Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

Abstract

We are exposed to a wide spectrum of fungi including innocuous environmental organisms, opportunistic pathogens, commensal organisms, and fungi that can actively and explicitly cause disease. Much less is understood about effective host immunity to fungi than is generally known about immunity to bacterial and viral pathogens. Innate and adaptive arms of the immune system are required for effective host defense against Candida, Aspergillus, Cryptococcus, and others, with specific elements of the host response regulating specific types of fungal infections (e.g., mucocutaneous versus systemic). Here we will review themes and controversies that are currently shaping investigation of antifungal immunity (primarily to Candida and Aspergillus) and will also examine the emerging field of the role of fungi in the gut microbiome.

Skin Immunity to Candida albicans

“…The increased rate is thought to result from increased use of immunosuppressive agents, anti-cancer treatments, increased anti-microbial resistance and the frequency of invasive surgeries [1]. The genetic susceptibilities associated with systemic candidiasis as well as infections of gastrointestinal and female reproductive organs differ significantly from those associated with CMC[2] . Unlike CMC patients that have defects with type 3 immunity, genetic defects upstream or downstream of IL-17 have not been implicated in patients with disseminated candidiasis[3].…”

Immunity against fungi

“…Novel pathogenic fungi that pose a threat to humans (e.g., Cryptococcus gattii), amphibians (e.g., Batrachochytrium dendrobatidis), and bats (e.g., Pseudogymnoascus destructans) have also been identified (4). In response, research in fungal pathogenesis and antifungal immunity has intensified to inform vaccine-and therapy-based approaches for mycoses (5). This review focuses on insights gained from animal models and patients with primary immune deficiency disorders (PIDDs), but does not cover allergenic or toxinmediated fungal disease (6, 7).…”

“…Collectively, these interactions facilitate signaling responses by membranebound receptors and the induction of antifungal effector mechanisms (5,9). In the lung, the collectin pentraxin-3 (PTX3) binds to A. fumigatus conidial galactomannan (19) and facilitates complement deposition and CD32-dependent conidial uptake by neutrophils (20).…”

“…The C-type lectin receptor (CLR) dectin-1 (encoded by Clec7a) binds β-glucans from a variety of fungi, including those on C. albicans bud scars and germinating A. fumigatus conidia, and activates signaling responses to Pneumocystis jiroveci, H. capsulatum, Coccidioides posadasii, and Paracoccidioides brasiliensis (5,9,(22)(23)(24) (Figure 2). β-Glucan binding displaces regulatory phosphatases CD45 and CD148 (25), induces SRC-dependent phosphorylation of the intracellular ITAM-like motif, and recruits the SHP-2 phosphatase (26).…”

“…Fungal ligands activate TLR1-4, TLR-6, TLR-9, and NOD2 signaling in a variety of cell types (5,9). For example, PTX3-opsonized A. fumigatus conidia activate TLR-4/MD-2/TRIF-dependent signaling that mediates IL-10 production (62).…”