Therapeutic effects of recombinant forms of full-length and truncated human surfactant protein D in a murine model of invasive pulmonary aspergillosis.

Journal article

Aspergillus fumigatus (Afu) is an opportunistic fungal pathogen that can cause fatal invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. Previously, surfactant protein D (SP-D), a surfactant-associated innate immune molecule, has been shown to enhance phagocytosis and killing of Afu conidia by phagocytic cells in vitro. An intranasal treatment of SP-D significantly increased survival in a murine model of IPA. Here we have examined mechanisms via which recombinant forms of full-length (hSP-D) or truncated human SP-D (rhSP-D) offer protection in a murine model of IPA that were immunosuppressed with hydrocortisone and challenged intranasally with Afu conidia prior to the treatment. SP-D or rhSP-D treatment increased the survival rate to 70% and 80%, respectively (100% mortality on day 7 in IPA mice), with concomitant reduction in the growth of fungal hyphae in the lungs, and increased levels of TNF-alpha and IFN-gamma in the lung suspension supernatants, as compared to untreated IPA mice. The level of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the lung cell suspension was also raised considerably following treatment with SP-D or rhSP-D. Our results appear to reaffirm the notion that under immunocompromised conditions, human SP-D or its truncated form can offer therapeutic protection against fatal challenge with Afu conidia challenge. Taken together, the SP-D-mediated protective mechanisms include enhanced phagocytosis by recruited macrophages and neutrophils and fungistatic properties, suppression of the levels of pathogenic Th2 cytokines (IL-4 and IL-5), enhanced local production of protective Th1 cytokines, TNF-alpha and IFN-gamma, and that of protective C-C chemokine, MIP-1 alpha.

Authors: Singh, M; Madan, T; Waters, P; Sonar, S; Singh, S

• Publication status: Published
• Journal: Molecular immunology
• Volume: 46
• Issue: 11-12
• Pages: 2363-2369
• Publication date: 2009-07-01
• DOI: 10.1016/j.molimm.2009.03.019
• EISSN: 1872-9142
• ISSN: 0161-5890
• Language: English
• Keywords: Male; Tumor Necrosis Factor-alpha; Interferon-gamma; Invasive Pulmonary Aspergillosis; Chemokine CCL3; Humans; Aspergillus fumigatus; Mice; Recombinant Proteins; Pulmonary Surfactant-Associated Protein D; Animals; Mice, Inbred BALB C; Mutation