The molecular immunology of human susceptibility to fungal diseases: lessons from single gene defects of immunity

ABSTRACT

Introduction: Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paradigms.

Areas covered: A systematic literature search in PubMed, Scopus, and abstracts of international congresses was performed to review the history of genetic resistance/susceptibility to fungi and identify IEIs associated with fungal diseases. Immunologic mechanisms from relevant IEIs were integrated with current definitions and understandings of mycoses to establish a framework to map out critical immunobiological pathways of human antifungal immunity.

Expert opinion: Specific immune responses non-redundantly govern susceptibility to their corresponding mycoses. Defining these molecular pathways will guide the development of host-directed immunotherapies that precisely target distinct fungal diseases. These findings will pave the way for novel strategies in the treatment of these devastating infections.

KEYWORDS:

• Fungal immunity
• inborn errors of immunity
• primary immunodeficiency
• mycoses
• human susceptibility to fungi
• yeast
• mould
• genetic

Article highlights

• Inborn errors of immunity (IEI) are human models of immunobiology, revealing indispensable insight into human immunity to microbes.

• IEIs can predispose to chronic fungal diseases within a context of broader susceptibility to other microbes or restricted to finite fungal genera.

• Because IEIs are associated with specific fungal diseases, their mechanistic dissection permits formulation of immunologic frameworks governing resistance/susceptibility to fungi:

• Impaired Th17 responses lead to chronic mucocutaneous candidiasis (CMC).

• CARD9 deficiency results in invasive disease, particularly with central nervous system involvement, with Candida, dermatophytes (especially Trichophyton), or phaeohyphomyctetes (dematiaceous fungi), though the immunologic mechanism(s) remain to be defined.

• Defects in the IL12/IFN-γ axis are associated with increased susceptibility to disseminated disease with Cryptococcus and thermally dimorphic endemic mycoses.

• Aspergillus can cause a variety of syndromes. Cystic fibrosis predisposes to allergic bronchopulmonary aspergillosis (ABPA). Pneumatocele formation in autosomal-dominant hyper-IgE (Job’s) syndromes provides a nidus for chronic pulmonary aspergillosis (CPA), implying the importance of STAT3 in respiratory epithelium regeneration. Invasive pulmonary aspergillosis (IPA) is a salient feature of chronic granulomatous disease (CGD), highlighting the key role of the phagocyte NADPH oxidase in host defense to this mold.

• IEIs with susceptibility to other fungal diseases are increasingly being identified, which will help refine these immunologic frameworks.

Declaration of interest

DC Vinh has received an unrestricted educational grant, clinical trial support, and advisory board honoraria from CSL Behring Canada; clinical trial support from Cidara Therapeutics; advisory board honoraria from Avir Pharma; and clinical trial support from Shire Canada. He has also received peer-reviewed research funding from La Fondation du Grand Défi Pierre Lavoie, the Fonds de la recherche en santé du Québec (FRSQ), the Canadian Institutes of Health Research (CIHR), the United States Department of Defense, and the Research Institute – McGill University Health Centre (RI-MUHC). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.