Mutagenic potency of<i>Helicobacter pylori</i>in the gastric mucosa of mice is determined by sex and duration of infection

Sheh, Alexander; Lee, Chung-Wei; Masumura, Ken-ichi; Rickman, Barry; Nohmi, Takehiko; Wogan, Gerald N.; Fox, James G.; Schauer, David B.

doi:10.1073/pnas.1009017107

Cited by 40 publications

(46 citation statements)

References 56 publications

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“…This number represents a notable increase over the spontaneous mutation rate, estimated for mammalian cells to be on average 1.1-1.5 mutations per cell division (52,53). Given that no repair pathway specific for 5ClC has yet been described (perhaps explaining the accumulation and persistence of this lesion in the genome), it is plausible that 5ClC is an important contributor to the mutagenic burden previously observed in tissues subjected to chronic inflammation (54,55) and thus increases the probability that such tissues progress toward malignancy.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.5-chloro-deoxycytidine | hypochlorite | myeloperoxidase | inflammatory bowel disease | carcinogenesis

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Section: Discussionmentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…[31][32][33][34][35][36] Males generally exhibit lower immune responses than females. 22,31,37 The phagocytic activity of macrophages and production of inflammatory cytokines are higher in females than in males.…”

Section: Discussionmentioning

confidence: 99%

Effect of Sex Steroids on Babesia microti Infection in Mice

Sasaki¹,

Fujii²,

Iwamoto³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. Sex-based-differences are known to affect susceptibility to protozoan infections, but their effects on parasitemia and clinical symptoms in Babesia infections remain unclear. We examined the sex-based susceptibility of various mouse strains to Babesia microti Munich strain infection. In all strains, male mice exhibited significantly higher peak parasitemia and more severe anemia than female mice. Testosterone and estradiol-17β treatment caused an increase in parasitemia and aggravation of anemia. Orchidectomized male mice receiving testosterone exhibited smaller splenic macrophage populations three days after infection, smaller B cell populations 10 days after infection, and reduced splenic tumor necrosis factor-α and interferon-γ mRNA expression than mice that did not receive testosterone. Mice receiving estradiol-17β did not exhibit immunosuppressive effects. Thus, a weakened and delayed innate immunity response may lead to acquired immunity failure. The results suggested that testosterone directly affects T or B cells, leading to delayed acquired immunity, dramatically increased parasitemia, and severe anemia.

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“…Arguably, the latter would have to consider the diverse roles of the iNOS product, NO and its derivatives. In the context of H. pylori infection, this may include antimicrobial (4) and, potentially, tumorigenic (7,(43)(44)(45)(46)(47) effects during infection. Interestingly, iNOS polymorphisms have allegedly been implicated in disease outcome with respect to gastric cancer (48,49).…”

Section: Discussionmentioning

confidence: 99%

Mucosal Inducible NO Synthase–Producing IgA+ Plasma Cells in Helicobacter pylori–Infected Patients

Neumann

Mueller

Moos

et al. 2016

The Journal of Immunology

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The mucosal immune system is relevant for homeostasis, immunity, and also pathological conditions in the gastrointestinal tract. Inducible NO synthase (iNOS)–dependent production of NO is one of the factors linked to both antimicrobial immunity and pathological conditions. Upregulation of iNOS has been observed in human Helicobacter pylori infection, but the cellular sources of iNOS are ill defined. Key differences in regulation of iNOS expression impair the translation from mouse models to human medicine. To characterize mucosal iNOS-producing leukocytes, biopsy specimens from H. pylori–infected patients, controls, and participants of a vaccination trial were analyzed by immunohistochemistry, along with flow cytometric analyses of lymphocytes for iNOS expression and activity. We newly identified mucosal IgA-producing plasma cells (PCs) as one major iNOS+ cell population in H. pylori–infected patients and confirmed intracellular NO production. Because we did not detect iNOS+ PCs in three distinct infectious diseases, this is not a general feature of mucosal PCs under conditions of infection. Furthermore, numbers of mucosal iNOS+ PCs were elevated in individuals who had cleared experimental H. pylori infection compared with those who had not. Thus, IgA+ PCs expressing iNOS are described for the first time, to our knowledge, in humans. iNOS+ PCs are induced in the course of human H. pylori infection, and their abundance seems to correlate with the clinical course of the infection.

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Mutagenic potency ofHelicobacter pyloriin the gastric mucosa of mice is determined by sex and duration of infection

Cited by 40 publications

References 56 publications

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Effect of Sex Steroids on Babesia microti Infection in Mice

Mucosal Inducible NO Synthase–Producing IgA+ Plasma Cells in Helicobacter pylori–Infected Patients

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