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Toll-like receptor 9 modulates macrophage antifungal effector function during innate recognition of Candida albicans and Saccharomyces cerevisiae.

ABSTRACT: Phagocytic responses are critical for effective host defense against opportunistic fungal pathogens. Macrophages sample the phagosomal content and orchestrate the innate immune response. Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and is activated by fungal DNA. Here we demonstrate that specific triggering of TLR9 recruitment to the macrophage phagosomal membrane is a conserved feature of fungi of distinct phylogenetic origins, including Candida albicans, Saccharomyces cerevisiae, Malassezia furfur, and Cryptococcus neoformans. The capacity to trigger phagosomal TLR9 recruitment was not affected by a loss of fungal viability or cell wall integrity. TLR9 deficiency has been linked to increased resistance to murine candidiasis and to restriction of fungal growth in vivo. Macrophages lacking TLR9 demonstrate a comparable capacity for phagocytosis and normal phagosomal maturation compared to wild-type macrophages. We now show that TLR9 deficiency increases macrophage tumor necrosis factor alpha (TNF-?) production in response to C. albicans and S. cerevisiae, independent of yeast viability. The increase in TNF-? production was reversible by functional complementation of the TLR9 gene, confirming that TLR9 was responsible for negative modulation of the cytokine response. Consistently, TLR9 deficiency enhanced the macrophage effector response by increasing macrophage nitric oxide production. Moreover, microbicidal activity against C. albicans and S. cerevisiae was more efficient in TLR9 knockout (TLR9KO) macrophages than in wild-type macrophages. In conclusion, our data demonstrate that TLR9 is compartmentalized selectively to fungal phagosomes and negatively modulates macrophage antifungal effector functions. Our data support a model in which orchestration of antifungal innate immunity involves a complex interplay of fungal ligand combinations, host cell machinery rearrangements, and TLR cooperation and antagonism.

SUBMITTER: Kasperkovitz PV

PROVIDER: S-EPMC3232661 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Toll-like receptor 9 modulates macrophage antifungal effector function during innate recognition of Candida albicans and Saccharomyces cerevisiae.

Kasperkovitz Pia V PV Khan Nida S NS Tam Jenny M JM Mansour Michael K MK Davids Peter J PJ Vyas Jatin M JM

Infection and immunity 20110926 12

Phagocytic responses are critical for effective host defense against opportunistic fungal pathogens. Macrophages sample the phagosomal content and orchestrate the innate immune response. Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and is activated by fungal DNA. Here we demonstrate that specific triggering of TLR9 recruitment to the macrophage phagosomal membrane is a conserved feature of fungi of distinct phylogenetic origins, including Candida albicans, Saccharomyces cerevisiae ...[more]

PMID: 21947771

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Project description:Candida albicans, a ubiquitous opportunistic fungal pathogen, plays a pivotal role in human health and disease. As a commensal organism, it normally resides harmlessly within the human microbiota. However, under certain conditions, C. albicans can transition into a pathogenic state, leading to various infections collectively known as candidiasis. With the increasing prevalence of immunocompromised individuals and the widespread use of invasive medical procedures, candidiasis has become a significant public health concern. The emergence of drug-resistant strains further complicates treatment options, highlighting the urgent need for alternative therapeutic strategies. Antifungal peptides (AFPs) have gained considerable attention as potential candidates for combating Candida spp. infections. These naturally occurring peptides possess broad-spectrum antimicrobial activity, including specific efficacy against C. albicans. AFPs exhibit several advantageous properties, such as rapid killing kinetics, low propensity for resistance development, and diverse mechanisms of action, making them promising alternatives to conventional antifungal agents. In recent years, extensive research has focused on discovering and developing novel AFPs with improved efficacy and selectivity against Candida species. Advances in biotechnology and synthetic peptide design have enabled the modification and optimization of natural peptides, enhancing their stability, bioavailability, and therapeutic potential. Nevertheless, several challenges must be addressed before AFPs can be widely implemented in clinical practice. These include optimizing peptide stability, enhancing delivery methods, overcoming potential toxicity concerns, and conducting comprehensive preclinical and clinical studies. This commentary presents a short overview of candidemia and AFP; articles and reviews published in the last 10 years were searched on The National Library of Medicine (National Center for Biotechnology Information-NIH-PubMed). The terms used were C. albicans infections, antimicrobial peptides, antifungal peptides, antifungal peptides mechanisms of action, candidemia treatments and guidelines, synthetic peptides and their challenges, and antimicrobial peptides in clinical trials as the main ones. Older publications were cited if they brought some relevant concept or helped to bring a perspective into our narrative. Articles older than 20 years and those that appeared in PubMed but did not match our goal to bring updated information about using antifungal peptides as an alternative to C. albicans infections were not considered.

Dataset Information

Toll-like receptor 9 modulates macrophage antifungal effector function during innate recognition of Candida albicans and Saccharomyces cerevisiae.

Publications

Toll-like receptor 9 modulates macrophage antifungal effector function during innate recognition of Candida albicans and Saccharomyces cerevisiae.

Similar Datasets

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