The tropic life forms of Pneumocystis alter alveolar macrophage responses to inflammatory stimuli

Abstract

Abstract Pneumocystis is an opportunistic fungal pathogen that causes pneumonia in immunosuppressed individuals including patients with HIV. There are two identifiable life forms of Pneumocystis including a cyst or ascus form that has a β-glucan-rich fungal cell wall and a trophic form that lacks the cell wall. In infected lungs the trophic forms can outnumber the asci by as much as 10 to 1. We have previously published that the trophic forms of Pneumocystis are able to inhibit the production of pro-inflammatory cytokines such as TNF induced by β-glucans or LPS in bone marrow-derived dendritic cells. Recently we found that trophic forms also inhibit TNF production by alveolar macrophages when stimulated in vitro. To understand relevance of this observation during Pneumocystis infection, RAG−/− mice were infected with the trophic forms of Pneumocystis, treated with an echinocandin drug to prevent the formation of ascus forms, and challenged with a low dose of LPS given intratracheally. Twenty-four hours later bronchial alveolar lavage fluids were obtained and TNF quantitated. The trophic forms of Pneumocystis significantly inhibited the production of TNF in mice challenged with LPS compared to those given LPS alone or LPS plus echinocandin. Interestingly, there was no difference in the influx of neutrophils into the lungs in LPS-treated mice compared to trophic form infected and LPS-treated mice. It is well known that TNF is an important factor in host defense against Pneumocystis while neutrophils have not been shown to enhance clearance but coincide with lung pathology. Together our data indicates that trophic forms of Pneumocystis alter selected parts of the inflammatory milieu of the lungs.