This application proposes the simple hypothesis that highly virulent clinical isolates of Mycobacterium tuberculosis, associated as they are with severe inflammation and lung damage, are far more likely as a result to induce regulatory T cell subsets compared to strains of relatively lower virulence. To test this hypothesis we have selected six clinically relevant isolates of an increasing range of virulence. We will use newly developed techniques to follow their emergence, influx, and positioning in the lungs of mice infected by a low dose aerosol with these isolates, use new processes to specifically ablate them, and perform cell transfer studies to directly examine their effects on TH1 immunity. Not only should these studies reveal some basic information regarding the conditions under which regulatory T cells are induced, but they have the potential to provide fundamental information relevant to issues such as the efficacy of new vaccines against clinical strains that acquire high levels of such T cells, and the status of subsequent immunity in individuals infected with highly virulent strains who have successfully been treated with chemotherapy. This then forms the basis of this R21 application. Is the induction of regulatory T cells restricted to this particular strain or is it a more general clinical phenomenon? If just a facet of HN878, is this due to its possession of an unusual cell wall lipid? Is it a specific property of the highly transmitted W-Beijing family? Do such cells directly inhibit effector T cells, or are they designed to reduce inflammation? Efforts are now underway to genomically sequence multiple clinical strains, and we hope to include these strains to be used here in a newly formed sequencing Consortium. As yet, nobody actually knows why certain strains of TB are """"""""virulent"""""""" and others less so, and it will require a combination of genomic information compared to basic biological information to try to uncover this. One aspect of virulence could be the ability of the organism to subvert immunity, as we hypothesize here.
We aim to determine the kinetics of generation of regulatory T cells in mice infected with a representative panel of clinical isolates of M.tuberculosis, in comparison to effector T cell subsets. We will also track and deplete regulatory T cells in GFP-Foxp3+ and transgenic mice, and further characterize their function in an innovative new adoptive cell transfer system.

Public Health Relevance

Over the past decade the number of isolates of M.tuberculosis that are multi-drug resistant has risen alarmingly. Many of these isolates are from the Beijing/W family which stand out due to the considerable morbidity and mortality they cause worldwide. The basis of this R21 proposal is to characterize if M.tuberculosis strains of extremely high virulence interacted differently with the innate and/or acquired specific host response compared to other strains.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI081959-02
Application #
8082635
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Parker, Tina M
Project Start
2010-06-15
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$218,295
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Henao-Tamayo, Marcela I; Obregón-Henao, Andres; Arnett, Kimberly et al. (2016) Effect of bacillus Calmette-Guérin vaccination on CD4+Foxp3+ T cells during acquired immune response to Mycobacterium tuberculosis infection. J Leukoc Biol 99:605-17
Bai, Xiyuan; Kinney, William H; Su, Wen-Lin et al. (2015) Caspase-3-independent apoptotic pathways contribute to interleukin-32?-mediated control of Mycobacterium tuberculosis infection in THP-1 cells. BMC Microbiol 15:39
Henao-Tamayo, Marcela; Obregón-Henao, Andrés; Creissen, Elizabeth et al. (2015) Differential Mycobacterium bovis BCG vaccine-derived efficacy in C3Heb/FeJ and C3H/HeOuJ mice exposed to a clinical strain of Mycobacterium tuberculosis. Clin Vaccine Immunol 22:91-8
Bai, Xiyuan; Shang, Shaobin; Henao-Tamayo, Marcela et al. (2015) Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:5111-6
Obregón-Henao, Andrés; Henao-Tamayo, Marcela; Orme, Ian M et al. (2013) Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium tuberculosis infection. PLoS One 8:e80669
Henao-Tamayo, Marcela; Obregón-Henao, Andrés; Ordway, Diane J et al. (2012) A mouse model of tuberculosis reinfection. Tuberculosis (Edinb) 92:211-7
Shang, Shaobin; Shanley, Crystal A; Caraway, Megan L et al. (2012) Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis. Vaccine 30:1572-82
Kato-Maeda, Midori; Shanley, Crystal A; Ackart, David et al. (2012) Beijing sublineages of Mycobacterium tuberculosis differ in pathogenicity in the guinea pig. Clin Vaccine Immunol 19:1227-37
Somashekar, Bagganahalli S; Amin, Anita G; Tripathi, Pratima et al. (2012) Metabolomic signatures in guinea pigs infected with epidemic-associated W-Beijing strains of Mycobacterium tuberculosis. J Proteome Res 11:4873-84
Walter, Nicholas D; Strong, Michael; Belknap, Robert et al. (2012) Translating basic science insight into public health action for multidrug- and extensively drug-resistant tuberculosis. Respirology 17:772-91

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