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16 pages, 1966 KiB

Open AccessFeature PaperArticle

Cj0683 Is a Competence Protein Essential for Efficient Initialization of DNA Uptake in Campylobacter jejuni

by Julia C. Golz, Sandra Preuß, Christoph Püning, Greta Gölz and Kerstin Stingl

Biomolecules 2023, 13(3), 514; https://doi.org/10.3390/biom13030514 - 11 Mar 2023

Cited by 1 | Viewed by 1838

Abstract

C. jejuni is an important food-borne pathogen displaying high genetic diversity, substantially based on natural transformation. The mechanism of DNA uptake from the environment depends on a type II secretion/type IV pilus system, whose components are partially known. Here, we quantified DNA uptake [...] Read more.

C. jejuni is an important food-borne pathogen displaying high genetic diversity, substantially based on natural transformation. The mechanism of DNA uptake from the environment depends on a type II secretion/type IV pilus system, whose components are partially known. Here, we quantified DNA uptake in C. jejuni at the single cell level and observed median transport capacities of approximately 30 kb per uptake location. The process appeared to be limited by the initialization of DNA uptake, was finite, and, finalized within 30 min of contact to DNA. Mutants lacking either the outer membrane pore PilQ or the inner membrane channel ComEC were deficient in natural transformation. The periplasmic DNA binding protein ComE was negligible for DNA uptake, which is in contrast to its proposed function. Intriguingly, a mutant lacking the unique periplasmic protein Cj0683 displayed rare but fully functional DNA uptake events. We conclude that Cj0683 was essential for the efficient initialization of DNA uptake, consistent with the putative function as a competence pilus protein. Unravelling features important in natural transformation might lead to target identification, reducing the adaptive potential of pathogens. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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14 pages, 3912 KiB

Open AccessArticle

Intestinal Barrier in Post-Campylobacter jejuni Irritable Bowel Syndrome

by Sholpan Omarova, Karem Awad, Verena Moos, Christoph Püning, Greta Gölz, Jörg-Dieter Schulzke and Roland Bücker

Biomolecules 2023, 13(3), 449; https://doi.org/10.3390/biom13030449 - 28 Feb 2023

Cited by 9 | Viewed by 2631

Abstract

Background: Campylobacter jejuni (C. jejuni) is one of the most common causes of bacterial gastroenteritis worldwide. One sequela of this infection is the development of post-infectious irritable bowel syndrome (PI-IBS). It has been suggested that a dysfunctional intestinal barrier may promote [...] Read more.

Background: Campylobacter jejuni (C. jejuni) is one of the most common causes of bacterial gastroenteritis worldwide. One sequela of this infection is the development of post-infectious irritable bowel syndrome (PI-IBS). It has been suggested that a dysfunctional intestinal barrier may promote IBS development. We aimed to test this hypothesis against the background of the leaky gut concept for low-grade inflammation in PI-IBS. Methods: We identified patients with persistent PI-IBS symptoms after C. jejuni infection. During sigmoidoscopy, forceps biopsies were obtained for electrophysiological measurements of epithelial transport and barrier function in miniaturized Ussing devices. C. jejuni absence was checked by PCR and cytokine production with immunohistochemistry. Results: In PI-IBS, the epithelial resistance of the colon epithelium was unaltered, reflecting an intact paracellular pathway. In contrast, temperature-dependent horseradish peroxidase (HRP, 44 kDa) permeation increased. Short-circuit current (Isc) reflecting active anion secretion and ENaC-dependent electrogenic sodium absorption was unaffected. Early endosome antigen-1 (EEA1) and IL-4 levels increased. C. jejuni is not incorporated into the resident microbiota of the colon mucosa in PI-IBS. Conclusions: In PI-IBS after C. jejuni infection, macromolecule uptake via endocytosis was enhanced, leading to low-grade inflammation with pro-inflammatory cytokine release. The findings will allow C. jejuni-induced pathomechanisms to be targeted during infection and, thereafter to reduce sequelae such as PI-IBS. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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19 pages, 3555 KiB

Open AccessArticle

Therapeutic Oral Application of Carvacrol Alleviates Acute Campylobacteriosis in Mice Harboring a Human Gut Microbiota

by Minnja S. Foote, Ke Du, Soraya Mousavi, Stefan Bereswill and Markus M. Heimesaat

Biomolecules 2023, 13(2), 320; https://doi.org/10.3390/biom13020320 - 8 Feb 2023

Cited by 7 | Viewed by 1920

Abstract

Human Campylobacter jejuni infections are rising globally. Since antibiotics are usually not indicated in acute campylobacteriosis, antibiotic-independent intervention measures are desirable. The phenolic compound carvacrol constitutes a promising candidate molecule given its antimicrobial and immune-modulatory features. To test the disease-alleviating effects of oral [...] Read more.

