A small secreted protein triggers a TLR2/4-dependent inflammatory response during invasive Candida albicans infection

Wenjuan Wang,Hui Xiao,Hongyu Wu,Chengshu Wang,Longhai Tang,Wencheng Zhu,Xiongjun Wang,Tiantian Li,Shu-Zhong Cui,Zihou Deng,Jiangye Chen,Qun Zhao

doi:10.1038/s41467-019-08950-3

Abstract

Candida albicans can switch from commensal to pathogenic mode, causing mucosal or disseminated candidiasis. The host relies on pattern-recognition receptors including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) to sense invading fungal pathogens and launch immune defense mechanisms. However, the complex interplay between fungus and host innate immunity remains incompletely understood. Here we report that C. albicans upregulates expression of a small secreted cysteine-rich protein Sel1 upon encountering limited nitrogen and abundant serum. Sel1 activates NF-κB and MAPK signaling pathways, leading to expression of proinflammatory cytokines and chemokines. Comprehensive genetic and biochemical analyses reveal both TLR2 and TLR4 are required for the recognition of Sel1. Further, SEL1-deficient C. albicans display an impaired immune response in vivo, causing increased morbidity and mortality in a bloodstream infection model. We identify a critical component in the Candida-host interaction that opens a new avenue to tackle Candida infection and inflammation.

Highlights

Fungal infection has been constantly increasing worldwide, posing great threat to human health and life
Upon detecting the presence of Olinked mannosyl proteins[3], TLR4 engages adaptors MyD88 and TRIF (TIRdomain-containing adapter-inducing interferon-β) to initiate the complex signaling cascades leading to the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinase (JNK), extracellular signalregulated kinase (ERK), and p38, culminating in the induction of a myriad of proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF), interleukin (IL)-6, IL-1, and chemokine (C-X-C motif) ligand-1/2 (CXCL-1/2)
C. albicans can cause either superficial infection on mucosae or invasive infection to the bloodstream

Summary

Introduction

Fungal infection has been constantly increasing worldwide, posing great threat to human health and life. While the vast majority of fungalsecreted proteins have been demonstrated to function as virulence factors by suppressing the plant defense mechanism, some of them can be recognized by the host surveillance systems and act as elicitors of host defense response, playing an important role in host–fungus interaction[32,33,34,35] Most of these secreted proteins shared common characteristics, such as being of small size, rich in cysteine content, and with a signal peptide, as demonstrated by previous studies on small secreted cysteine-rich proteins (SCPs) mining in plant fungal pathogens[29,36,37,38,39]. Our results shed light on the complex host immune recognition of fungal pathogens, and open a new avenue for the development of treatment on fungus-induced sepsis

Methods

Results

Conclusion