Dataset Information

Giardia lamblia Decreases NF-?B p65^RelA Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

ABSTRACT: The protozoan Giardia lamblia is the most common cause of parasitic gastrointestinal infection worldwide. The parasite developed sophisticated, yet not completely disclosed, mechanisms to escape immune system and growth in the intestine. To further understand the interaction of G. lamblia with host immune cells, we investigated the ability of parasites to modulate the canonical activation of mouse macrophages (Raw 264.7 cell line) and human monocyte-derived macrophages triggered by the TLR4 agonist, lipopolysaccharide (LPS). We observed that G. lamblia impairs LPS-evoked pro-inflammatory status in these macrophage-like cells through inhibition of cyclooxygenase-2 and inducible nitric oxide synthase expression and subsequent NO production. This effect was in part due to the activity of three G. lamblia proteases, a 135?kDa metalloprotease and two cysteine proteases with 75 and 63?kDa, that cleave the p65^RelA subunit of the nuclear factor-kappa B (NF-?B). Moreover, Tnf and Ccl4 transcription was increased in the presence of the parasite. Overall, our data indicates that G. lamblia modulates macrophages inflammatory response through impairment of the NF-?B, thus silencing a crucial signaling pathway of the host innate immune response.

SUBMITTER: Faria CP

PROVIDER: S-EPMC7148380 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Giardia lamblia Decreases NF-κB p65<sup>RelA</sup> Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

Faria Clarissa Perez CP Neves Bruno Miguel BM Lourenço Ágata Á Cruz Maria Teresa MT Martins João D JD Silva Ana A Pereira Sónia S Sousa Maria do Céu MDC

Scientific reports 20200410 1

The protozoan Giardia lamblia is the most common cause of parasitic gastrointestinal infection worldwide. The parasite developed sophisticated, yet not completely disclosed, mechanisms to escape immune system and growth in the intestine. To further understand the interaction of G. lamblia with host immune cells, we investigated the ability of parasites to modulate the canonical activation of mouse macrophages (Raw 264.7 cell line) and human monocyte-derived macrophages triggered by the TLR4 agon ...[more]

PMID: 32277133

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Project description:The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

Dataset Information

Giardia lamblia Decreases NF-?B p65^RelA Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

Publications

Giardia lamblia Decreases NF-κB p65<sup>RelA</sup> Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

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Dataset Information

Giardia lamblia Decreases NF-?B p65RelA Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

Publications

Giardia lamblia Decreases NF-κB p65<sup>RelA</sup> Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Giardia lamblia Decreases NF-?B p65^RelA Protein Levels and Modulates LPS-Induced Pro-Inflammatory Response in Macrophages.