Recent in vitro studies have implicated galectin-3 as an important receptor in host recognition and response to specific Candida species; however its role in protection against disseminated candidiasis in vivo has not been evaluated. This study investigated the importance of galectin-3 in host defense against systemic infection with the highly virulent species Candida albicans (C. albicans), and the less virulent species, Candida parapsilosis (C. parapsilosis). Mice deficient in galectin-3 (gal3−/−) were more susceptible to infection than wild type (WT) mice. When infected with C. albicans, gal3−/− mice died significantly faster and exhibited a trend towards increased fungal burden and increased abscess formation in infected brains compared to WT mice. When infected with C. parapsilosis, gal3−/− mice had significantly higher renal fungal burdens and abscess formation compared to WT mice. To evaluate whether galectin-3 may contribute to susceptibility to candidiasis in human infants, galectin-3 levels in sera of newborn infants, a patient population uniquely susceptible to infections with both C. albicans and C. parapsilosis, were compared to serum galectin-3 levels of adults. Galectin-3 levels were significantly lower in newborn infant sera compared to adult sera. These data indicate that galectin-3 plays an important role in a murine model of disseminated candidiasis and suggest a potential mechanism of neonatal susceptibility to these infections.

SUMMARY Candida albicans causes the majority of invasive candidiasis in immunocompromised adults while Candida parapsilosis is a leading cause of neonatal candidiasis. While much work has focused on how the immune system recognizes and responds to C. albicans, less is known about host interaction with C. parapsilosis. This study investigates the human neutrophil phagocytic response to these species. Neutrophils underwent phagocytosis of C. parapsilosis yeast and C. albicans hyphae much more efficiently than C. albicans yeast. Treatment of neutrophils with a galectin-3 (gal3) blocking antibody inhibited phagocytosis of C. parapsilosis yeast and C. albicans hyphae, but not C. albicans yeast. The majority of neutrophil gal3 was expressed intracellularly and was secreted from neutrophils after treatment with C. parapsilosis mannan. When neutrophils were treated with exogenous gal3, phagocytosis of both C. albicans and C. parapsilosis yeast increased. Exposure of neutrophils to C. parapsilosis yeast increased phagocytosis of C. albicans yeast and was inhibited by gal3 blocking antibody. Taken together, these data indicate that gal3 secreted from neutrophils may act as a proinflammatory autocrine/paracrine signal in neutrophil phagocytosis and suggest that gal3 has a unique role in neutrophil response to C. parapsilosis yeast and C. albicans hyphae distinct from C. albicans yeast.

Release of neutrophil extracellular traps (NETs) is a significant antimicrobial host defense mechanism in adults. In neonates, fungal sepsis is a frequent cause of morbidity and mortality and may be a consequence of inadequate neutrophil defense functions. Like neutrophils from adult donors, we found that neutrophils from neonates formed robust cellular aggregates and released NETs in response to fungal β-glucan and Candida albicans hyphae when presented with extracellular matrix. Therefore, in response to fungal stimulation, neonatal neutrophils are capable of NETosis. Neonate susceptibility to fungal infections may not be due to an inability of their neutrophils to produce NETs.