Genotyping of Mycobacterium tuberculosis has shown that specific geographic regions are dominated by genetically distinct genotypes of Mycobacterium tuberculosis. This global distribution of strains, such as that seen with the Beijing family, may not be random or solely based upon virulence, socioeconomics, or geography but may be partly determined by the genetics of the host and the microbe, both of which are under environmental and natural selection forces. In this proposal, we hypothesize that such forces have played a role in the co-evolution of host and microbe, such that ethnic-specific susceptibility and resistance exists for particular strains of M. tuberculosis. This interplay between the strain and the ethnic background of the host is plausible, given that susceptibility to and outcome of infection with M. tuberculosis appears to vary with ethnic background and that a strong association between specific ethnic backgrounds and specific strains has been noted in urban settings outside of the host's native country. In the research proposed herein, we will measure and compare the cytokine repertoire produced by cells from subjects of different ethnicities in response to lysates of different strains of M. tuberculosis to determine the ability of various strains of M. tuberculosis to evade protective innate and adaptive immune mechanisms - possibly by selective induction of anti-inflammatory cytokines. We plan to accomplish this by evaluating the immune response of healthy human donor macrophages to a Beijing strain (HN878), a Manila strain (T31), a clinical strain isolated in the US (CDC1551), and a laboratory reference strain (H37Rv), as well as by evaluating the effect of these same strains in an integrative, whole blood assay. We will stratify the donors by ethnicity, looking for the presence of ethnic-specific immunogenetic predisposition to distinct strains of M. tuberculosis. This research aims to establish whether the genetically diverse strains of M. tuberculosis induce different innate and adaptive responses amongst and between select ethnicities, and thus pave the way for tailoring vaccines to specific populations. I have assembled a mentoring committee of internationally recognized scientists with strong track records in the study of tuberculosis, particularly in molecular genotyping (Dr. Philip Hopewell - primary mentor) and immunology (Dr. David Lewinsohn) of M. tuberculosis, and in admixture analysis (Dr. Neil Risch) and epidemiology (Drs. Dennis Osmond and Neil Risch). Together, these senior investigators represent the diversity of fields that are essential for my training and proposed research study.