Human Campylobacter jejuni infections are rising globally. Since antibiotics are usually not indicated in acute campylobacteriosis, antibiotic-independent intervention measures are desirable. The phenolic compound carvacrol constitutes a promising candidate molecule given its antimicrobial and immune-modulatory features. To test the disease-alleviating effects of oral carvacrol treatment in acute murine campylobacteriosis, IL-10^−/− mice harboring a human gut microbiota were perorally infected with C. jejuni and treated with carvacrol via the drinking water. Whereas C. jejuni stably established in the gastrointestinal tract of mice from the placebo cohort, carvacrol treatment resulted in lower pathogen loads in the small intestines on day 6 post infection. When compared to placebo, carvacrol ameliorated pathogen-induced symptoms including bloody diarrhea that was accompanied by less distinct histopathological and apoptotic cell responses in the colon. Furthermore, innate and adaptive immune cell numbers were lower in the colon of carvacrol- versus placebo-treated mice. Notably, carvacrol application dampened C. jejuni-induced secretion of pro-inflammatory mediators in intestinal, extra-intestinal and systemic organs to naive levels and furthermore, resulted in distinct shifts in the fecal microbiota composition. In conclusion, our preclinical placebo-controlled intervention study provides evidence that therapeutic carvacrol application constitutes a promising option to alleviate campylobacteriosis in the infected vertebrate host. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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14 pages, 2376 KiB

Open AccessArticle

Cysteine Biosynthesis in Campylobacter jejuni: Substrate Specificity of CysM and the Dualism of Sulfide

by Noah Hitchcock, David J. Kelly, Andrew Hitchcock and Aidan J. Taylor

Biomolecules 2023, 13(1), 86; https://doi.org/10.3390/biom13010086 - 31 Dec 2022

Cited by 3 | Viewed by 3283

Abstract

Campylobacter jejuni is a highly successful enteric pathogen with a small, host-adapted genome (1.64 Mbp, ~1650 coding genes). As a result, C. jejuni has limited capacity in numerous metabolic pathways, including sulfur metabolism. Unable to utilise ionic sulfur, C. jejuni relies on the [...] Read more.

Campylobacter jejuni is a highly successful enteric pathogen with a small, host-adapted genome (1.64 Mbp, ~1650 coding genes). As a result, C. jejuni has limited capacity in numerous metabolic pathways, including sulfur metabolism. Unable to utilise ionic sulfur, C. jejuni relies on the uptake of exogenous cysteine and its derivatives for its supply of this essential amino acid. Cysteine can also be synthesized de novo by the sole cysteine synthase, CysM. In this study, we explored the substrate specificity of purified C. jejuni CysM and define it as an O-acetyl-L-serine sulfhydrylase with an almost absolute preference for sulfide as sulfur donor. Sulfide is produced in abundance in the intestinal niche C. jejuni colonises, yet sulfide is generally viewed as highly toxic to bacteria. We conducted a series of growth experiments in sulfur-limited media and demonstrate that sulfide is an excellent sulfur source for C. jejuni at physiologically relevant concentrations, combating the view of sulfide as a purely deleterious compound to bacteria. Nonetheless, C. jejuni is indeed inhibited by elevated concentrations of sulfide and we sought to understand the targets involved. Surprisingly, we found that inactivation of the sulfide-sensitive primary terminal oxidase, the cbb₃-type cytochrome c oxidase CcoNOPQ, did not explain the majority of growth inhibition by sulfide. Therefore, further work is required to reveal the cellular targets responsible for sulfide toxicity in C. jejuni. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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13 pages, 2222 KiB

Open AccessEditor’s ChoiceArticle

Iron Deprivation by Oral Deferoxamine Application Alleviates Acute Campylobacteriosis in a Clinical Murine Campylobacter jejuni Infection Model

by Stefan Bereswill, Soraya Mousavi, Dennis Weschka, Agnes Buczkowski, Sebastian Schmidt and Markus M. Heimesaat

Biomolecules 2023, 13(1), 71; https://doi.org/10.3390/biom13010071 - 29 Dec 2022

Cited by 6 | Viewed by 1784

Abstract

The progressively rising food-borne Campylobacter jejuni infections pose serious health problems and socioeconomic burdens. Given that antibiotic therapy is not recommended for most campylobacteriosis patients, novel treatment options include strategies targeting iron homeostasis that impacts both C. jejuni virulence and inflammatory cell damage [...] Read more.

