Genetic Susceptibility to Fungal Infections in Humans

Abstract

Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a “normal” host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed.

CX 3 CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

“…Specifically, it would appear that the adaptive immune response is most important for the development of effective host defense against mucosal infection, as patients with HIV and idiopathic CD4 lymphocytopenia are prone to mucocutaneous candidiasis but not systemic candidiasis (4,31). Furthermore, patients with either mutations in various components of the IL-17 pathway (i.e., IL-17RA, IL-17F, and ACT1 [14,32]) or with inherited immunodeficiencies that result in impaired IL-17 signaling (i.e., mutations in STAT1, STAT3, STK4, DOCK8, AIRE, and DECTIN-1 [11]) are susceptible to mucosal but not systemic candidiasis. In Ϫ/Ϫ mice were infected sublingually with C. albicans strains 529L, Y42, and Y72.…”

“…The data are combined from 2 independent experiments (n ϭ 10 mice/group). stark contrast, patients with inherited or acquired neutropenia, chronic granulomatous disease, and complete myeloperoxidase deficiency have an increased likelihood of developing systemic but not mucosal Candida infections (11,(33)(34)(35), indicating a stronger requirement for innate immune cell mechanisms for the protection against systemic infection. The only immune factor known to date to confer heightened susceptibility to both mucosal and systemic candidiasis on humans is CARD9, attesting to the central positioning of this adaptor protein downstream of several C-type lectin receptors (30,36).…”

“…In agreement with the mouse data, the mutant human CX 3 CR1-M280 allele was shown to be an independent risk factor for the development of candidemia and disseminated candidiasis in two different cohorts of patients from the United States and Europe (10). However, whether this receptor plays a role in mucosal host defense against Candida is unknown.In recent years, it has become evident that interleukin 23 (IL-23)-dependent IL-17 and IL-22 signaling is critical for protection against mucosal candidiasis in mice and humans (11)(12)(13)(14)(15)(16)(17). Of interest, Cx3cr1 has previously been shown to promote IL-23-dependent IL-22 production and mucosal immune responses in the context of bacterial gastrointestinal (GI) tract infection and intestinal inflammation (18,19).…”

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

“…However, it can become an opportunistic pathogen in immunocompromised patients and frequently causes mucocutaneous or disseminated candidiasis (1). Furthermore, patients with innate immune defects, particularly neutropenia, are prone to systemic candidiasis because of an inability to clear the pathogen (2). In contrast, an exaggerated inflammatory response is often observed during neutrophil recovery in acute leukemia patients with systemic Candida infection (3).…”

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

“…Patients with primary immunodeficiencies are also at risk for fungal infections but these conditions are quite rare (Lionakis 2012). In general, resource-rich regions also have good access to combined antiretroviral therapy and, consequently, the rates of opportunistic infections associated with HIV/AIDS have decreased significantly.…”