Abstract
Initiation of a protective immune response to infection by the pathogenic fungus Cryptococcus neoformans is mediated in part by host factors that promote interactions between immune cells and C. neoformans yeast. Surfactant protein A (SP-A) contributes positively to pulmonary host defenses against a variety of bacteria, viruses, and fungi in part by promoting the recognition and phagocytosis of these pathogens by alveolar macrophages. In the present study we investigated the role of SP-A as a mediator of host defense against the pulmonary pathogen, C. neoformans. Previous studies have shown that SP-A binds to acapsular and minimally encapsulated strains of C. neoformans. Using in vitro binding assays we confirmed that SP-A does not directly bind to a fully encapsulated strain of C. neoformans (H99). However, we observed that when C. neoformans was incubated in bronchoalveolar fluid, SP-A binding was detected, suggesting that another alveolar host factor may enable SP-A binding. Indeed, we discovered that SP-A binds encapsulated C. neoformans via a previously unknown IgG dependent mechanism. The consequence of this interaction was the inhibition of IgG-mediated phagocytosis of C. neoformans by alveolar macrophages. Therefore, to assess the contribution of SP-A to the pulmonary host defenses we compared in vivo infections using SP-A null mice (SP-A-/-) and wild-type mice in an intranasal infection model. We found that the immune response assessed by cellular counts, TNFα cytokine production, and fungal burden in lungs and bronchoalveolar lavage fluids during early stages of infection were equivalent. Furthermore, the survival outcome of C. neoformans infection was equivalent in SP-A-/- and wild-type mice. Our results suggest that unlike a variety of bacteria, viruses, and other fungi, progression of disease with an inhalational challenge of C. neoformans does not appear to be negatively or positively affected by SP-A mediated mechanisms of pulmonary host defense.
Highlights
Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that is responsible for significant morbidity and mortality in immunocompromised hosts
In contrast to the previous conditions, we were able to detect a small amount of SPA binding under these conditions (Figure 1B). Our interpretation of these results was that another factor present in Bronchoalveolar lavage (BAL) may have enabled Surfactant protein A (SP-A) to bind to C. neoformans
In the process of considering factors in BAL that might mediate SP-A binding to C. neoformans, immunoglobulins were selected as candidates for binding assays
Summary
Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that is responsible for significant morbidity and mortality in immunocompromised hosts. A pulmonary infection occurs following inhalation of C. neoformans cells. Initiation of an innate and adaptive cellular immune response limits the severity of the infection to an asymptomatic and often self-resolving pulmonary infection in most cases. The identification of those host factors that contribute to effective defenses against C. neoformans will broaden our understanding of C. neoformans pathogenesis but may aide in the development of therapeutic strategies for the prevention and treatment of this important fungal disease
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