Calling Neutrophils to the Nervous System—Study Reveals Mechanisms of Antifungal Immunity

NIAID Now | April 17, 2019

Inexorable fungal invasion with defective neutrophil recruitment in the CARD9-deficient brain.

Credit: NIAID

NIAID researchers have unraveled the immune responses that recruit infection-fighting neutrophils to the brain during fungal infections. Notably, they found that a fungal protein known to promote infections of the mucous membranes instead plays a protective role in the brain by stimulating these antifungal immune responses. These findings from mouse models, published online April 17 in Nature Immunology, provide new insights into antifungal immunity and highlight how the complex interactions between pathogens and the immune system depend on the tissue or organ system in which infection takes place.

The yeast fungus Candida albicans, which is naturally present on human skin and mucous membranes, usually does not cause problems in healthy people. However, people whose immune systems have been weakened or compromised are vulnerable to systemic candidiasis, a life-threatening condition in which Candida spreads throughout the body. Systemic candidiasis can affect multiple tissues and organ systems, including the central nervous system, or CNS.

The most striking risk factor for Candida infections of the CNS is a rare genetic disorder called CARD9 deficiency. CARD9 deficiency is caused by gene mutations that disrupt the production or function of the CARD9 protein, which helps activate antifungal immune defenses. NIAID researchers previously found that CARD9 plays a crucial role in recruiting neutrophils to the CNS during fungal infection.

In the current study, scientists led by Michail Lionakis, M.D., Sc.D., chief of the Fungal Pathogenesis Section in NIAID’s Laboratory of Clinical Immunology and Microbiology, delved into the molecular events that promote neutrophil accumulation in the CNS during Candida infection. First, the research team explored the potential contributions of a variety of cell-signaling molecules using mouse models of fungal CNS infection. Like mice engineered to lack CARD9, mice lacking an immune system protein called IL-1β had poor recruitment of neutrophils to the brain and a high burden of Candida in the CNS. The researchers observed similar characteristics in mice lacking a protein called CXCL1, as well as in animals lacking CXCR2, a cell-surface protein that interacts with CXCL1.  

IL-1β and CXCL1 are produced by various cell types including microglia, a type of immune cell that resides in the CNS. Further experiments revealed that production of IL-1β by microglia drives subsequent production of CXCL1, which recruits CXCR2-expressing neutrophils to the site of Candida infection in the CNS. Production of both IL-1β and CXCL1 by microglia depends on CARD9.

To investigate how fungal infection of the CNS triggers these immune responses, the scientists infected mice with Candida strains lacking different virulence factors—agents that help the pathogen establish infection and cause disease. Interestingly, they found that Candidalysin, which promotes Candida infections of the mucous membranes, plays a very different role in the CNS. Strains lacking Candidalysin grew readily in the brain, and the researchers observed a near-absence of neutrophils and low levels of IL-1β and CXCL1 in the CNS of mice infected with Candidalysin-deficient Candida albicans.

These findings suggest that Candidalysin released by the fungus stimulates CARD9-producing microglia and sets in motion the chain of events that promotes recruitment of neutrophils to the fungal-infected CNS. In the future, the researchers plan to examine whether CARD9 promotes microglial immune defenses beyond neutrophil recruitment, such as uptake and killing of fungi by immune cells.

Developing a better understanding of the intricate network of interactions between the fungus and the immune system in the CNS provides new insights into human CARD9 deficiency. Beyond this rare disease, the findings also have implications for recognizing the potential fungal infection risk among people receiving medications that target cell-signaling networks involving CARD9 for treatment of autoimmune diseases and cancers.

Reference

RA Drummond et al. CARD9+ microglia promote antifungal immunity via IL-1β and CXCL1-mediated neutrophil recruitment. Nature Immunology DOI: 10.1038/s41590-019-0377-2 (2019).

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