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Neisseria gonorrhoeae infection induces altered amphiregulin processing and release.

ABSTRACT: Adhesion of the human pathogen Neisseria gonorrhoeae has established effects on the host cell and evokes a variety of cellular events including growth factor activation. In the present study we report that infection with N. gonorrhoeae causes altered amphiregulin processing and release in human epithelial cells. Amphiregulin is a well-studied growth factor with functions in various cell processes and is upregulated in different forms cancer and proliferative diseases. The protein is prototypically cleaved on the cell surface in response to external stimuli. We demonstrate that upon infection, a massive upregulation of amphiregulin mRNA is seen. The protein changes its subcellular distribution and is also alternatively cleaved at the plasma membrane, which results in augmented release of an infection-specific 36 kDa amphiregulin product from the surface of human cervical epithelial cells. Further, using antibodies directed against different domains of the protein we could determine the impact of infection on pro-peptide processing. In summary, we present data showing that the infection of N. gonorrhoeae causes an alternative amphiregulin processing, subcellular distribution and release in human epithelial cervical cells that likely contribute to the predisposition cellular abnormalities and anti-apoptotic features of N. gonorrhoeae infections.

SUBMITTER: Lofmark S

PROVIDER: S-EPMC3029346 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Neisseria gonorrhoeae infection induces altered amphiregulin processing and release.

Löfmark Sonja S de Klerk Nele N Aro Helena H

PloS one 20110127 1

Adhesion of the human pathogen Neisseria gonorrhoeae has established effects on the host cell and evokes a variety of cellular events including growth factor activation. In the present study we report that infection with N. gonorrhoeae causes altered amphiregulin processing and release in human epithelial cells. Amphiregulin is a well-studied growth factor with functions in various cell processes and is upregulated in different forms cancer and proliferative diseases. The protein is prototypical ...[more]

PMID: 21298020

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Project description:Pharyngeal gonorrhoea is a common sexually transmitted infection among 'men having sex with other men' (MSM). Neisseria gonorrhoeae (NG) pharyngeal infections are usually characterized by the absence of symptoms, acting as an important reservoir for their further spread. To the best of our knowledge, no information about the composition of the pharyngeal microbiome during an ongoing NG infection is currently available. Therefore, in this study, we characterized the pharyngeal bacterial community profiles associated with NG infection in a well-selected cohort of HIV-negative MSM reporting unsafe oral intercourse. A total of 70 pharyngeal swabs were considered, comparing non-infected subjects (n = 45) versus patients with pharyngeal gonorrhoea (n = 25) whose microbiota composition was analyzed from pharyngeal swabs through sequencing of hypervariable V3-V4 regions of the 16S rRNA gene. The pharyngeal microbiome of all subjects was dominated by Prevotellaceae, Veillonellaceae and Streptococcaceae families. Patients with pharyngeal gonorrhoea harboured a pharyngeal microbiome quite similar to negative subjects. Nevertheless, when looking to less-represented bacterial species (relative abundance approximately 1% or less), an imbalance between aerobe and anaerobe microorganisms was observed in NG-infected patients. In particular, the pharyngeal microbiome of NG-positive individuals was richer in several anaerobes (e.g. Treponema, Parvimonas, Peptococcus, Catonella, Filifactor) and poorer in various aerobe genera (i.e. Pseudomonas, Escherichia), compared to non-infected controls. No significant differences were noticed in the distribution of commensal Neisseria species of the oropharynx between NG-positive and negative subjects. Metabolic variations induced by changes in the microbiome abundance were assessed by a functional prediction of the bacterial metabolic pathways: a more abundant involvement of D-glutamine and D-glutamate metabolism, carbohydrate metabolism, as well as a greater activation of the energy metabolism was observed in patients with pharyngeal gonorrhoea compared to non-infected individuals. Information about the bacterial composition of the pharyngeal microbiome in case of gonorrhoea could shed light on the pathogenesis of the infection and open new perspectives for the prevention and control of this condition.

Project description:Neisseria gonorrhoeae (gonococci) and Neisseria meningitidis (meningococci) are human pathogens that cause gonorrhea and meningococcal meningitis, respectively. Both N. gonorrhoeae and N. meningitidis release a number of small peptidoglycan (PG) fragments, including proinflammatory PG monomers, although N. meningitidis releases fewer PG monomers. The PG fragments released by N. gonorrhoeae and N. meningitidis are generated in the periplasm during cell wall remodeling, and a majority of these fragments are transported into the cytoplasm by an inner membrane permease, AmpG; however, a portion of the PG fragments are released into the extracellular environment through unknown mechanisms. We previously reported that the expression of meningococcal ampG in N. gonorrhoeae reduced PG monomer release by gonococci. This finding suggested that the efficiency of AmpG-mediated PG fragment recycling regulates the amount of PG fragments released into the extracellular milieu. We determined that three AmpG residues near the C-terminal end of the protein modulate AmpG's efficiency. We also investigated the association between PG fragment recycling and release in two species of human-associated nonpathogenic Neisseria: N. sicca and N. mucosa Both N. sicca and N. mucosa release lower levels of PG fragments and are more efficient at recycling PG fragments than N. gonorrhoeae Our results suggest that N. gonorrhoeae has evolved to increase the amounts of toxic PG fragments released by reducing its PG recycling efficiency.Neisseria gonorrhoeae and Neisseria meningitidis are human pathogens that cause highly inflammatory diseases, although N. meningitidis is also frequently found as a normal member of the nasopharyngeal microbiota. Nonpathogenic Neisseria, such as N. sicca and N. mucosa, also colonize the nasopharynx without causing disease. Although all four species release peptidoglycan fragments, N. gonorrhoeae is the least efficient at recycling and releases the largest amount of proinflammatory peptidoglycan monomers, partly due to differences in the recycling permease AmpG. Studying the interplay between bacterial physiology (peptidoglycan metabolism) and pathogenesis (release of toxic monomers) leads to an increased understanding of how different bacterial species maintain asymptomatic colonization or cause disease and may contribute to efforts to mitigate disease.

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Neisseria gonorrhoeae infection induces altered amphiregulin processing and release.

Publications

Neisseria gonorrhoeae infection induces altered amphiregulin processing and release.

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