Main human inborn errors of immunity leading to fungal infections.

ABSTRACT

BACKGROUND: The host's molecular and genetic features are essential in providing susceptibility to a broad spectrum of fungal infections; most of these do not cause disease in healthy individuals because of mutual benefits with opportunistic fungi besides the host's capacity to control the infections. In contrast, patients with primary immunodeficiency can develop mild superficial to life-threatening invasive infections. In the last years, thanks to next-generation sequencing, several inborn-error variants have been discovered in genes encoding protein acting against fungal infections, contributing to better defining the role of innate and adaptive immunity cooperation during infection resolution. Candida fungal infection that sometimes strikes healthy subjects is responsible for the chronic mucocutaneous candidiasis that is one of the principal clinical manifestations occurring in several rare primary immunodeficiencies associated with an inborn error of interleukin-17 (IL-17) immunity. OBJECTIVE: This review aimed to provide an overview of chronic mucocutaneous candidiasis-derived genetic defects, including IL17 deficiencies (IL17A, IL17F, IL17RA, IL17RC), STAT1 gain-of-function deficiency, STAT3 hyper-IgE syndrome, and CARD9 deficiency. SOURCES We carried out detailed research work to identify interesting articles, commentaries, and reviews in the PubMed literature to ensure a correct and updated narrative review. CONTENT We propose an in-depth description and an update of genetic and cellular mechanisms underlying fungal infections, focusing on the IL17-mediated response, a report of clinical manifestations, and a description of therapeutic options. IMPLICATIONS This narrative review will help clinician to identify the correct management of patients based on molecular and cellular findings underlying pathogenic mechanisms of different inborn errors of immunity. Moreover, enabling clinicians to achieve the genetic diagnosis will be useful to offer genetic counselling intra- and inter-family and to ensure a personalised treatment of patients.