Card9 protects fungal peritonitis through regulating Malt1-mediated activation of autophagy in macrophage

Fungal peritonitis is an inflammatory condition of the peritoneum which occurs secondary to peritoneal dialysis. Most cases of peritonitis are caused by microbial invasion into the peritoneal cavity, resulting in high morbidity and mortality. Unlike bacterial peritonitis, little is known on fungal peritonitis. Card9, an adapter protein, plays a critical role in anti-fungal immunity. In this study, by using zymosan-induced peritonitis and C. albicans-induced peritonitis mouse model, we demonstrated that fungal peritonitis was exacerbated in Card9^-/- mice, compared with WT mice. Next, we found the autophagy activation of peritonealmacrophages was impaired in Card9^-/- peritonitis mice. The autophagy agonist, MG132, ameliorated peritonitis in Card9^-/- mice. The result of microarray analysis indicates Malt1 was significantly decreased in Card9^-/- peritonitis mice. Furthermore, we demonstrated that Malt1 interacts with P62 and mediates the function of P62 to clear ubiquitinated proteins. After overexpression of Malt1, impaired autophagy activation caused by Card9 deficient was significantly rescued. Together, our results indicate that Card9 protects fungal peritonitis by regulating Malt1-mediated autophagy in macrophages. Our research provides a new idea for the pathogenesis of fungal peritonitis, which is of great significance for the clinical treatment of fungal peritonitis.