Neutrophils Restrain CCR2-Dependent Monocyte Immunopathology During Pulmonary Cryptococcosis
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Neutrophils are essential for host defense against most invasive fungal pathogens, yet their role in cryptococcosis remains paradoxical. Neutropenia is not a recognized risk factor for cryptococcal disease, and an early study reported that neutrophil depletion improves survival in mice, supporting the prevailing view that these cells are dispensable. Here we re-examined this question using Ly6G-specific depletion strategies. Contrary to prior reports, neutrophil-depleted mice infected with Cryptococcus neoformans succumbed significantly more rapidly than isotype-treated controls. Accelerated mortality occurred without any increase in pulmonary fungal burden at 24h, 48h, or day 7, or in brain and spleen at day 7, indicating host-mediated rather than pathogen-driven death. This phenotype was independent of mouse genetic background, depletion antibody, inoculum, and fungal strain. Within 24h, neutrophil depletion provoked an early chemokine and IL-17A response, followed by pronounced pulmonary accumulation of inflammatory monocytes and macrophages by day 7. Strikingly, the increased mortality associated with neutrophil depletion was completely absent in Ccr2 −/− mice, implicating CCR2-dependent inflammatory responses in disease severity. Together, these findings reveal a previously underappreciated protective function of neutrophils during cryptococcosis, whereby they constrain inflammatory monocyte-associated immunopathology and promote host survival independently of measurable changes in fungal burden.
IMPORTANCE
Cryptococcus neoformans causes life-threatening infections, particularly in individuals with weakened immune systems. Neutrophils are white blood cells that protect against many fungal infections, but their role in cryptococcosis has remained unclear. We found that depleting neutrophils from infected mice consistently accelerated mortality without increasing fungal burden in their tissues. Instead, neutrophil depletion triggered excessive lung inflammation and accumulation of inflammatory monocytes. Mice that could not recruit inflammatory monocytes into the lungs were completely protected, identifying those cells as the cause of lethal damage. Neutrophils therefore act as a brake on a damaging inflammatory response, highlighting the potential of targeting host immune responses to improve outcomes during cryptococcosis.
