Immune responses to human fungal pathogens and therapeutic prospects

Abstract

Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.

Fig. 1. Host defence against Candida at the oral mucosal interface.

a, Protective responses to Candida at mucosal surfaces are mediated by IL-17 and IL-22 produced by T helper 17 (T_H17) cells, CD8⁺ T cells, type 3 innate lymphoid cells (ILC3s) and γδ T cells. T_H17 cell differentiation depends on signal transducer and activator of transcription 3 (STAT3)-mediated retinoic acid receptor-related orphan receptor-γt (RORγt) induction downstream of signalling through IL-6 receptor (IL-6R) and IL-23R, which is defective in individuals with mutations in RORC (which encodes RORγt), STAT3 or ZNF341 (which regulates STAT3 expression and function), making them highly susceptible to chronic mucocutaneous candidiasis (CMC). T_H17 cells produce IL-17A, IL-17F and IL-22. IL-17A, IL-17F and IL-17A–IL-17F bind to IL-17R, consisting of IL-17RA and IL-17RC, on suprabasal epithelial cells, which leads to the activation of ACT1 and induces the production of antimicrobial peptides (AMPs; such as β-defensin 3 and S100A8/S100A9) that restrict Candida growth. CMC also develops in patients with mutations in IL17F, IL17RA, IL17RC or TRAF3IP2 (which encodes ACT1), and in patients with thymoma or AIRE mutations, both of which are associated with autoantibodies to IL-17 and/or IL-22. Furthermore, mild oral thrush can develop in a subset of patients receiving IL-17 pathway-targeted biologics such as those inhibiting IL-17A, IL-17RA, IL-12p40 (not shown) or IL-23 (Table 3). IL-22 produced by T_H17 cells, CD8⁺ T cells, ILC3s and γδ T cells binds to the IL-22 receptor consisting of IL-22RA1 and IL-10RB on basal epithelial cells, which activates STAT3 and facilitates epithelial cell proliferation and repair, thereby enabling the replenishment and responsiveness of the IL-17R-expressing suprabasal epithelial cell layer. b, Mucosal type II interferonopathy. In the setting of autoimmunity caused by autoimmune regulator (AIRE) deficiency, mucosal CD4⁺ T_H1 cells and CD8⁺ T cells locally produce increased levels of interferon-γ (IFNγ), which binds to the IFNγ receptor consisting of IFNGR1 and IFNGR2 on epithelial cells, activates STAT1 and impairs oral epithelial barrier integrity. This leads to increased susceptibility to oropharyngeal candidiasis. JAK, Janus kinase; TYK2, tyrosine kinase 2.

Fig. 2. Cellular crosstalk regulates antifungal innate immunity in the lung.

a, Fungal recognition and epithelial cell–leukocyte crosstalk coordinate the recruitment of neutrophils and monocytes to the alveoli. Alveolar macrophages and lung-resident dendritic cells (DCs; not shown) engulf Aspergillus fumigatus conidia that reach the terminal airways, which are the site of gas exchange. Rapid release of IL-1α/β by macrophages and DCs stimulates the IL-1 receptor (IL-1R)–MYD88-dependent production of the neutrophil-recruiting chemokines CXCL1 and CXCL5 by lung epithelial cells. The release of CXCL2 by haematopoietic cells, including macrophages, through C-type lectin receptor (CLR)–CARD9 activation, and the rapid production of leukotriene B₄ (LTB4) and complement component C5a also contribute to sustained neutrophil recruitment. In addition, CCR2⁺ circulating monocytes enter the lung parenchyma and differentiate into monocyte-derived DCs. Opsonization of A. fumigatus conidia by pentraxins enables their efficient uptake and killing by neutrophils. b, The recruited neutrophils and monocyte-derived DCs engulf conidia into phagolysosomes, which are the site of intracellular conidial killing. Both resident myeloid cells and infiltrating CCR2⁺ monocytes produce type I interferon early in the response and regulate ensuing type III interferon release. Fungus-engaged neutrophils and monocyte-derived DCs secrete CXCL9 and CXCL10 (through CLR–CARD9–SYK and type I interferon-dependent pathways, respectively), which recruit CXCR3⁺ plasmacytoid DCs (pDCs) to the lung. c, Innate crosstalk licenses the full spectrum of neutrophil antifungal activity. Conidial killing by neutrophils and monocyte-derived DCs is enhanced by the entry of CXCR3⁺ pDCs and by type I and type III interferons that converge on signal transducer and activator of transcription 1 (STAT1) signalling in neutrophils. Fungus-induced release of granulocyte–macrophage colony-stimulating factor (GM-CSF) also potentiates neutrophil antifungal properties by enhancing NADPH oxidase activity and the production of reactive oxygen species (ROS). In the context of blastomycosis, CCR6⁺ innate lymphocytes and natural T helper 17 cells contribute to GM-CSF production during acute pulmonary infection.

