NLRP3 and mTOR Reciprocally Regulate Macrophage Phagolysosome Formation and Acidification Against Vibrio vulnificus Infection.

Xian-Hui Huang,Yong-Liang Lou,Na Chen,Mei-Na Hu,Meng-Meng Zheng,Yao Ma,Yi Zheng,Dan-Li Xie,Liu-Ying Wu

doi:10.3389/fcell.2020.587961

Abstract

The marine bacterium Vibrio vulnificus causes potentially fatal bloodstream infections, typically in patients with chronic liver diseases. The inflammatory response and anti-bacterial function of phagocytes are crucial for limiting bacterial infection in the human hosts. How V. vulnificus affects macrophages after phagocytosis is unclear. In this report, we found that the bactericidal activity of macrophages to internalize V. vulnificus was dependent on mammalian target of rapamycin (mTOR) and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) interaction. Additionally, the NLRP3 expression was dependent on mTORC1 activation. Inhibited mTORC1 or absence of NLRP3 in macrophages impaired V. vulnificus-induced phagosome acidification and phagolysosome formation, leading to a reduction of intracellular bacterial clearance. mTORC1 signaling overactivation could increase NLRP3 expression and restore insufficient phagosome acidification. Together, these findings indicate that the intracellular bactericidal activity of macrophages responding to V. vulnificus infection is tightly controlled by the crosstalk of NLRP3 and mTOR and provide critical insight into the host bactericidal activity basis of clearance of V. vulnificus through lyso/phagosome.

Highlights

Vibrio vulnificus is a Gram-negative bacterium that causes primary septicemia, inflammationmediated septic shock, and necrotizing wound infection (Blake et al, 1979; Park and Lee, 2018; Baker-Austin and Oliver, 2020)
Our study demonstrates that intracellular bactericidal activity of macrophages against V. vulnificus infection is tightly controlled by the novel crosstalk of NLRP3 and mammalian target of rapamycin (mTOR), and it could be a new therapeutic approach for bacterial infections
We found that NLRP3 mRNA expression was increased in Kupffer cells (KCs) from V. vulnificus-infected mice

Summary

Introduction

Vibrio vulnificus is a Gram-negative bacterium that causes primary septicemia, inflammationmediated septic shock, and necrotizing wound infection (Blake et al, 1979; Park and Lee, 2018; Baker-Austin and Oliver, 2020). Cases of V. vulnificus infection have been reported worldwide, including the United States, China, Australia, Germany, Korea, and Japan (Zhao et al, 2015; Heng et al, 2017). Infection with this bacterium is related to V. vulnificus contaminated raw seafood consumption or an open wound that was exposed to warm seawater containing this bacteria (BakerAustin and Oliver, 2020). V. vulnificus infection can lead to death by developing an overwhelming primary sepsis (Chou et al, 2010; Baker-Austin and Oliver, 2018, 2020). Little is known about the underlying mechanisms by which molecules in human hosts regulate the host’s innate immunity-mediated anti-V. vulnificus defense

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