Abstract
Fungal pathogens kill approximately 1.5 million individuals per year and represent a severe disease burden worldwide. It is estimated over 150 million people have serious fungal disease such as recurrent mucosal infections or life-threatening systemic infections. Disease can ensue from commensal fungi or new infection and involves different fungal morphologies and the expression of virulence factors. Therefore, anti-fungal immunity is complex and requires coordination between multiple facets of the immune system. IL-1 family cytokines are associated with acute and chronic inflammation and are essential for the innate response to infection. Recent research indicates IL-1 cytokines play a key role mediating immunity against different fungal infections. During mucosal disease, IL-1R and IL-36R are required for neutrophil recruitment and protective Th17 responses, but function through different mechanisms. During systemic disease, IL-18 drives protective Th1 responses, while IL-33 promotes Th2 and suppresses Th1 immunity. The IL-1 family represents an attractive anti-fungal immunotherapy target. There is a need for novel anti-fungal therapeutics, as current therapies are ineffective, toxic and encounter resistance, and no anti-fungal vaccine exists. Furthering our understanding of the IL-1 family cytokines and their complex role during fungal infection may aid the development of novel therapies. As such, this review will discuss the role for IL-1 family cytokines in fungal infections.
Highlights
Fungal pathogens represent an increasingly severe disease burden and are responsible for ∼1.5 million deaths per year
Aside from the induction of IL-18 during Aspergillus and Candida disease, IL-18 has been functionally implicated in P. brasiliensis infection (Panagio et al, 2008; Alves et al, 2018), S. schenckii infection (Goncalves et al, 2015), and C. neoformans infection (Kawakami et al, 2000b; Wang et al, 2011), suggesting at the very least a general role in host immune response
When the mitogen-activated protein kinase (MAPK) phosphatase MKP1 was knocked down, IL-36α/γ expression increased (Verma et al, 2018). While these results suggest p38 MAPK induces IL-36 expression and this is negatively regulated by MKP1, MAPK pathways did not fully account for IL-36 expression
Summary
Fungal pathogens represent an increasingly severe disease burden and are responsible for ∼1.5 million deaths per year. IL-1α/β deficient mice continued to possess higher fungal burdens in a neutropenic model of systemic C. albicans infection, suggesting the role of IL-1α/β is not just in neutrophil recruitment. IL-18 signaling drives inflammation and promotes innate and adaptive immunity.
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