Macrophage Expression Quantitative Trait Loci and Tuberculosis Pathogenesis

Despite continuous efforts to eradicate tuberculosis (TB), Mycobacterium tuberculosis (Mtb) is still the leading infectious agent worldwide. Most people heavily exposed to Mtb become infected and develop latent Mtb infection (LTBI). Importantly, Dr. Hong’s collaborators identified ~7% of individuals who are heavily and repeatedly exposed to Mtb resist developing LTBI (resister or “RSTR”) in a household contact (HHC) study in Uganda. However, clinical and epidemiological studies were not able to differentiate these clinical phenotypes (RSTR vs. LTBI). To discover genetic determinants of this resistance phenotype, Dr. Hong mapped expression quantitative trait loci (eQTLs) associated with gene expression in Mtb-infected, but not uninfected monocytes from the same patient cohort. This genetic approach revealed that 29 eQTLs were significantly associated with the expression of 16 genes in response to Mtb infection. Despite the discovery of Mtb-specific genetic signatures, the functional importance of these eQTLs and their target genes in macrophage responses to Mtb infection deserves to be further investigated. In the current proposal, the primary goal is to discover the global human genetic regulators (genes and variants) of Mtb-induced macrophage antimicrobial pathways. Dr. Hong hypothesizes that Mtb-dependent eQTL monocyte response genes (termed “Mtb eQTL gene”) and variants are global regulators of macrophage responses to Mtb and mediate critical proinflammatory and antimicrobial responses. Alternatively, these genes may be hijacked by Mtb to favor its survival. In Aim 1, she will determine the mechanisms of how Mtb eQTL genes regulate macrophage antimicrobial responses to Mtb and other pathogens. In Aim 2, she will determine the allele-specific antimicrobial macrophage mechanisms of Mtb eQTLs and their association with clinical outcomes. Significant findings from this project will enrich our understanding of how Mtb eQTL genes and variants modulate macrophage responses to Mtb, directing towards understanding why individuals have different susceptibility to Mtb infection and TB disease as well as whether these insights can lead to novel treatment or diagnostic strategies. Dr. Hong, Assistant Professor at the University of Pennsylvania School of Nursing (primary) and the Perelman School of Medicine (secondary), is a clinician scientist with a Ph.D. in TB research and epidemiology. Dr. Hong is seeking a K08 Mentored Clinical Scientist Research Career Development Award to acquire advanced training and mentorship for further studying the influence of genetic determinants on resistance and susceptibility to Mtb infection and TB disease. Since her research focus has shifted from clinical epidemiology to immunogenetics in TB, this K08 training award will provide her with the necessary protected time to fill the gaps in her research skills. By implementing the studies described in this proposal under the guidance of expert mentors, Dr. Hong will be well-positioned as an independent investigator, characterizing novel mechanisms of TB susceptibility with expertise in TB immunogenetics.