Joshua T Mattila, PhD

TB is characterized by formation of structures called granulomas that are both the host's mechanism for containing the bacteria and as the environmental niche for bacterial persistence. Fortunately, most people restrain bacterial growth in a subclinical state (latency) and never experience active TB. HIV-infected individuals, even with near-normal numbers of peripheral blood CD4+ T cells are highly susceptible to TB. Efforts to find single-factor causes explaining this synergy have not been successful and the mechanisms underlying the pathogenesis of TB-HIV remain to be elucidated. My primary interest is understanding interactions between M. tuberculosis and the host at the granuloma level especially with regard to macrophage responses against M. tuberculosis that can be disrupted by HIV infection. My primary research projects include:

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Macrophage cytokine expression and signaling in the granuloma

Macrophages play a central role in TB, acting as the primary host and effector cell against the bacterium. In addition to their interactions with M. tuberculosis, macrophages engage in reciprocal cytokine-based interactions with T cells that can result in either activation or deactivation. Both macrophages and T cells are susceptible to HIV infection, and macrophage infection may represent an additional source of dysregulation in TB. Type 1 interferons (IFN1) are of particular importance in TB and HIV, because they can have positive and negative consequences for both diseases and I have current projects focusing on the macrophage IFN1 expression and signaling, and how HIV infection modifies this at the level of the granuloma.

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Macrophage polarization and arginine metabolism in the granuloma

Macrophages express arginine-using enzymes that mediate their function – inducible nitric oxide synthase (iNOS) is expressed in bactericidal M1 macrophages while arginases are expressed by pro-healing M2 macrophages. Macrophage-based arginase and iNOS expression can also inhibit T cell activation and cytokine expression. In TB, appropriate iNOS expression is important for bacterial control whereas excessive arginase expression is associated with decreased protection. I am interested in clarifying drivers of nitric oxide synthase and arginase expression in TB and the consequence these enzymes have on the pathology of TB.

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Neutrophils as a source of pathology and protection in the granuloma

Neutrophil's play a poorly defined role in TB - at early stages of disease they are likely to be protective, but a later stages of disease they are pathologic. Identifying how these two ends of a spectrum differ, and how we can manipulate them may have therapeutic potential. I have several ongoing projects examining unappreciated aspects of neutrophil biology. Beyond elucidating neutrophil function, addition of neutrophils to an in silico computational model of granuloma biology would be of great benefit for understanding potential functions for neutrophils in TB.

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Computational modeling to identify the factors that determine granuloma function

While much can be learned from wet lab experiments, in silico computational models are a tool for performing experiments that cannot otherwise be performed in vivo. For example, what is the consequence of HIV infection of only T cells in a granuloma, or only macrophages, or only classically-activated macrophages? And what would happen if the pharmacology of anti-retrovirals could be changed to penetrate the granuloma more completely? Answers to these questions could improve our ability to limit TB in HIV-infected individuals, lower rates of reactivated TB, and improve drug treatment in ways that lower viral burdens or drug resistance in both HIV and TB. A computational model of granuloma biology (GranSim) has already been created by JoAnne Flynn (University of Pittsburgh) and Denise Kirschner (University of Michigan) using data from cynomologus macaque granulomas. This model has become increasingly complex as we’ve improved our understanding of the components of a granuloma and elucidated aspects of cell-cell interactions that were previously unknown or unappreciated.