The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression

Abstract

Bacterial infections typically elicit a strong Heat Shock Response (HSR) in host cells. However, the gastric pathogen Helicobacter pylori has the unique ability to repress this response, the mechanism of which has yet to be elucidated. This study sought to characterize the underlying mechanisms by which H. pylori down-modulates host HSP expression upon infection. Examination of isogenic mutant strains of H. pylori defective in components of the type IV secretion system (T4SS), identified the secretion substrate, CagA, to be essential for down-modulation of the HSPs HSPH1 (HSP105), HSPA1A (HSP72), and HSPD1 (HSP60) upon infection of the AGS gastric adenocarcinoma cell line. Ectopic expression of CagA by transient transfection was insufficient to repress HSP expression in AGS or HEK293T cells, suggesting that additional H. pylori factors are required for HSP repression. RT-qPCR analysis of HSP gene expression in AGS cells infected with wild-type H. pylori or isogenic cagA-deletion mutant found no significant change to account for reduced HSP levels. In summary, this study identified CagA to be an essential bacterial factor for H. pylori-mediated suppression of host HSP expression. The novel finding that HSPH1 is down-modulated by H. pylori further highlights the unique ability of H. pylori to repress the HSR within host cells. Elucidation of the mechanism by which H. pylori achieves HSP repression may prove to be beneficial in the identification of novel mechanisms to inhibit the HSR pathway and provide further insight into the interactions between H. pylori and the host gastric epithelium.

Association between Active Helicobacter pylori Infection and Glaucoma: A Systematic Review and Meta-Analysis

“…Autoantibodies against proteins in the retina and/or the optic nerve, resulting from the possible molecular mimicry between H. pylori and ocular proteins, might be involved in glaucomatous neuropathy of the optic nerve [63,64]. More specifically, H. pylori antigens stimulate the production of specific antibodies which recognize homologous host protein sequences, such as in glycoproteins, heat-shock proteins (Hsps), H + /K + ATPase, H + /K + -adenosine triphosphatase, Human leukocyte antigens (HLA), chemokine receptors, Lewis antigens, and act as autoantibodies [58,[67][68][69][70]. In this regard, an example could be autoimmune gastritis, in which similarities of H + , K + -ATPase and bacterial epitopes may result in the production of antibodies against parietal cells, thereby suggesting that bacterial infection may be the trigger of an autoimmune mucosal inflammation resulting to mucosa atrophy in patients with chronic H. pylori gastritis [71].…”

Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity

“…CDX1 activation promotes cell proliferation, invasion/migration, intestinalization of gastric epithelial cells, and stem cell-like phenotype induction leading to cancer development and failure of common gastric cancer chemotherapies [160]. Recently, another study discovered CagA-mediated downregulation of heat shock protein 1 (HSP1) expression after H. pylori infection [54]. CagA-dependent acute HSP1 suppression represses the host immune response, so H. pylori may escape from the immune response and enhance infection establishment [55].…”

Transcriptional Responses of Dictyostelium discoideum Exposed to Different Classes of Bacteria

“…Finally, 11 out of the 20 most down-regulated genes in cells exposed to M. marinum were hsp20-containing heat shock proteins with Hspg1 showing the highest fold change (=36). At this stage, we lack a functional interpretation for this observation, but a similar phenotype has been observed upon exposure of AGS gastric adenocarcinoma cells to H. pylori (Lang et al, 2016). This observation may thus warrant further scrutiny.…”