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, NK cells, and their secreted cytokines in host defense against this infection are far less clear. As it is unknown at the present time, whether highly active antiretroviral therapy will result in long term immune reconstitution in patients with AIDS, understanding non-CD4+ T cell dependent host defense mechanisms operative in opportunistic infections may be critical. Among CD4+ T cell derived cytokines, interferon-gamma (IFN-g) is likely to play a key role in host defense against PC infection. Lymphocytes exposed to PC organisms or the major surface glycoprotein of PC in vitro elaborate IFN and lymphocytes recovered from HIV-infected individuals are deficient in IFN-g production. Preliminary studies from our laboratory demonstrate that overexpression of IFN-g in the lung, using adenoviral-mediated lung delivery of the murine IFN cDNA, (AdIFN) enhances clearance of PC in normal mice, and eradication of infection in mice depleted of CD4 lymphocytes, with a monoclonal antibody. Moreover, this augmented host response is associated with a significant increase in lung CD8+ T-cells. Furthermore, AdIFN fails to eradicate PC infection in scid mice which lack both T and B cells, suggesting that overexpression of IFN is not solely through macrophage activation and/or NK cells. We hypothesize that IFN is critical to host defense against PC and that overexpression of IFN in the lungs of mice depleted of CD4+ T cells will substitute for CD4+ T-lymphocytes, and mediate clearance of PC pneumonia through a CD8 T-cell-dependent mechanism. We will test this hypothesis with the following Specific Aims.
Specific Aim 1. Our hypothesis predicts that overexpression of IFN-g will enhance recruitment of inflammatory cells and permit clearance of P. carinii in CD4-depleted mice.
Specific Aim 2. Our hypothesis predicts that AdIFN induces the recruitment of CD8+ T cells, specifically of the Tc1-like phenotype, in CD4-depleted mice challenged with P. carinii.
Specific Aim 3. To elucidate cytokine and cytotoxic mechanisms of CD8+ T cell mediated clearance of P. carinii in CD4-depleted mice. These studies will investigate non-CD4 dependent host defenses utilizing a novel form of immunotherapy against an important opportunistic pathogen. The results of these studies will not only aid us in further understanding lung host defenses, but also may lead to novel methods of therapy for opportunistic infections.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061271-03
Application #
6343624
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Peavy, Hannah H
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
2001-03-01
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$76,076
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Kumar, Pawan; Kolls, Jay K (2016) Lymphocyte Isolation, Th17 Cell Differentiation, Activation, and Staining. Bio Protoc 6:
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 44:659-671
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; Elsegeiny, Waleed; Nelson, Michael P et al. (2015) Eosinophils Contribute to Early Clearance of Pneumocystis murina Infection. J Immunol 195:185-93
Eddens, Taylor; Kolls, Jay K (2015) Pathological and protective immunity to Pneumocystis infection. Semin Immunopathol 37:153-62
Zheng, Mingquan; Cai, Yang; Eddens, Taylor et al. (2014) Novel pneumocystis antigen discovery using fungal surface proteomics. Infect Immun 82:2417-23
Chakraborty, Sourav; Cai, Yang; Tarr, Matthew A (2014) In vitro oxidative footprinting provides insight into apolipoprotein B-100 structure in low-density lipoprotein. Proteomics 14:2614-22
Newcomb, Dawn C; Boswell, Madison G; Sherrill, Taylor P et al. (2013) IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia. Am J Respir Cell Mol Biol 48:711-6
Eddens, Taylor; Kolls, Jay K (2013) Lung pathology associated with Pneumocystis colonization in infants. Clin Infect Dis 56:180-1
Kelly, Michelle N; Zheng, Mingquan; Ruan, Sanbao et al. (2013) Memory CD4+ T cells are required for optimal NK cell effector functions against the opportunistic fungal pathogen Pneumocystis murina. J Immunol 190:285-95

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