Joshua T Mattila, PhD

It is estimated that nearly a third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB).  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:

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.  

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 intrested in clarifying drivers of nitric oxide synthase and arginase expression in TB and the consequence these enzymes have on the pathology of TB.

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.    

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.

1992-1996       Bemidji State University, Bemidji, MN - B.S. in Biology

1999-2006       University of Minnesota, St. Paul, MN - Ph.D. in Entomology

2007-2013       University of Pittsburgh, Pittsburgh, PA - Postdoctoral Training in the Immunology of Tuberculosis with JoAnne Flynn 

IDM 2010 Pathogen Biology - Topic: Mycobacteria and tuberculosis

IDM 2038 Prevention and Control of Global Infectious Disease - Topic: Tuberculosis

IDM 2040 Scientific Communication

IDM 3440: Vaccines and Immunity - Topic: TB vaccinology

Mattila JT, Beaino W, Maiello P, Coleman MT, White AG, Scanga CA, Flynn JL, Anderson CJ. Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4β1-Expressing Immune Cells. J Immunol. 2017 Jun 7. pii: ji1700231. doi: 10.4049/jimmunol.1700231.

Mattila JT, Maiello P, Sun T, Via LE, Flynn JL. Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques. Cell Microbiol. 2015 Aug;17(8):1085-97. doi: 10.1111/cmi.12428. Epub 2015 Mar 12.

Flynn JL, Gideon HP, Mattila JT, Lin PL. Immunology studies in non-human primate models of tuberculosis. Immunol Rev. 2015 Mar;264(1):60-73. doi:10.1111/imr.12258.

Pienaar E, Cilfone NA, Lin PL, Dartois V, Mattila JT, Butler JR, Flynn JL, Kirschner DE, Linderman JJ. A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment. J Theor Biol. 2015 Feb 21;367:166-79. doi: 10.1016/j.jtbi.2014.11.021. Epub 2014 Dec 9.

Cilfone NA, Ford CB, Marino S, Mattila JT, Gideon HP, Flynn JL, Kirschner DE,  Linderman JJ. Computational modeling predicts IL-10 control of lesion sterilization by balancing early host immunity-mediated antimicrobial responses with caseation during mycobacterium tuberculosis infection. J Immunol. 2015 Jan 15;194(2):664-77. doi: 10.4049/jimmunol.1400734.

Marino S, Cilfone NA, Mattila JT, Linderman JJ, Flynn JL, Kirschner DE. Macrophage polarization drives granuloma outcome during Mycobacterium tuberculosis infection. Infect Immun. 2015 Jan;83(1):324-38. doi:10.1128/IAI.02494-14. Epub 2014 Nov 3.

Mattila JT, Fine MJ, Limper AH, Murray PR, Chen BB, Lin PL. Pneumonia. Treatment and diagnosis. Ann Am Thorac Soc. 2014 Aug;11 Suppl 4:S189-92. doi: 10.1513/AnnalsATS.201401-027PL. Review.

Mattila JT, Thomas AC. Nitric oxide synthase: non-canonical expression patterns. Front Immunol. 2014 Oct 9;5:478. doi: 10.3389/fimmu.2014.00478. eCollection 2014. Review.

Thomas AC, Mattila JT. "Of mice and men": arginine metabolism in macrophages. Front Immunol. 2014 Oct 7;5:479. doi: 10.3389/fimmu.2014.00479. eCollection 2014.Review.

Gong C, Mattila JT, Miller M, Flynn JL, Linderman JJ, Kirschner D. Predicting lymph node output efficiency using systems biology. J Theor Biol. 2013 Oct 21;335:169-84. doi:10.1016/j.jtbi.2013.06.016. Epub 2013 Jun 29.

Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, Eum SY, Via LE, Barry CE 3rd, Klein E, Kirschner DE, Morris SM Jr, Lin PL, Flynn JL. Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol. 2013 Jul 15;191(2):773-84. doi: 10.4049/jimmunol.1300113.

Diedrich CR, Mattila JT, Flynn JL. Monocyte-derived IL-5 reduces TNF production by Mycobacterium tuberculosis-specific CD4 T cells during SIV/M. tuberculosis coinfection. J Immunol. 2013 Jun 15;190(12):6320-8. doi: 10.4049/jimmunol.1202043. PMCID: PMC3677169.

Phuah JY, Mattila JT, Lin PL, Flynn JL. Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. Am J Pathol. 2012 Aug;181(2):508-14. doi: 10.1016/j.ajpath.2012.05.009. Epub 2012 Jun 19. Erratum in: Am J Pathol. 2012 Nov;181(5):1889.

Mattila JT, Diedrich CR, Lin PL, Phuah J, Flynn JL. Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation. J Immunol. 2011 Mar 15;186(6):3527-37. doi:10.4049/jimmunol.1003773. Epub 2011 Feb 11.

Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, Flynn JL. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010 Aug 15;202(4):533-41. doi: 10.1086/654896.

Diedrich CR, Mattila JT, Klein E, Janssen C, Phuah J, Sturgeon TJ, Montelaro RC, Lin PL, Flynn JL. Reactivation of latent tuberculosis in cynomolgus macaques infected with SIV is associated with early peripheral T cell depletion and not virus load. PLoS One. 2010 Mar 10;5(3):e9611. doi: 10.1371/journal.pone.0009611.

Windish HP, Lin PL, Mattila JT, Green AM, Onuoha EO, Kane LP, Flynn JL. Aberrant TGF-beta signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis. J Leukoc Biol. 2009 Sep;86(3):713-25. doi:10.1189/jlb.1208740. Epub 2009 May 19. Erratum in: J Leukoc Biol. 2014 Sep;96(3):503-4.

Complete list of work available via NCBI My Bibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/1zcguUgIGy35Z/bibliography/47892992/public