Abstract

Pneumocystis carinii (Pc) is a fungus of low virulence that is major cause of pneumonia (P) in HIV patients. Surfactant protein (SP-A), a member of the collectins, plays an important role in the host's innate immunity against pulmonary pathogens. Studies of the interaction of SP-A with Pc have mainly been conducted in vitro and have produced conflicting results. Gene targeted mice deficient in SP-A appear more susceptible to PcP than wild type mice administered the same immunosuppression. The application proposes the following hypotheses: SP-A facilitates the clearance of Pc in the immunocompetent host; this activity can be localized to specific domains of SP-A and is mediated at least in part by alveolar macrophages; SP-A delays the development and reduces the severity of PcP in the immunocompromised host; SP-A down regulates the host immune/inflammatory response to Pc.
The specific aims are: 1) To analyze the effects of SP-A on Pc infection in the immunocompetent host. These studies will: 1.1) investigate the effects of SP-A on the clearance of Pc from the lungs; 1.2) determine if the administration of SP-A can reverse the changes in SP-A deficient mice and to localize the specific domains involved; 1.3) study the effects of SP-A on the interaction of Pc with alveolar macrophages; and 1.4) analyze the effects of SP-A on the host immune/inflammatory response to Pc infection. 2) To analyze the effects of SP-A on PcP in the immunocompromised host. These studies will: 2.1) analyze the effects of SP-A on the development of PcP induced by different forms of immunosuppression; 2.2) examine the influence of SP-A on the changes in alveolar cells, sufactant constituents, and lung function that occur with PcP; and 2.3) analyze the influence of SP-A on the host immune/inflammatory response that occurs during the recovery from PcP.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064570-04
Application #
6638606
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F2))
Program Officer
Peavy, Hannah H
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$382,500
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Linke, Michael J; Ashbaugh, Alan A; Koch, Judith V et al. (2009) Effects of surfactant protein-A on the interaction of Pneumocystis murina with its host at different stages of the infection in mice. J Eukaryot Microbiol 56:58-65
Linke, Michael J; Ashbaugh, Alan D; Demland, Jeffery A et al. (2009) Pneumocystis murina colonization in immunocompetent surfactant protein A deficient mice following environmental exposure. Respir Res 10:10
Daly, K R; Koch, J V; Shire, N J et al. (2006) Human immunodeficiency virus-infected patients with prior Pneumocystis pneumonia exhibit increased serologic reactivity to several major surface glycoprotein clones. Clin Vaccine Immunol 13:1071-8
Linke, Michael; Ashbaugh, Alan; Demland, Jeffery et al. (2006) Resolution of Pneumocystis murina infection following withdrawal of corticosteroid induced immunosuppression. Microb Pathog 40:15-22
Cushion, Melanie T; Walzer, Peter D; Ashbaugh, Alan et al. (2006) In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice. Antimicrob Agents Chemother 50:2337-43
Linke, Michael; Ashbaugh, Alan; Koch, Judith et al. (2005) Surfactant protein A limits Pneumocystis murina infection in immunosuppressed C3H/HeN mice and modulates host response during infection. Microbes Infect 7:748-59
Thullen, Timothy D; Ashbaugh, Alan D; Daly, Kieran R et al. (2004) Sensitized splenocytes result in deleterious cytokine cascade and hyperinflammatory response in rats with Pneumocystis pneumonia despite the presence of corticosteroids. Infect Immun 72:757-65
Daly, Kieran R; Koch, Judy; Levin, Linda et al. (2004) Enzyme-linked immunosorbent assay and serologic responses to Pneumocystis jiroveci. Emerg Infect Dis 10:848-54
Walzer, Peter D; Ashbaugh, Alan (2002) Use of terbinafine in mouse and rat models of Pneumocystis carinii pneumonia. Antimicrob Agents Chemother 46:514-6
Daly, Kieran R; Fichtenbaum, Carl J; Tanaka, Reiko et al. (2002) Serologic responses to epitopes of the major surface glycoprotein of Pneumocystis jiroveci differ in human immunodeficiency virus-infected and uninfected persons. J Infect Dis 186:644-51

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