Despite current strategies to treat HIV infection and its complications, Pneumocystis carinii pneumonia (PCP) remains a common clinical problem. Although there is a well- known relationship between CD4+ lymphocyte count and the risk of PC infection, the role of mononuclear phagocytes, CD8+ cells, gamma/delta T cells, and their secreted cytokines in host defense against this infection are far less clear. During the prior funding period we demonstrated that overexpression of the interferon-gamma (IFN) gene in the lung in CD4-deficient mice results in eradication of PC. Clearance of PC is mediated by augmented lung recruitment of CD8+ T cells, which have a Tc1-like phenotype (as defined by strong endogenous IFN production). We demonstrated that CD8+ T-cell effectors expressed CXCR3 and were recruited to the lung via IP-10. These cells mediate clearance of PC by secreting GM-CSF which augments macrophage clearance of the organism. In the absence of IFN overexpression GMCSF+ CD8+ T-cells require CD4+ T-cell help however the Th subset requirement is not defined. We hypothesize that clinical PCP is due to loss of Th1, Th2, and Th17 immunity and that vaccine induced CD4+ T-cells belonging to any of these CD4+ T-cell subsets will be sufficient to induce clearance of PC infection in the lung.
The aims are 1. Determine the role of IFNAR, IL- 23, and IL-12, in regulating Th1 immunity to PC. 2. To generate mice deficient in Th1, Th2, and Th17 immunity to determine contributions of these CD4+ T-cell subsets in the clearance of PCP. 3. Our hypothesis predicts that vaccination of mice sufficient for Th1, Th2, or Th17 immunity will be sufficient to protect against PCP. These studies will confirm the role of Th subsets in PCP and optimize vaccination strategies for this important opportunistic infection.

Public Health Relevance

This project defines the types of T-cells required for prevention of Pneumocystis pneumonia a major complication of AIDS and organ transplantation. This research will improve the potential development of a vaccine for this infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062052-17
Application #
8475637
Study Section
Special Emphasis Panel (ZRG1-AARR-E (02))
Program Officer
Caler, Elisabet V
Project Start
1998-09-30
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
17
Fiscal Year
2013
Total Cost
$375,633
Indirect Cost
$125,823
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Eddens, Taylor; Campfield, Brian T; Serody, Katelin et al. (2016) A Novel CD4(+) T Cell-Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology. Am J Respir Crit Care Med 194:807-820
Eddens, Taylor; Song, Eunkyung; Ardura, Monica I et al. (2016) A protracted course of Pneumocystis pneumonia in the setting of an immunosuppressed child with GMS-negative bronchoalveolar lavage. Med Mycol Case Rep 11:48-52
Kumar, Pawan; Monin, Leticia; Castillo, Patricia et al. (2016) Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation. Immunity 44:659-71
Elsegeiny, Waleed; Eddens, Taylor; Chen, Kong et al. (2015) Anti-CD20 antibody therapy and susceptibility to Pneumocystis pneumonia. Infect Immun 83:2043-52
Eddens, Taylor; Kolls, Jay K (2015) Pathological and protective immunity to Pneumocystis infection. Semin Immunopathol 37:153-62
Eddens, Taylor; Elsegeiny, Waleed; Nelson, Michael P et al. (2015) Eosinophils Contribute to Early Clearance of Pneumocystis murina Infection. J Immunol 195:185-93
Deshmukh, Hitesh S; Liu, Yuhong; Menkiti, Ogechukwu R et al. (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20:524-30
Zheng, Mingquan; Cai, Yang; Eddens, Taylor et al. (2014) Novel pneumocystis antigen discovery using fungal surface proteomics. Infect Immun 82:2417-23
Way, Emily E; Chen, Kong; Kolls, Jay K (2013) Dysregulation in lung immunity - the protective and pathologic Th17 response in infection. Eur J Immunol 43:3116-24
Eddens, Taylor; Kolls, Jay K (2013) Lung pathology associated with Pneumocystis colonization in infants. Clin Infect Dis 56:180-1

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