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Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2−/− mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2−/− mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2−/− mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2−/− mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2−/− mice. Furthermore, the reduction in apoptosis is observed in Aim2−/− mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2−/− mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections. [ABSTRACT FROM AUTHOR]

Simple Summary: The pathogenesis of intestinal inflammatory disorders such as colitis and colorectal cancer is complicated and dysregulation of gut microbiota is considered an important contributing factor. Inflammation is often initiated by the activation of pattern recognition receptors. However, the relationship between these innate immune receptors and gut microbiota is not fully understood. Here, we show that pattern recognition receptors not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses, but also influence the composition of intestinal microorganisms, thus affecting the development of intestinal inflammation and cancer through various mechanisms. This suggests that the modification of innate immune receptors and relevant molecules could be therapeutic targets for the treatment of colitis and colorectal cancer by regulating gut microbiota. Disorders of gut microbiota have been closely linked to the occurrence of various intestinal diseases including colitis and colorectal cancer (CRC). Specifically, the production of beneficial bacteria and intestinal metabolites may slow the development of some intestinal diseases. Recently, it has been proposed that pattern recognition receptors (PRRs) not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses but also influence the composition of intestinal microorganisms. However, the mechanisms through which PRRs regulate gut microbiota in the setting of colitis and CRC have rarely been systematically reviewed. Therefore, in this paper, we summarize recent advances in our understanding of how PRRs shape gut microbiota and how this influences the development of colitis and CRC. [ABSTRACT FROM AUTHOR]