Mycobacterium tuberculosis (Mtb) infects about one third of the world's population, killing ~1.3 million individuals worldwide every year. Although, te majority of infected persons are asymptomatically infected, latent tuberculosis (LTBI) can reactivate into pulmonary tuberculosis (PTB). A clear understanding of immune correlates associated with risk of disease progression and inflammation during TB is necessary for design of new immunotherapies and treatments to promote control of Mtb. Animal models such as the inbred mouse model of TB are commonly used to study mechanisms of immunity or inflammation in TB. However, disease outcomes seen in inbred mouse models do not reflect the heterogeneity seen in human TB. Thus, we established a mouse model of TB in diversity outbred (DO) mice that demonstrate considerable heterogeneity in disease severity following Mtb infection. In addition, non-human primate (NHP) animal model of TB is a pre-clinical model for studying TB disease progression, where granulomas mirror the morphology and physiology observed in human TB. Thus, using the DO Mtb mouse model, NHP model of TB and human clinical samples, we recently implicated neutrophils and S100A8/A9 proteins in mediating inflammation and disease severity in TB. However, the pace of such translational discoveries will be much more robust and rapid if we have a more comprehensive understanding of common immune correlates of protection and inflammation across relevant animal models and the spectrum of TB in humans. To overcome this bottleneck, we propose the following Aims.
In Aim 1, we will identify common gene expression signatures from peripheral blood and lung samples from DO Mtb-infected mice, NHPs with PTB and LTBI, and compare them to existing whole blood transcriptional profiles from a well characterized longitudinal study of SA adolescents. In addition, we will validate the expression of genes identified from the inter-species gene expression analysis by measuring protein levels in our human adolescent progressor cohort.
In Aim 2, using animal models of Mtb infection, we will mechanistically address the functional role of specific genes identified as correlates of risk of TB in human progressors, specifically focusing on the Type I Interferon pathway. Together, these aims will provide novel information on common immune protective and inflammatory pathways that exist between relevant animal models and human TB. Identifying such common correlates will allow us to more effectively use animal models to screen for new vaccines and therapies that have a better likelihood of translating to improved efficacy in human TB.
Tuberculosis (TB) infects about one third of the world's population, killing approximately 1.3 million individuals worldwide every year. The aims of this proposal will identify and validate common immune protective and inflammatory pathways that exist between relevant animal models and human TB, and will bridge the gap between observational human and mechanistic animal TB immunology.
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| Howard, Nicole C; Marin, Nancy D; Ahmed, Mushtaq et al. (2018) Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes. Nat Microbiol 3:1099-1108 |
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