Tuberculosis (TB) is a major public health burden globally. After close contact with a person with pulmonary TB, most people become infected by inhaling aerosolized Mycobacterium tuberculosis (MTB). Most control this infection without eliminating it and develop latent MTB infection (LTBI) as measured by a positive tuberculin skin test (TST) and/or interferon-? release assay (IGRA). In a large TB household contact study in urban Uganda we were surprised to find that 9.1% of close adult household contacts (HHC) remained persistently TST negative during two years of follow-up. The persistently TST negative state suggests that some individuals may either resist and/or rapidly abort MTB infection. Characterization of immune responses in persons resisting MTB infection (RSTR) will enable identification of natural resistance mechanisms to MTB. The epidemiological risk profiles of RSTRs did not differ significantly from HHC who had or developed LTBI. Using microarrays and mRNA isolated from MTB-infected blood-derived monocytes, we identified transcriptional signatures that distinguish RSTR from persons with LTBI. Specifically, using Gene Set Enrichment Analysis and Linear Neural Network analysis, we found that the imatinib-ABL pathway and the COLEC10 gene may distinguishes RSTR from LTBI and thus are either directly involved in or markers of resistance to MTB infection. Using a genome-wide linkage study, we also discovered gene variants in innate immune pathways that distinguished RSTR from persons with LTBI. These result support the hypothesis for this ICIDR that RSTR have protective innate immune responses that are mediated by macrophages. This hypothesis will be tested in 3 aims.
Aim1. Determine the long-term stability of the RSTR phenotype and identify elite RSTRs. Determine whether whole blood MTB killing differentiates RSTRs from LTBI individuals.
Aim2. Determine the mechanism of how the candidate resistance genes ABL and COLEC10 regulate responses to MTB infection in macrophages from RSTR and LTBI individuals.
Aim3. Determine ABL and COLEC10 function and MTB-induced transcriptional signatures in alveolar macrophages that are associated with susceptibility or resistance to MTB infection and validate findings in a new cohort of RSTRs. To accomplish this ICIDR's aims we bring together a multidisciplinary and experienced team of long-term collaborating researchers at Makerere University (Mayanja, Mupere) in Kampala (Uganda), Univ. of Washington (Hawn, Seshadri) and Case Western Reserve University (Boom, Johnson, Stein). This ICIDR project will provide capacity building and training opportunities in clinical and laboratory TB research.
Understanding innate resistance to infection with Mycobacterium tuberculosis (MTB), the cause of human TB, will provide new insight into our understanding how MTB causes infection and disease, point to new approaches to TB vaccine and drug development, and identify markers of resistance to and/or clearance of MTB infection. This is particularly urgent in light of recent failures of a new TB vaccine in infants and drug therapy of adult miners with latent TB infection to prevent re-infection and development of TB.
|Simmons, Jason D; Stein, Catherine M; Seshadri, Chetan et al. (2018) Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection. Nat Rev Immunol 18:575-589|
|Stein, Catherine M; Zalwango, Sarah; Malone, LaShaunda L et al. (2018) Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda. Am J Epidemiol 187:1477-1489|
|Stein, Catherine M; Nsereko, Mary; Malone, LaShaunda L et al. (2018) Long-term stability of resistance to latent M. tuberculosis infection in highly exposed TB household contacts in Kampala, Uganda. Clin Infect Dis :|
|Stein, Catherine M; Sausville, Lindsay; Wejse, Christian et al. (2017) Genomics of human pulmonary tuberculosis: from genes to pathways. Curr Genet Med Rep 5:149-166|
|Seshadri, Chetan; Sedaghat, Nafiseh; Campo, Monica et al. (2017) Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection. PLoS One 12:e0175844|