Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

Abstract

Aspergillus fumigatus, as opportunistic fungi, lead to infection in the lungs and even systemic infection. The A. fumigatus interacts with the body through a series of complex and dynamic processes. After the fungi have invaded the host, it has a series of adaptive mechanisms which it applies to evade being detected by a host immune system also ways to retaliate against the immune responses. Regulatory T cells (Tregs) in enhancing immune tolerance and immune escape by inhibiting the body's immune response are concerned. It could increase the sensitivity of bacterial infections. When A. fumigatus enters the host, it stimulates Toll-like receptor 2 (TLR2) and triggers the signal transduction pathway. However, how Tregs affects susceptibility to A. fumigatus and TLR2 changes Tregs in A. fumigatus infection is unclear. We examined whether A. fumigatus induces Tregs proliferation in vivo, molecular mechanisms underlying A. fumigatus-stimulated TLR2 activation and the contribution of Tregs activation to susceptibility to A. fumigatus. We observed that Tregs to CD4+T cells ratio increased in samples from patients infected with Aspergillus fumigatus. After conducting tests in mice, it was revealed that when mice were infected with A. fumigatus, there was an enhancement in the Tregs to CD4+T cells ratio and Foxp3 expression levels which happen in the lungs also up-regulate. Inhibited Tregs by using CD25 neutralizing antibodies, and we found that the number of fungal burdens in the lung was decreased when these CD25 neutralizing antibodies are used. In our research, A. fumigatus infection can indeed stimulate TLR2 expression to increase, and for the lungs, damages and fungal burden caused by TLR2−/−mice were reduced. Then it also found that in TLR2−/-mice, pyrolysis-related proteins (GSDMD, IL-1α, and IL-1β) changed. It was concluded that for TLR2 knockout animals, the Treg cells quantities are significantly linked to vulnerability to be infected with A. fumigatus. The infection triggered the proliferation and differentiation of CD4+CD25+Foxp3+ Tregs through the activation of TLR2 pathway. It is a potential mechanism to evade host defense in A. fumigatus infection of the lung. And this effect can regulate GSDMD-dependent pyrolysis, and may involve TRL2 signals partially.