This proposal describes a 5 year training program designed to provide the education and laboratory experience required for a successful academic career in basic science research in infectious diseases. This multidisciplinary program will include formal coursework in immunology and basic science fundamentals as well as an extensive lab experience encompassing cellular, molecular and immunologic techniques. Dr. JoAnne Flynn, an internationally recognized expert in host defenses in Mycobacterium tuberculosis (Mtb) infection, will mentor the principal investigator. Research progress and career development will be reviewed quarterly by an advisory committee. Tumor necrosis factor-alpha(TNF) neutralization in acute and chronic Mtb-infected mice results in poor granuloma structure, disseminated disease and poor survival. Similar results have been observed in patients treated with anti-TNF antibody. We hypothesize that TNF neutralization dysregulates cell migration factors critical to granuloma formation and maintenance. This proposal seeks to determine the role of TNF and its influence on chemokines, chemokine receptors and adhesion molecules in the context of granuloma structure in the lungs during primary and latent Mtb infection. We will focus on chemokines, chemokine receptors and adhesion molecules induced in TH1 immune responses in the lung. We will determine how Mtb-induced production of TNF alters expression of chemokines, chemokine receptors and adhesion molecules using both in vitro and in vivo models; in this latter part we will examine changes in granuloma histology, immune phenotype and function in animal models of primary and latent Mtb infection treated with TNF neutralizing antibody. These changes will be analyzed the context of granuloma structure and host response to infection. The University of Pittsburgh provides an ideal research environment to support this training program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI063101-01
Application #
6859822
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Jacobs, Gail G
Project Start
2005-01-15
Project End
2009-12-31
Budget Start
2005-01-15
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$111,691
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
Flynn, JoAnne L; Gideon, Hannah P; Mattila, Joshua T et al. (2015) Immunology studies in non-human primate models of tuberculosis. Immunol Rev 264:60-73
Mattila, Joshua T; Ojo, Olabisi O; Kepka-Lenhart, Diane et al. (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191:773-84
Lin, Philana Ling; Rutledge, Tara; Green, Angela M et al. (2012) CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques. AIDS Res Hum Retroviruses 28:1693-702
Ford, Christopher B; Lin, Philana Ling; Chase, Michael R et al. (2011) Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet 43:482-6
Lin, Philana Ling; Flynn, Joanne L (2010) Understanding latent tuberculosis: a moving target. J Immunol 185:15-22
Lin, Philana Ling; Myers, Amy; Smith, Le'Kneitah et al. (2010) Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum 62:340-50
Lin, Philana Ling; Rodgers, Mark; Smith, Le'kneitah et al. (2009) Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77:4631-42
Via, Laura E; Lin, P Ling; Ray, Sonja M et al. (2008) Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76:2333-40
Lin, Philana Ling; Plessner, Hillarie L; Voitenok, Nikolai N et al. (2007) Tumor necrosis factor and tuberculosis. J Investig Dermatol Symp Proc 12:22-5
Lin, Philana Ling; Pawar, Santosh; Myers, Amy et al. (2006) Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun 74:3790-803