ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions.

Yuzhang Du,Liyun Shi,Danfeng Dong,Yue Song,Shu Huang,Zhihui Ma,Xiaobao Yang,Juanjuan Zheng,Dakang Xu

doi:10.3389/fimmu.2022.839502

Abstract

The clinical severity of Staphylococcus aureus (S. aureus) respiratory infection correlates with antibacterial gene signature. S. aureus infection induces the expression of an antibacterial gene, as well as a central stress response gene, thus activating transcription factor 3 (ATF3). ATF3-deficient mice have attenuated protection against lethal S. aureus pneumonia and have a higher bacterial load. We tested the hypothesis that ATF3-related protection is based on the increased function of macrophages. Primary marrow-derived macrophages (BMDM) were used in vitro to determine the mechanism through which ATF3 alters the bacterial-killing ability. The expression of ATF3 correlated with the expression of antibacterial genes. Mechanistic studies showed that ATF3 upregulated antibacterial genes, while ATF3-deficient cells and lung tissues had a reduced level of antibacterial genes, which was accompanied by changes in the antibacterial process. We identified multiple ATF3 regulatory elements in the antibacterial gene promoters by chromatin immunoprecipitation analysis. In addition, Wild type (WT) mice had higher F4/80 macrophage migration in the lungs compared to ATF3-null mice, which may correlate with actin filament severing through ATF3-targeted actin-modifying protein gelsolin (GSN) for the macrophage cellular motility. Furthermore, ATF3 positively regulated inflammatory cytokines IL-6 and IL-12p40 might be able to contribute to the infection resolution. These data demonstrate a mechanism utilized by S. aureus to induce ATF3 to regulate antibacterial genes for antimicrobial processes within the cell, and to specifically regulate the actin cytoskeleton of F4/80 macrophages for their migration.

Highlights

Staphylococcus aureus (S. aureus) is a major human pathogen that causes severe respiratory infections [1]
To determine whether the difference in survival was due to the difference in bacterial load in various organs, we measured the bacterial load in the lungs, Bronchoalveolar Lavage Fluid (BALF), and extrapulmonary organs after infecting mice with a sublethal inoculum (5 × 107 colony-forming units (CFU)) of S. aureus
We showed that infection with S. aureus significantly increased activating transcription factor 3 (ATF3) expression, which accelerated bacterial clearance and could reduce the symptoms of pneumonia in mice

Summary

Introduction

Staphylococcus aureus (S. aureus) is a major human pathogen that causes severe respiratory infections [1]. Mainly macrophages and neutrophils, act as gatekeepers in their interactions with S. aureus, killing the strain by phagocytosis to clear the infection [2]. The important role of macrophages in protecting from S. aureus infection by using a wide range of ATF3 Positively Regulates Antibacterial Immunity killing mechanisms has attracted increasing attention. S. aureus has evolved multiple strategies to survive, such as manipulating and evading macrophages [2, 3]. Macrophages and S. aureus affect the outcome of infection through various direct interactions. S. aureus has developed resistance to a variety of antibiotics; effective treatment strategies for these bacteria are limited [4]. S. aureus can exploit the immune system to evade the host’s defense system. S. aureus is a serious threat to human health, and new treatment strategies are needed

Methods

Results

Conclusion