Fig. 3. Crosstalk between macrophages and T cells during infection with intracellular fungi.

Type 1 immune responses, characterized by interferon-γ (IFNγ)-producing T cells and macrophages, are crucial for protection against intramacrophagic fungi (such as Cryptococcus and Histoplasma). Infected macrophages produce IL-12, which drives T helper 1 (T_H1) cell polarization of CD4⁺ T cells through Janus kinase 2 (JAK2)–signal transducer and activator of transcription 4 (STAT4) signalling. T_H1 cells produce IFNγ, which binds to the IFNγ receptor, comprising IFNGR1 and IFNGR2, on macrophages and activates JAK1/JAK2–STAT1-dependent signalling to induce expression of inducible nitric oxide synthase (iNOS). In turn, iNOS mediates fungal killing together with the production of reactive oxygen species (ROS), which is partly controlled by sphingosine 1-phosphate receptor 3 (S1PR3) in the setting of cryptococcal infection. Tumour necrosis factor (TNF) activates macrophages for fungal killing and promotes the formation of granulomas and IFNγ production by lymphocytes. Granulocyte–macrophage colony-stimulating factor (GM-CSF) also primes macrophages to effectively kill fungi intracellularly. The transcription factor GATA2 regulates fungal uptake by macrophages. Disruption of these protective antifungal immune pathways by biologics, inborn errors of immunity or anti-cytokine autoantibodies enhances susceptibility to infections with intracellular fungi in humans.

Fig. 4. Endogenous fungal communities and their relationship to invasive fungal disease.

a, Mucosal and intestinal bacterial communities outnumber and compete with site-specific endogenous fungi. In the intestine, commensal anaerobic bacteria, exemplified by Blautia producta and Bacteroides thetaiotaomicron, provide colonization resistance against Candida species by activating the transcription factor hypoxia-inducible factor 1α (HIF1α) in intestinal epithelial cells to regulate the release of LL-37, an antimicrobial peptide (AMP) that restricts Candida albicans growth. Bacterial products of fermentation, specifically short-chain fatty acids (SCFAs), and metabolites likely also contribute to fungal colonization resistance and inhibition of Candida filamentation. Nutrient competition and regulation of tissue oxygen levels contribute to the balance between endogenous bacteria and competing fungal species in the gastrointestinal and reproductive tracts. CX3CR1⁺ mononuclear phagocytes recognize intestinal fungi through C-type lectin receptor (CLR)–CARD9 signalling and regulate the production of IgA and IgG antibodies to Candida by B cells. IgA antibodies recognize and target C. albicans adhesins (such as agglutinin-like sequence 3 (Als3)) that are primarily expressed by pseudohyphae and thus promote maintenance of the commensal yeast cell morphology. Candida-targeted IgG antibodies can protect against bloodstream invasion and disseminated candidiasis. b, In the intestinal and reproductive tracts, antibiotic-induced loss of predominantly anaerobic bacterial taxa reduces Candida colonization resistance and facilitates domination by individual fungal taxa. C. albicans strains from patients with inflammatory bowel disease with fungal dysbiosis can aggravate tissue damage, correlating with fungal strain-specific induction of IL-1β production by immune cells. The induction of T helper 17 (T_H17) cells and IL-17 production can promote neutrophil recruitment to inhibit fungal tissue invasion and dissemination. However, Candida-specific T_H17 cells can also promote extraintestinal inflammation. For example, mould aeroallergens can stimulate C. albicans-primed T_H17 cells and aggravate fungus-associated asthma. c, Systemic bloodstream infections can arise from intestinal fungal dysbiosis with concomitant epithelial cell damage (for example, following chemotherapy) and with defects in the number or function of circulating myeloid phagocytes.