Candida albicans secrete a small cysteine-rich protein Sel1 to trigger TLR2/4-dependent inflammatory response during invasive infection

Abstract

Abstract Despite being a commensal for healthy individuals, Candida albicans can rapidly switch to pathogenic mode featured with hyphal development, altered cell wall composition and secreted virulence factors, thereby causing mucosal or disseminated candidiasis in immunocompromised patients. The host relies on a diversity of pattern-recognition receptors, particularly Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) to sense invading fungal pathogens and launch immune defense mechanisms. However, the complex interplay between fungus and host innate immune system remains incompletely understood. Here we report that Candida albicans upregulate the expression of a small secreted cysteine-rich protein Sel1 upon encountering limited nitrogen and abundant serum, two hallmarks of human bloodstream, leading to marked proinflammatory response. Notably, Sel1 was able to trigger the activation of signaling pathways NF-kB and MAP kinases, leading to the expression of a myriad of proinflammatory cytokines and chemokines in macrophages and dendritic cells. Comprehensive genetic and biochemical analyses revealed that both TLR2 and TLR4 are required for the recognition of Sel1, and TLR2/4-deficient macrophages were blunted in response to Sel1 stimulation. Further, SEL1-deficient mutant of C. albicans was less efficient in eliciting immune response in vivo, thus causing severer morbidity and mortality in bloodstream infection model. Together, our results reveal a previous unsuspected mechanism underlying TLRs-mediated immune recognition of C. albicans, hence open a new avenue to tackle candida infection and inflammation.