S3.4d The role of NLRP3 inflammasome in host defense during Talaromyces marneffei infection

Abstract

Abstract S3.4 Free oral paper session, September 21, 2022, 4:45 PM - 6:15 PM Talaromyces (Penicillium) marneffei (T. marneffei) is the only thermally dimorphic pathogen in Talaromyces. The pathogenesis of T. marneffei in mammals is not yet fully understood. Inhalation of T. marneffei conidia without normal clearance may result in conidia dissemination throughout the body and lead to disseminated infection. In TSM patients, study have shown that IL-1β and IL-18 levels increased and were consistently associated with the severity of sepsis and outcomes of post-treatment. That means poor outcome likely was associated with an overly strong immune response. Several studies have identified inflammasome activation as an essential immune response in host defense against fungal pathogens. Among them, NLRP3 inflammasome is the most widely characterized. However, the role of NLRP3 inflammasomes in T. marneffei-induced immunopathology remains to be elucidated. Therefore, in the present study, we aimed to address the role played by the NLRP3 inflammasome in the T. marneffei systemic infection in mice.   We established T. marneffei infected murine pulmonary model with two groups of mice, including the Nlrp3-/- mice and wild-type mice.   We found that infected mice displayed NLRP3 inflammasome activation and increased production of IL-1β upon pulmonary T. marneffei infection. Further, we demonstrated that T. marneffei conidia activated the NLRP3 inflammasome both in mice and human macrophages. And T. marneffei conidia induced IL-1β released by infected macrophages is NLRP3 inflammasome-dependent. In vivo study, we found that NLRP3 contributes to the development of lethality in the early stage of pulmonary T. marneffei infection. However, Nlrp3-/- mice showed a similar fungal load to the WT in the middle stage of infection and a significantly increased number of fungi recovered from the lung of the WT mice could be seen in the late stage of infection. Moreover, NLRP3 contributes to pathogenic inflammation in pulmonary T. marneffei infection and contributes to neutrophil recruitment and pulmonary injury.   So, in the present study, we demonstrated that the NLRP3 inflammasome is activated during T. marneffei infection. But NLRP3 inflammasome plays a dual role during pathogenic T. marneffei: an early inflammatory response inducing a protective environment, and a subsequent excessive damaging inflammatory response that contributes to pathogenesis and mortality. This study identifies for the first time that activation of the inflammasome in the later stages of TSM detrimentally contributes to pathogenesis and suggests that targeting the inflammasome may be a therapeutic option to treat pathogenic T. marneffei infections.