Antifungal Innate Immunity: A Perspective from the Last 10 Years

Abstract

Fungal pathogens can rarely cause diseases in immunocompetent individuals. However, commensal and normally nonpathogenic environmental fungi can cause life-threatening infections in immunocompromised individuals. Over the last few decades, there has been a huge increase in the incidence of invasive opportunistic fungal infections along with a worrying increase in antifungal drug resistance. As a consequence, research focused on understanding the molecular and cellular basis of antifungal immunity has expanded tremendously in the last few years. This review will provide an overview of the most exciting recent advances in innate antifungal immunity, discoveries that are helping to pave the way for the development of new strategies that are desperately needed to combat these devastating diseases.

Keywords: Antifungal immunity; Fungal pathogens; Pathogenesis.

Fig. 1

Novel insights into the dectin-1 signaling pathway. Following dectin-1 engagement, Src-dependent phosphorylation of the dectin-1 ITAM results in Syk activation. The E3 ubiquitin ligase CBLB ubiquitinates dectin-1 and Syk inhibiting downstream immune responses. Downstream of Syk, PKCδ phosphorylates CARD9 and promotes the assembly of the CARD9/Bcl10/MALT1 complex, which subsequently activates the canonical NF-κB pathway to induce proinflammatory cytokines. Dectin-1 also activates NF-κB via the Raf-1 signaling cascade. Vav proteins and the ubiquitin ligase TRIM62 are newly identified molecules that can regulate CARD9 activation. CD23 is a recently described CLR that is upregulated upon dectin-1 engagement and leads to nitric oxide production. Activatory signals are in blue, inhibitory signals are in red.

Fig. 2

Crosstalk between different PRRs in antifungal immunity. Dectin-2 and MCL can form heterodimers and amplify proinflammatory cytokine production upon Candida infection. Dectin-1 and dectin-2 can synergize to induce the NLRP3 inflammasome against Histoplasma capsulatum challenge. In addition, dectin-1 and CR3 can collaboratively trigger proinflammatory cytokine production against histoplasmosis. Fonsecaea pedrosoi activates the Mincle signaling pathway but requires costimulation with TLR ligands to induce protective immunity. Mincle can also antagonize dectin-1 signaling upon recognition of F. pedrosoi. Finally, dectin-1 and TLR2 interact in the recognition and phagocytosis of zymosan particles leading to proinflammatory cytokine production. Activatory signals are in blue, inhibitory signals are in red.

Fig. 3

Effector mechanisms against fungal pathogens. Fungi can invade tissue by inducing endocytosis or actively penetrating the epithelium. Epithelial cells can produce antimicrobial peptides with antifungal activities and proinflammatory cytokines that can recruit other immune cells, such as monocytes, which will also contribute to fungal clearance. Tissue resident macrophages can phagocyte and kill fungal pathogens; in addition, neutrophils can also produce ROS and release neutrophil extracellular traps (NETs) that capture fungi and contain antimicrobial proteins that inhibit their growth. Dendritic cells can migrate to lymph nodes and activate specific T-cell responses depending on the microbial morphology and site of infection. Innate lymphoid cells can also produce proinflammatory cytokines that contribute to mucosal antifungal responses. Finally, in the last steps of invasion, fungi breach the endothelium allowing them access to the bloodstream where they can activate platelets to produce cytokines and molecules with antifungal activity. Adapted from Netea et al. [84].