<i>Helicobacter pylori</i>
            actively suppresses innate immune nucleic acid receptors

Dooyema, Samuel D.R.; Noto, Jennifer M.; Wroblewski, Lydia E.; Piazuelo, M. Blanca; Krishna, U. Murali; Suárez, Giovanni; Romero–Gallo, Judith; Delgado, Alberto; Peek, Richard M.

doi:10.1080/19490976.2022.2105102

Cited by 28 publications

(13 citation statements)

References 73 publications

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“…A key finding of our study was that AIM2 messenger RNA and protein levels were upregulated in H. pylori –positive human gastric biopsies and gastric tissues from H. felis– infected mice, consistent with inflammasome activity. Interestingly, this contrasts recent findings that other DNA sensors, namely, stimulator of interferon genes (STING) and retinoid acid inducible gene I (RIG‐I), are downregulated by Helicobacter in an 8‐week infection mouse model where deletion of Sting1 or Rigi reduced acute immune responses but not chronic gastric inflammation 32 . The expression of both these genes also negatively correlates with GC prognosis in patients 32–34 .…”

Section: Discussioncontrasting

confidence: 57%

The cytosolic DNA sensor AIM2 promotes Helicobacter‐induced gastric pathology via the inflammasome

et al. 2023

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Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori-induced gastric pathology remain ill-defined. The innate immune cytosolic DNA sensor absent in melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild-type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2 À/À versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felisdriven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2 À/À stomachs. These observations in Aim2 À/À mouse stomachs correlated with decreased levels of inflammasome activity (caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1b. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter-induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and precancerous gastric disease.

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Section: Discussioncontrasting

confidence: 57%

The cytosolic DNA sensor AIM2 promotes Helicobacter‐induced gastric pathology via the inflammasome

et al. 2023

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“…Evasion of RIG-I-mediated innate immune responses may help EBV-infected cells transformation. Except for viruses, H. pylori also actively suppresses STING and RIG-I signaling via the downregulation of IRF3 activation [ 106 ]. Decreased RIG-I expression is associated with poor prognosis and promotes cell invasion in human gastric cancer and HCC [ 107 , 108 ].…”

Section: Rationale For Therapeutic Targeting Rlrs In Cancermentioning

confidence: 99%

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

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“…The stimulation of the RIG-I receptor leads to the activation of the transcription factors IRF3 and IRF7 and subsequent expression of IFN-I (233). According to in vitro and ex vivo experiments, recently it was shown that through the downregulation of IRF3 activation, H. pylori actively inhibits cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) and RIG-I signalling (234). DCs-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) is a member of the CLR family which plays a critical role in H. pylori recognition and pathogenesis.…”

Section: Escape From Innate Immune Recognitionmentioning

confidence: 99%

Helicobacter pylorivirulence factors: subversion of host immune system and development of various clinical outcomes

Mohammadzadeh,

Menbari,

Pishdadian

et al. 2023

Expert Rev. Mol. Med.

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Helicobacter pylori (H. pylori) is a worldwide spread bacterium, co-evolving with humans for at least 100 000 years. Despite the uncertainty about the mode of H. pylori transmission, the development of intra-gastric and extra-gastric diseases is attributed to this bacterium. The morphological transformation and production of heterogenic virulence factors enable H. pylori to overcome the harsh stomach environment. Using numerous potent disease-associated virulence factors makes H. pylori a prominent pathogenic bacterium. These bacterial determinants are adhesins (e.g., blood group antigen-binding adhesin (BabA)/sialic acid-binding adhesin (SabA)), enzymes (e.g., urease), toxins (e.g., vacuolating cytotoxin A (VacA)), and effector proteins (e.g., cytotoxin-associated gene A (CagA)) involved in colonisation, immune evasion, and disease induction. H. pylori not only cleverly evades the immune system but also robustly induces immune responses. This insidious bacterium employs various strategies to evade human innate and adaptive immune responses, leading to a life-long infection. Owing to the alteration of surface molecules, innate immune receptors couldn't recognise this bacterium; moreover, modulation of effector T cells subverts adaptive immune response. Most of the infected humans are asymptomatic and only a few of them present severe clinical outcomes. Therefore, the identification of virulence factors will pave the way for the prediction of infection severity and the development of an effective vaccine. H. pylori virulence factors are hereby comprehensively reviewed and the bacterium evasion from the immune response is properly discussed.

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Helicobacter pylori actively suppresses innate immune nucleic acid receptors

Cited by 28 publications

References 73 publications

The cytosolic DNA sensor AIM2 promotes Helicobacter‐induced gastric pathology via the inflammasome

The cytosolic DNA sensor AIM2 promotes Helicobacter‐induced gastric pathology via the inflammasome

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Helicobacter pylorivirulence factors: subversion of host immune system and development of various clinical outcomes

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