Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

Area of Science:

• Immunology
• Microbiology
• Pharmacology

Background:

• Candida albicans causes life-threatening sepsis, particularly in immunocompromised individuals.
• Existing antifungal drugs face challenges with efficacy and resistance, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of p38γ and p38δ kinases in the innate immune response to Candida albicans infection.
• To explore a novel TAK1-TPL2-MKK1-ERK1/2 pathway regulated by p38γ/p38δ in macrophages.

Main Methods:

• Utilized mouse models of Candida albicans infection.
• Investigated immune cell function, including reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) production.
• Assessed inflammatory mediator production and leukocyte recruitment.
• Examined the effects of pharmacological inhibition of p38γ/p38δ.

Main Results:

• p38γ/p38δ deficiency protected mice against C. albicans infection.
• Deficiency led to increased ROS and iNOS, enhancing neutrophil and macrophage antifungal capacity.
• Reduced hyper-inflammation, leukocyte recruitment, and inflammatory mediators mitigated host damage and septic shock.
• Pharmacological inhibition of p38γ/p38δ decreased fungal burden in vivo.

Conclusions:

• p38γ and p38δ kinases are critical regulators of the innate immune response to C. albicans.
• Targeting p38γ/p38δ in myeloid cells presents a promising therapeutic strategy for invasive candidiasis.
• Pharmacological inhibition of p38γ/p38δ offers a potential new treatment for C. albicans infections.