Immune mechanism in lung prevents fungal infection

Abstract

Aspergillus fumigatus is a filamentous fungus that can cause fatal infections in people with defective immunity. Healthy individuals have a strong resistance to this fungus, even when exposed to high concentrations of the organism in the air they breathe. It is not well understood how the immune system in healthy individuals prevents germination of the inhaled spore-like conidia of A. fumigatus. However, alveolar macrophages are a primary immune defensive cell in the lung and have been implicated in the resistance to invasive aspergillosis. We are examining the hypothesis that macrophages prevent conidial germination by depriving them of critical nutrients, rather than by killing them with destructive antimicrobials. Most pathogens, including A. fumigatus, preferentially metabolize glucose and other highly-reduced carbohydrates for energy. If A. fumigatus cannot obtain preferred nutrients, it will utilize alternative molecules for survival, as shown in the expression of unique metabolic enzymes. Using conidia as a molecular probe, we have identified changes in fungal gene expression when engulfed in macrophages, which is consistent with a starvation response. Isocitrate lyase is known to be increased during the starvation response in fungi, and we have observed that it is upregulated in conidia when phagocytosed within macrophages. Our results indicate A. fumigatus conidia reprogram their metabolism due to the lack of nutrients in the macrophages. Our in vitro data indicate nutrient loss is sufficient to block conidial development. This information suggests alveolar macrophages prevent germination of A. fumigatus conidia by starving them, thereby avoiding both infection and inflammation in the lung.