The progressively rising food-borne Campylobacter jejuni infections pose serious health problems and socioeconomic burdens. Given that antibiotic therapy is not recommended for most campylobacteriosis patients, novel treatment options include strategies targeting iron homeostasis that impacts both C. jejuni virulence and inflammatory cell damage caused by toxic oxygen species. In our preclinical intervention study, we tested potential disease-alleviating effects upon prophylactic oral application of the iron-chelating compound desferoxamine (DESF) in acute murine campylobacteriosis. Therefore, microbiota-depleted IL-10^−/− mice received synthetic DESF via the drinking water starting seven days before oral infection with C. jejuni strain 81-176. Results revealed that the DESF application did not reduce gastrointestinal pathogen loads but significantly improved the clinical outcome of infected mice at day 6 post-infection. This was accompanied by less pronounced colonic epithelial cell apoptosis, attenuated accumulation of neutrophils in the infected large intestines and abolished intestinal IFN-γ and even systemic MCP-1 secretion. In conclusion, our study highlights the applied murine campylobacteriosis model as suitable for investigating the role of iron in C. jejuni infection in vivo as demonstrated by the disease-alleviating effects of specific iron binding by oral DESF application in acute C. jejuni induced enterocolitis. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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Review

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17 pages, 745 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets in Campylobacter Infections

by Markus M. Heimesaat, Steffen Backert, Thomas Alter and Stefan Bereswill

Biomolecules 2023, 13(3), 409; https://doi.org/10.3390/biom13030409 - 22 Feb 2023

Cited by 8 | Viewed by 4159

Abstract

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients [...] Read more.

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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21 pages, 2071 KiB

Open AccessReview

Evolution and Role of Proteases in Campylobacter jejuni Lifestyle and Pathogenesis

by Bodo Linz, Irshad Sharafutdinov, Nicole Tegtmeyer and Steffen Backert

Biomolecules 2023, 13(2), 323; https://doi.org/10.3390/biom13020323 - 8 Feb 2023

Cited by 9 | Viewed by 3124

Abstract

Infection with the main human food-borne pathogen Campylobacter jejuni causes campylobacteriosis that accounts for a substantial percentage of gastrointestinal infections. The disease usually manifests as diarrhea that lasts for up to two weeks. C. jejuni possesses an array of peptidases and proteases that [...] Read more.

Infection with the main human food-borne pathogen Campylobacter jejuni causes campylobacteriosis that accounts for a substantial percentage of gastrointestinal infections. The disease usually manifests as diarrhea that lasts for up to two weeks. C. jejuni possesses an array of peptidases and proteases that are critical for its lifestyle and pathogenesis. These include serine proteases Cj1365c, Cj0511 and HtrA; AAA+ group proteases ClpP, Lon and FtsH; and zinc-dependent protease PqqE, proline aminopeptidase PepP, oligopeptidase PepF and peptidase C26. Here, we review the numerous critical roles of these peptide bond-dissolving enzymes in cellular processes of C. jejuni that include protein quality control; protein transport across the inner and outer membranes into the periplasm, cell surface or extracellular space; acquisition of amino acids and biofilm formation and dispersal. In addition, we highlight their role as virulence factors that inflict intestinal tissue damage by promoting cell invasion and mediating cleavage of crucial host cell factors such as epithelial cell junction proteins. Furthermore, we reconstruct the evolution of these proteases in 34 species of the Campylobacter genus. Finally, we discuss to what extent C. jejuni proteases have initiated the search for inhibitor compounds as prospective novel anti-bacterial therapies. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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32 pages, 2924 KiB

Open AccessFeature PaperReview

The Missing Pieces: The Role of Secretion Systems in Campylobacter jejuni Virulence

by Amber D. Gabbert, Jennifer L. Mydosh, Prabhat K. Talukdar, Lisa M. Gloss, Jason E. McDermott, Kerry K. Cooper, Geremy C. Clair and Michael E. Konkel

Biomolecules 2023, 13(1), 135; https://doi.org/10.3390/biom13010135 - 9 Jan 2023

Cited by 16 | Viewed by 5698

Abstract

Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. Further, C. jejuni infections are associated with post-infection sequelae in developed countries and [...] Read more.

Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. Further, C. jejuni infections are associated with post-infection sequelae in developed countries and malnutrition and growth-stunting in low- and middle-income countries. Despite the increasing prevalence of the disease, campylobacteriosis, and the recognition that this pathogen is a serious health threat, our understanding of C. jejuni pathogenesis remains incomplete. In this review, we focus on the Campylobacter secretion systems proposed to contribute to host-cell interactions and survival in the host. Moreover, we have applied a genomics approach to defining the structural and mechanistic features of C. jejuni type III, IV, and VI secretion systems. Special attention is focused on the flagellar type III secretion system and the prediction of putative effectors, given that the proteins exported via this system are essential for host cell invasion and the inflammatory response. We conclude that C. jejuni does not possess a type IV secretion system and relies on the type III and type VI secretion systems to establish a niche and potentiate disease. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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