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Innate immune detection of flagellin positively and negatively regulates salmonella infection.

ABSTRACT: Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems for host defense against wild type Salmonella infection is complex, and innate immune detection of flagellin contributes to both protection and susceptibility. We hypothesized that efficient modulation of flagellin expression in vivo permits Salmonella to evade innate immune detection and limit the functional role of flagellin-specific host innate defenses. To test this hypothesis, we used Salmonella deficient in the anti-sigma factor flgM, which overproduce flagella and are attenuated in vivo. In this study we demonstrate that flagellin recognition by the innate immune system is responsible for the attenuation of flgM(-) S. Typhimurium, and dissect the contribution of each flagellin recognition pathway to bacterial clearance and inflammation. We demonstrate that caspase-1 controls mucosal and systemic infection of flgM(-) S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum and systemic infection, but attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition helps Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.

SUBMITTER: Lai MA

PROVIDER: S-EPMC3747147 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Innate immune detection of flagellin positively and negatively regulates salmonella infection.

Lai Marvin A MA Quarles Ellen K EK López-Yglesias Américo H AH Zhao Xiaodan X Hajjar Adeline M AM Smith Kelly D KD

PloS one 20130819 8

Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems for host defense against wild type Salmonella infection is ...[more]

PMID: 23977202

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Project description:Elaborate regulation of innate immunity is necessary for the host to effectively respond to invading pathogens. As an important component of antiviral immunity transcription factors, the stability and activity of interferon (IFN) regulatory factor 3 (IRF3) are tightly controlled via multiple post-translational modifications. Here, we identified a human ovarian tumor domain-containing deubiquitinase OTUD6B as a positive regulator of IRF3 that facilitates type I IFN innate antiviral immune signaling. Mechanically, we found that OTUD6B interacts with IRF3 and directly hydrolyzes both the lysine 11 (K11)- and the lysine 33 (K33)-linked polyubiquitin chain, but only K33-linked polyubiquitin at Lys315 of IRF3 is responsible for IRF3 proteasome degradation. Notably, OTUD6B enhanced cellular antiviral responses in vivo, as evidenced by mice that overexpressed human OTUD6B were more resistant to RNA virus infection and had reduced viral load and morbidity. These findings revealed a previously unknown role for OTUD6B in the regulation of innate antiviral immunity and may provide a potential target for enhancing host antiviral defense. IMPORTANCE Interferon (IFN) regulatory factor (IRF3) is one of the key factors for type I IFN transcription. To sophisticatedly regulate type I IFN antiviral immune response, IRF3 activity is closely controlled by a variety of post-translational modifications. However, the regulatory mechanisms are still not fully elucidated. In the present study, we found that human deubiquitinase OTUD6B positively regulates IRF3-mediated antiviral immune response. OTUD6B can stabilize the IRF3 protein level via hydrolyzing (Lys33)-linked polyubiquitin at Lys315. More importantly, mice with OTUD6B overexpression exhibited more resistance to RNA virus infection. Thus, unlike the previous report that zebrafish OTUD6B negatively regulates the antiviral response by suppressing K63-linked ubiquitination of IRF3 and IRF7, we demonstrate that human OTUD6B actually enhances type I IFN response and has the potential for antiviral therapy.

Dataset Information

Innate immune detection of flagellin positively and negatively regulates salmonella infection.

Publications

Innate immune detection of flagellin positively and negatively regulates salmonella infection.

Similar Datasets

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