Despite advances in diagnosis, therapy, and prophylaxis, Pneumocystis carinii pneumonia (PCP) remains a leading cause of morbidity and mortality in patients with HIV infection. The disease is caused by an enigmatic pathogen whose basic biology remains poorly understood because of difficulty in culturing the organism in vitro. Thus, animal models remain a mainstay of investigation into the pathogenesis of PCP. Although progress has been made in the definition of protective immunity in the immediate response to P carinii infection, an extremely important gap remains related to studies of the pathogenesis of this infection which centers around an inability to quantify various steps in pathogenesis in vivo. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are collagen like lectins (collectins) which are highly expressed in the distal airways and alveolus. Both proteins have been shown to bind to and mediate the attachment of P carinii to the alveolar macrophage and to modulate cytokine elaboration by T-cell populations. Recent development of both SP-A and SP-D knockout mice has begun to implicate important roles for these proteins in local lung host defense and in modulation of the pulmonary inflammatory response. We hypothesize that SP-A and SP-D: a) Augment clearance of P. carinii from the alveolar space; b) Moderate a balance between pro- and anti-inflammatory responses which occurs during PCP. We propose to utilize the recently developed SP-A and SP-D knockout mice as new models of P. carinii infection to define the role of the collectins in host defense against PCP.
The specific aims are: 1) Using SP-A and SP-D knockout mice, determine the role of the lung collectins (SP-A, SP-D) in the establishment and clearance of P. carinii infection in vivo; 2) Characterize the host immune response to P. carinii in SP-A and SP-D deficient models.; 3) Characterize changes in surfactant composition and function during development and progression of PC pneumonia in surfactant protein knockout mice; 4) Determine the effect of exogenous replacement of SP-A and/or SP-D on the clearance of P. carinii infection. The project will combine elements of several established thematic research programs to yield a comprehensive investigative proposal including: 1) A Principal Investigator with expertise in all major aspects of surfactant biology 2) Consultants recognized as authorities on immunocompromised mouse models of PCP and in generation of surfactant protein knockout mice. Results from these studies will extend our understanding of the pathogenesis of P. carinii infection.
| Atochina-Vasserman, Elena N (2012) S-nitrosylation of surfactant protein D as a modulator of pulmonary inflammation. Biochim Biophys Acta 1820:763-9 |
| Atochina-Vasserman, Elena N; Winkler, Carla; Abramova, Helen et al. (2011) Segmental allergen challenge alters multimeric structure and function of surfactant protein D in humans. Am J Respir Crit Care Med 183:856-64 |
| Atochina-Vasserman, Elena N; Bates, Sandra R; Zhang, Peggy et al. (2011) Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome. Am J Respir Crit Care Med 184:449-58 |
| Atochina-Vasserman, Elena N; Beers, Michael F; Gow, Andrew J (2010) Review: Chemical and structural modifications of pulmonary collectins and their functional consequences. Innate Immun 16:175-82 |
| Atochina-Vasserman, Elena N; Gow, Andrew J; Abramova, Helen et al. (2009) Immune reconstitution during Pneumocystis lung infection: disruption of surfactant component expression and function by S-nitrosylation. J Immunol 182:2277-87 |
| Guo, Chang-Jiang; Atochina-Vasserman, Elena N; Abramova, Elena et al. (2008) S-nitrosylation of surfactant protein-D controls inflammatory function. PLoS Biol 6:e266 |
| Atochina-Vasserman, Elena N; Beers, Michael F; Kadire, Helchem et al. (2007) Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice. J Immunol 179:8090-7 |
| Jain, Deepika; Atochina-Vasserman, Elena; Kadire, Helchem et al. (2007) SP-D-deficient mice are resistant to hyperoxia. Am J Physiol Lung Cell Mol Physiol 292:L861-71 |
| Zhang, Yuzhen; Rath, Nibedita; Hannenhalli, Sridhar et al. (2007) GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development 134:189-98 |
| Casey, John; Kaplan, Jennifer; Atochina-Vasserman, Elena N et al. (2005) Alveolar surfactant protein D content modulates bleomycin-induced lung injury. Am J Respir Crit Care Med 172:869-77 |
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