An improved understanding of the factors contorlling host susceptibility to Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Our laboratory utilizes immunodeficient mouse models of P. Carinii pneumonia to study susceptibility to this organism, modeling the immune deficits present in HIV-infected individuals. Using these immunodeficient mouse models of P. Carinii pneumonia, we confirmed the roles of both CD4+ and CD8+ T cells in host defense against P. Carinii. Both CD4+ and CD8+ T cells are likely to control susceptibility to P. Carinii by elaboration of cytokines. Recent information shows that both of these T cell subsets can express either Th1 or Th2 cytokine repertoires. In an increasing number of model systems, it is apparent that the balance between susceptibility and defense does not depend on single cytokines with isolated actions. Rather, coordinated responses, precisely modulated in intensity and in sequence, control susceptibility. In preliminary data presented in this application, we characterize Th1 and Th2 cytokine production in the lungs of immunocompetent and immunodeficient mice after P. Carinii inoculation. We demonstrate differential, time-dependent patterns of cytokine production in vivo. Furthermore, we have successfully used mice deleted of specific cytokine genes (""""""""knockout"""""""" mice) to examine suceptibility to P. Carinii in vivo. Based o these data, we hypothesize that coordinated Th1 and Th2 responses are required for successful defense against p. Carinii, requiring early Th2-like responses and late Th1-like responses. There are four specific objectives: (1) to determine the cellular sources of cytokines responsible for successful defense against or susceptibility to P. Carinii in vivo; (2) to determine whether cytokine blockade can alter defense against or susceptibility to P. Carinii in vivo; (3) to isolate P. Carinii-specific CD4+ T cells with specific cytokine profiles in vitro and to determine whether these cells maintain their cytokine profiles in vivo; and (4) to determine whether reconstitution with CD4+ T cells of defined repertoire alters susceptibility to infection in vivo. These powerful animal models allow us to test the roles of cytokines in control of susceptibility to P. Carini using in vivo approaches that model human P. Carinii pneumonia. Ultimately, these studies can be extended to develop therapeutic strategies directed against this important opportunistic pathogen.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059823-05
Application #
6389833
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Peavy, Hannah H
Project Start
1997-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2001
Total Cost
$252,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Atochina, Elena N; Gow, Andrew J; Beck, James M et al. (2004) Delayed clearance of pneumocystis carinii infection, increased inflammation, and altered nitric oxide metabolism in lungs of surfactant protein-D knockout mice. J Infect Dis 189:1528-39
Beck, James M; Preston, Angela M; Wilcoxen, Steven E et al. (2003) Pneumocystis pneumonia increases the susceptibility of mice to sublethal hyperoxia. Infect Immun 71:5970-8
Beck, James M; Blackmon, Michael B; Rose, Christine M et al. (2003) T cell costimulatory molecule function determines susceptibility to infection with Pneumocystis carinii in mice. J Immunol 171:1969-77
Luikart, Sharon; Masri, Mohammed; Wahl, Dan et al. (2002) Urokinase is required for the formation of mactinin, an alpha-actinin fragment that promotes monocyte/macrophage maturation. Biochim Biophys Acta 1591:99-107
Atochina, E N; Beck, J M; Scanlon, S T et al. (2001) Pneumocystis carinii pneumonia alters expression and distribution of lung collectins SP-A and SP-D. J Lab Clin Med 137:429-39
Cushion, M T; Beck, J M (2001) Summary of Pneumocystis research presented at the 7th International Workshop on Opportunistic Protists. J Eukaryot Microbiol Suppl:101S-105S
Beck, J M (2000) Pneumocystis carinii and geographic clustering: evidence for transmission of infection. Am J Respir Crit Care Med 162:1605-6
Atochina, E N; Beers, M F; Scanlon, S T et al. (2000) P. carinii induces selective alterations in component expression and biophysical activity of lung surfactant. Am J Physiol Lung Cell Mol Physiol 278:L599-609
Beck, J M; Preston, A M; Gyetko, M R (1999) Urokinase-type plasminogen activator in inflammatory cell recruitment and host defense against Pneumocystis carinii in mice. Infect Immun 67:879-84
Beers, M F; Atochina, E N; Preston, A M et al. (1999) Inhibition of lung surfactant protein B expression during Pneumocystis carinii pneumonia in mice. J Lab Clin Med 133:423-33

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