<i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> clinical isolates from Thailand display diverse phenotypic interactions with macrophages

<p><i>Cryptococcus</i>-macrophage interaction is crucial in the development of cryptococcocal diseases. <i>C. neoformans</i> and <i>C. gattii</i> are major pathogenic species that occupy different niches and cause different clinical manifestations. However, the differences of macrophage interaction among these species in affecting different disease outcomes and immune responses have not been clearly addressed. Here, we examined the macrophage uptake rates, intracellular loads and intracellular proliferation rates of <i>C. neoformans</i> and <i>C. gattii</i> clinical isolates from Thailand and analyzed the effect of those interactions on fungal burdens and host immune responses. <i>C. neoformans</i> isolates showed a higher phagocytosis rate but lower intracellular proliferation rate than <i>C. gattii</i>. Indeed, the high intracellular proliferation rate of <i>C. gattii</i> isolates did not influence the fungal burdens in lungs and brains of infected mice, whereas infection with high-uptake <i>C. neoformans</i> isolates resulted in significantly higher brain burdens that associated with reduced survival rate. Interestingly, alveolar macrophages of mice infected with high-uptake <i>C. neoformans</i> isolates showed distinct patterns of alternatively activated macrophage (M2) gene expressions with higher <i>Arg1, Fizz1, Il13</i> and lower <i>Nos2, Ifng, Il6, Tnfa, Mcp1, csf2</i> and <i>Ip10</i> transcripts. Corresponding to this finding, infection with high-uptake <i>C. neoformans</i> resulted in enhanced arginase enzyme activity, elevated IL-4 and IL-13 and lowered IL-17 in the bronchoalveolar lavage. Thus, our data suggest that the macrophage interaction with <i>C. neoformans</i> and <i>C. gattii</i> may affect different disease outcomes and the high phagocytosis rates of <i>C. neoformans</i> influence the induction of type-2 immune responses that support fungal dissemination and disease progression.</p> <p><b>Abbreviation:</b> Arg1: Arginase 1; BAL: Bronchoalveolar lavage; CCL17: Chemokine (C-C motif) ligand 17; CNS: Central nervous system; CSF: Cerebrospinal fluid; Csf2: Colony-stimulating factor 2; Fizz1: Found in inflammatory zone 1; HIV: Human immunodeficiency virus; ICL: Intracellular cryptococcal load; Ifng: Interferon gamma; Ip10: IFN-g-inducible protein 10; IPR: Intracellular proliferation rate; Mcp1: Monocyte chemoattractant protein 1; Nos2: Nitric oxide synthase 2; PBS: Phosphate-Buffered Saline; Th: T helper cell; Tnfa: Tumor necrosis factor alpha.</p>