Dataset Information

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection.

ABSTRACT: Extraintestinal pathogenic Escherichia coli (ExPEC) is one of the top pathogens responsible for bloodstream infection and severe, often fatal, sepsis. Although the virulence factors and host immune responses to ExPEC infection have been investigated, the responses to a particular ExPEC strain could be very different. In this study, we investigated the mechanisms of Cyclooxygenase-2 (COX-2) up-regulation in influencing the host defenses against infection of ExPEC XM O2:K1:H7. Our results demonstrated that ExPEC XM O2:K1:H7 infection in mouse and RAW264.7 macrophages leads to COX-2 up-regulation, and COX-2 inhibition significantly enhances ExPEC infection. The up-regulation of COX-2 in macrophages was mediated by Toll-like receptor 4 (TLR4) through the activation of p38 and extracellular signal-regulated kinase/Mitogen-activated protein kinase (ERK/MAPK) pathways. Further studies showed that COX-2 inhibition significantly decreased autophagy in macrophages during ExPEC XM O2:K1:H7 infection. Autophagy inhibition significantly enhanced, while induction reduced ExPEC XM O2:K1:H7 survival in macrophages. In addition, COX-2 inhibition significantly increased macrophage cell death during ExPEC XM O2:K1:H7 infection and increased the expression of anti-inflammatory cytokine interleukin-10 (IL-10). Our results indicate that COX-2 up-regulation benefits host defense against ExPEC XM O2:K1:H7 infection by increasing autophagy in macrophages and by reducing IL-10 expression and macrophage cell death during ExPEC infection.

SUBMITTER: Ren H

PROVIDER: S-EPMC7180184 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic <i>Escherichia coli</i> Infection.

Ren Haiyan H Chen Xuhua X Jiang Fengwei F Li Ganwu G

Frontiers in microbiology 20200417

Extraintestinal pathogenic <i>Escherichia coli</i> (ExPEC) is one of the top pathogens responsible for bloodstream infection and severe, often fatal, sepsis. Although the virulence factors and host immune responses to ExPEC infection have been investigated, the responses to a particular ExPEC strain could be very different. In this study, we investigated the mechanisms of Cyclooxygenase-2 (COX-2) up-regulation in influencing the host defenses against infection of ExPEC XM O2:K1:H7. Our results d ...[more]

PMID: 32362888

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Project description:The extraintestinal pathogenic Escherichia coli (ExPEC) is a typical facultative intracellular bacterial pathogen. Sensing the environmental stimuli and undertaking adaptive change are crucial for ExPEC to successfully colonize in specific extraintestinal niches. The previous studies show that pathogens exploit two-component systems (TCSs) in response to the host environments during its infection. The PhoP/PhoQ is a typical TCS which is ubiquitous in Gram-negative bacteria. However, there is an incompletely understanding about critical regulatory roles of PhoP/PhoQ in ExPEC pathogenesis. Conjugative ColV-related plasmids are responsible for ExPEC virulence, which is associated with ExPEC zoonotic risk. In this study, the molecular characteristics of HlyF, Mig-14 ortholog (Mig-14p), and OmpT variant (OmpTp) encoded by ColV plasmids were identified. Mig-14p and OmpTp played important roles in conferring ExPEC resistance to cationic antimicrobial peptides (CAMPs) during the infection. Moreover, HlyF and Mig-14p acted as intracellular survival factors to promote ExPEC resistance to macrophages killing. The hlyF and Mig-14p formed an operon in ExPEC ColV plasmid, and PhoP acted as a transcriptional activator of hlyF operon by directly binding to the P hlyF promoter. The acidic pH and CAMPs could additively stimulate ExPEC PhoQ/PhoP activities to upregulate the expression of HlyF and Mig-14p. Our studies revealed that the novel PhoP/PhoQ-HlyF signaling pathway directly upregulates the production of ExPEC outer membrane vesicles. Furthermore, our study first clarified that this PhoP/PhoQ-HlyF pathway was essential for ExPEC intracellular survival in macrophages. It was required to prevent the fusion of ExPEC-containing phagosomes with lysosomes. Moreover, PhoP/PhoQ-HlyF pathway facilitated the inhibition of the phagolysosomal acidification and disruption of the phagolysosomal membranes. In addition, this pathway might promote the formation of ExPEC-containing autophagosome during ExPEC replication in macrophages. Collectively, our studies suggested that PhoP/PhoQ system and CloV plasmids could facilitate ExPEC survival and replication within macrophages.

Dataset Information

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection.

Publications

Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic <i>Escherichia coli</i> Infection.

Similar Datasets

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