TRPM7-dependent electrical signals drive phagocytic clearance for effective anti-fungal defense

Abstract

Sentinel phagocytes of the innate immune system have a critical role in detecting and eliminating fungal pathogens. We used patch clamp electrophysiology to explore the electrical signals elicited when macrophages engulf Candida albicans. In the perforated patch configuration, which is least disruptive to intracellular signaling, we detected a composite outwardly rectifying current during the engulfment of C. albicans or zymosan. FTY720, a known inhibitor of ion channel TRPM7, suppressed the current. We then tested the hypothesis that TRPM7 regulates the engulfment and clearance of C. albicans. We found that Trpm7-/- macrophages are highly deficient in the engulfment of C. albicans. Trpm7-/- macrophages initiate phagocytosis of yeast but are defective in sealing the phagocytic cups. While the precise mechanism through which TRPM7 regulates phagosome sealing is not clear, we tested the immunological significance of this discovery using a mouse model of systemic candidiasis. We show that in mice, wherein TRPM7 is deleted selectively in the myeloid cells, infection by C. albicans results in significantly higher lethality, increased colonization of vital organs and increased inflammatory cytokines in the blood. Our study establishes TRPM7 as an ion channel critical for the innate immune responses against fungal pathogens and sets the stage for cell biological studies that define the mechanisms through which TRPM7 regulates phagosome sealing. Significance statementThe worldwide increase in deadly or persistent fungal infections has prompted the research for alternative ways of treatment. We applied the specialized, perforated patch clamp technique to track and identify electrical currents elicited during the detection and engulfment of fungi by macrophages. The ion channel TRPM7 emerged as an important determinant of anti-fungal host defense as its deletion in the murine myeloid cells made the host mice highly susceptible to lethal candidiasis. Ion channels are attractive drug targets whose activation and inhibition can be manipulated with pharmacological therapeutics. This study raises the possibility of enhancing fungal clearance using activators of TRPM7. Such pharmacological strategy may benefit patients of persistent fungal infections that are recalcitrant to anti-fungal drugs.