The Hidden Cost of Modern Medical Interventions: How Medical Advances Have Shaped the Prevalence of Human Fungal Disease

Abstract

Life expectancy in the West is the highest it has ever been, due to the introduction of better hygiene practices and sophisticated medical interventions for cancer, autoimmunity and infectious disease. With these modern advances, a rise in the prevalence of opportunistic infections has also been observed. These include several fungal infections, which present a particular clinical challenge due to the lack of fungal vaccines, limited diagnostics and increasing antifungal drug resistance. This mini-review outlines how modern-day clinical practices have shaped the recent increase in fungal diseases observed in the last few decades. We discuss new research that has implicated the use of immune-modulating drugs in the enhanced susceptibility of vulnerable patients to life-threatening fungal infections.

Keywords: Aspergillus; Candida; antibiotics; corticosteroids; fungi; ibrutinib; macrophage.

Figure 1

Iatrogenic interference with the initiation of antifungal immunity. Pathogen-associated molecular patterns (PAMPs) in the fungal cell wall (e.g., β-glucan) are detected by pattern recognition receptors (PRRs) on the plasma membranes of host phagocytes (e.g., Dectin-1). This initiates Syk-dependent assembly of the CBM (CARD9-BCL10-MALT1) signalosome, leading to NF-κB activation, mitogen-activated protein kinase (MAPK) signalling and a calcium flux, resulting in antifungal cellular responses. Treatments for comorbidities, such as anti-cancer therapies plus antibiotics, can interfere with this fungal detection pathway, as highlighted by red inhibitory arrows. Syk, spleen tyrosine kinase; CARD9, caspase recruitment domain-containing protein 9; MALT1, mucosa associated lymphoid tissue translocation protein 1; BCL10, B-cell lymphoma 10; IL, interleukin; Th, T helper; MAF, macrophage-activating factor; ROS, reactive oxygen species; NFκB, nuclear factor kappa B.

Figure 2

Antibiotics affect lactobacilli-mediated modulation of NLRP3 activation, predisposing to vulvovaginal candidiasis (VVC). Lactobacilli induce AhR (aryl hydrocarbon receptor)-dependent IL-22 (interleukin-22) transcription, promoting barrier function and regulation of mucosal immune responses through NLRC4-mediated production of the IL-1 receptor antagonist (IL1Ra), which inhibits activation of the NLRP3 inflammasome and production of IL-1β, IL-1α and IL-18, preventing neutrophil recruitment and C. albicans infection. Antibiotic treatment eradicates lactobacilli from the vaginal tract, leading to NLRP3 inflammasome activation and pro-inflammatory cytokine release, leading to dysbiosis and infection.