC, Gandhi NR, Ernst JD, Blumberg HM, Ziegler TR
Tryptophan catabolism reflects disease activity in human tuberculosis.
JCI Insight. 2020 May 21;5(10). pii: 137131. doi: 10.1172/jci.insight.137131. 2020.
Dupont M, Souriant S, Balboa L, Vu Manh TP, Pingris K, Rousset S, Cougoule C, Rombouts Y, Poincloux R, Ben Neji M, Allers C, Kaushal D, Kuroda MJ, Benet S, Martinez-Picado J, Izquierdo-Useros N, Sasiain MDC, Maridonneau-Parini I, Neyrolles O, Verollet C, Lugo-Villarino G
Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages.
Elife. 2020 Mar 30;9. pii: 52535. doi: 10.7554/eLife.52535. 2020.
Ganatra SR, Bucsan AN, Alvarez X, Kumar S, Chatterjee A, Quezada M, Fish AI, Singh DK, Singh B, Sharan R, Lee TH, Shanmugasundaram U, Velu V, Khader SA, Mehra S, Rengarajan J, Kaushal D
Anti-retroviral therapy does not reduce tuberculosis reactivation in atuberculosis-HIV co-infection model.
J Clin Invest. 2020 Jun 16. pii: 136502. doi: 10.1172/JCI136502. 2020.
Scott NR, Swanson RV, Al-Hammadi N, Domingo-Gonzalez R, Rangel-Moreno J, Kriel BA, Bucsan AN, Das S, Ahmed M, Mehra S, Treerat P, Cruz-Lagunas A, Jimenez-Alvarez L, Munoz-Torrico M, Bobadilla-Lozoya K, Vogl T, Walzl G, du Plessis N, Kaushal D, Scriba T, Zuniga J, Khader S
S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronictuberculosis.
J Clin Invest. 2020 Mar 5. pii: 130546. doi: 10.1172/JCI130546. 2020.
Recent News Articles and Reference Materials
June 28, 2020
Emory Researchers Find T Cell Responses Key for Controlling Asymptomatic TB
December 19, 2019
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New Animal Model Shows Effective Treatment for Latent Tuberculosis
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June 25, 2019
Texas Biomed develops fast, cheap TB test for developing countries
May 30, 2019
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San Antonio researchers developing new, more promising tuberculosis vaccine
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Shelby O’Connor Part of $6m International Grant to Study HIV/TB Coinfection
April 30, 2019
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One study is using young macaques to hopefully carve a path to eradicate infectious diseases like tuberculosis.
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Texas Biomed Scientists Developing New Vaccine Strategy for Tuberculosis
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TX BioBytes from Texas Biomed Episode 029 — Out of Africa: Teaming up to Develop a New TB Test
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Varun Dwivedi on the Urgent Need for a New TB Vaccine
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Dr Eusondia Arnett on Apoptosis in M Tuberculosis Infection
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Developing a Vaccine for HIV-TB Co-Infection
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New Macaque Model to Study Pathology of TB in AIDS Patients
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Inexpensive TB Test Holds Promise for Low-Income Countries
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$2 Tuberculosis Test May Save Thousands of Lives
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Repurposing Promising Cancer Drugs May Lead to a New Approach to Treating TB
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TB or not TB – TXBioBytes Episode 001
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KLRN-TV Features Texas Biomed TB Research Team
December 19. 2017
Tulane researchers find therapy that may better treat tuberculosis
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In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis
October 19, 2017
Researcher on TB and the Intersection of Aging and Immune Function Joins Texas Biomed as Vice President for Research
September 25, 2017
Texas Biomed Adds Tuberculosis Researcher Dr. Jordi B. Torrelles to Institute’s Scientific Team
August 21, 2017
Texas Biomed part of team receiving five-year, $4.4 million NIH grant for novel TB vaccine testing
October 16, 2016
Experimental Aerosol TB Vaccine Protects Monkeys, NIH-Funded Researchers Find
September 13, 2016
TNPRC investigations into Tuberculosis and HIV co-infection
September 6, 2016
Other layers of immunity in TB/HIV co-infections discovered
September 6, 2016
Tulane researchers find other layers of immunity in TB/HIV co-infections
December 7, 2015
OHSU Doernbecher awarded $3 million to advance tuberculosis vaccine research
November 13, 2015
Study offers new recommendations for TB vaccine testing in humans
October 20, 2015
Tulane researchers have new TB vaccine in development
October 15, 2015
Tulane Researchers Working on New Tuberculosis Vaccine
October 14, 2015
Tulane researchers developing new tuberculosis vaccine
October 13, 2015
Researchers working on new tuberculosis vaccine
October 13, 2015
Tulane researchers working on new tuberculosis vaccine
April 2, 2015
UW Researchers Look for Best Way to Diagnose Tuberculosis
March 17, 2015
TB's ability to evade immune system becomes clearer in large study
March 12, 2015
Washington Finds Swab Test Holds Promise for Detecting Tuberculosis
February 25, 2015
Drug-resistant TB may be treatable with new small molecule drug
February 23, 2015
NIAID Tuberculosis Research Grant
February 19, 2015
NIH selects Emory-led partnership as one of four TB Research Units, with seven-year $18.7M grant
Febrary 6, 2015
'The Forgotten Plague' Review: How TB Changed America
December 15, 2014
UGA, Emory collaborate to leverage strengths in infectious disease research
June 21, 2012
From the mouths of monkeys: Swab technique spots tuberculosis in non-human primates
CDC Resource Page: Tuberculosis (TB)
Tuberculosis: Strategy Overview