C3 complement mediates neutrophil control of cryptococcal lung infection and dissemination

Abstract

Abstract The encapsulated budding yeast Cryptococcus neoformans causes meningitis and pneumonia particularly in immunocompromised individuals including HIV-infected patients. The organism is acquired by the pulmonary route where it disseminates via the bloodstream from the lung to the brain and causes meningitis. Since the lung vasculature is replete with several innate immune cells, it is conceivable that the host would mount an immune response in the pulmonary vasculature to prevent or at least limit the dissemination of C. neoformans to other sites of the body. Hence, we used intravital microscopy to study the host cell immune interactions that occur within the lung vasculature in a living mouse. We found that neutrophils, but not monocytes, interacted with and phagocytosed C. neoformans. Interestingly, additional neutrophils underwent accretion around the phagocytosed C. neoformans, forming a cast of the vasculature. Phagocytosis of C. neoformans was impaired by the presence of cryptococcal capsule, since acapsular strain of C. neoformans were rapidly phagocytosed by neutrophils compared with encapsulated strain. Neutrophil phagocytosis of C. neoformans and subsequent accretion was mediated by complement C3 in both acapsular and encapsulated strains. Mice deficient in C3 complement showed reduced clearance of C. neoformans from the lungs and brain, compared to C3 sufficient mice. These findings highlight the importance of neutrophils in the control of C. neoformans in the pulmonary vasculature and subsequent dissemination to the distal organs including the brain.