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Elucidating the mechanism of Helicobacter pylori-induced Caspase-1 activation and its role in immunity and immune tolerance


Koch, Katrin N. Elucidating the mechanism of Helicobacter pylori-induced Caspase-1 activation and its role in immunity and immune tolerance. 2015, University of Zurich, Faculty of Science.

Abstract

Helicobacter pylori is a Gram-negative, spiral shaped bacterium colonizing the human stomach. Infection with H. pylori is closely linked to the development of gastritis and gastric ulcers which can progress to gastric cancer. Lesions in the stomach are partially caused by the robust inflammatory response generated by the immune system to fight against the invading bacterium. Yet the infection can’t be cleared by the host, leading to chronic inflammation and bacterial persistence. During tens of thousands of years of co-evolution of H. pylori with its human host, H. pylori has evolved several mechanisms enabling it to persistently colonize the human stomach. Those include evasion of innate immune detection, suppression of T effector responses and the induction of a regulatory T cell (Treg) response. Even though these mechanisms have the negative effect of bacterial persistence, especially the induction of a Treg response also has a beneficial side. Specifically, infection with H. pylori has been shown to be protective against allergic asthma, which is Treg-dependent and particularly pronounced if infection happens early in life. In a previous study from our lab, development of a Treg response has been shown to be dependent on IL-18, a cytokine that needs to be cleaved by the protease caspase-1 in order to be bioactive and secreted. Caspase-1 itself also requires proteolytic activity, which takes place upon binding of a Nod-like receptor (NLR) to its ligand leading to the assembly of a multiprotein complex called inflammasome.
Herein, I aimed to elucidate the mechanistic basis of inflammasome assembly in dendritic cells (DCs) upon infection with H. pylori and to identify bacterial factors inducing caspase-1 activation. Moreover, I wanted to assess their role in H. pylori-induced immunity, immune tolerance and specifically asthma protection.
In this work, I could show that H. pylori urease induces signaling via Toll-like receptor (TLR) 2 to upregulate transcription of the NLR NLRP3. This represented the rate limiting step in caspase-1 activation and IL-18 secretion. Consequently, urease-deficient H. pylori abrogated both the suppression of an inflammatory Th1 responses and the induction of a Treg response. Mice infected with urease-deficient H. pylori were no longer protected against allergic asthma. The same phenotypes were observed in TLR2-deficient mice, confirming the importance of TLR2 in the immunosuppressive signaling pathway initiated by H. pylori urease.
Taken together, I identified a previously unrecognized role of H. pylori urease in innate immune detection, immunomodulation and H. pylori persistence. Moreover, I confirmed a critical role of TLR2-mediated IL-18 secretion in H. pylori-induced immune regulation and asthma protection.

Abstract

Helicobacter pylori is a Gram-negative, spiral shaped bacterium colonizing the human stomach. Infection with H. pylori is closely linked to the development of gastritis and gastric ulcers which can progress to gastric cancer. Lesions in the stomach are partially caused by the robust inflammatory response generated by the immune system to fight against the invading bacterium. Yet the infection can’t be cleared by the host, leading to chronic inflammation and bacterial persistence. During tens of thousands of years of co-evolution of H. pylori with its human host, H. pylori has evolved several mechanisms enabling it to persistently colonize the human stomach. Those include evasion of innate immune detection, suppression of T effector responses and the induction of a regulatory T cell (Treg) response. Even though these mechanisms have the negative effect of bacterial persistence, especially the induction of a Treg response also has a beneficial side. Specifically, infection with H. pylori has been shown to be protective against allergic asthma, which is Treg-dependent and particularly pronounced if infection happens early in life. In a previous study from our lab, development of a Treg response has been shown to be dependent on IL-18, a cytokine that needs to be cleaved by the protease caspase-1 in order to be bioactive and secreted. Caspase-1 itself also requires proteolytic activity, which takes place upon binding of a Nod-like receptor (NLR) to its ligand leading to the assembly of a multiprotein complex called inflammasome.
Herein, I aimed to elucidate the mechanistic basis of inflammasome assembly in dendritic cells (DCs) upon infection with H. pylori and to identify bacterial factors inducing caspase-1 activation. Moreover, I wanted to assess their role in H. pylori-induced immunity, immune tolerance and specifically asthma protection.
In this work, I could show that H. pylori urease induces signaling via Toll-like receptor (TLR) 2 to upregulate transcription of the NLR NLRP3. This represented the rate limiting step in caspase-1 activation and IL-18 secretion. Consequently, urease-deficient H. pylori abrogated both the suppression of an inflammatory Th1 responses and the induction of a Treg response. Mice infected with urease-deficient H. pylori were no longer protected against allergic asthma. The same phenotypes were observed in TLR2-deficient mice, confirming the importance of TLR2 in the immunosuppressive signaling pathway initiated by H. pylori urease.
Taken together, I identified a previously unrecognized role of H. pylori urease in innate immune detection, immunomodulation and H. pylori persistence. Moreover, I confirmed a critical role of TLR2-mediated IL-18 secretion in H. pylori-induced immune regulation and asthma protection.

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Additional indexing

Item Type:Dissertation
Referees:Müller Anne, Hardt Wolf-Dietrich, Guarda Greta, Borsig Lubor
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2015
Deposited On:14 Jan 2016 13:38
Last Modified:05 Apr 2016 19:55

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