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Somiah, T., Gebremariam, H. G., Zuo, F., Smirnova, K. & Jonsson, A.-B. (2022). Lactate causes downregulation of Helicobacter pylori adhesin genes sabA and labA while dampening the production of proinflammatory cytokines. Scientific Reports, 12, Article ID 20064.
Open this publication in new window or tab >>Lactate causes downregulation of Helicobacter pylori adhesin genes sabA and labA while dampening the production of proinflammatory cytokines
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 20064Article in journal (Refereed) Published
Abstract [en]

Chronic inflammation induced by Helicobacter pylori is strongly associated with gastric cancer development, which is influenced by both bacterial virulence and host genetics. The sialic acid-binding adhesin SabA and the MUC5AC-binding adhesin LabA are important H. pylori virulence factors that facilitate adhesion of the bacterium, which is a crucial step in colonization. Lactate utilization has been reported to play a key role in the pathogenicity of different bacterial species. However, this is poorly understood in H. pylori. In this study, we investigated the effect of lactate on H. pylori adhesin gene expression and the regulation of host inflammatory cytokines. We show that the bacterial adhesins SabA and LabA were downregulated at the transcriptional level during incubation of H. pylori with lactate. Downregulation of sabA required the involvement of the two-component system ArsRS, while labA was regulated via the CheA/CheY system, indicating differences in the regulation of these genes in response to lactate. The levels of the proinflammatory cytokines TNF and IL-6 in H. pylori-stimulated macrophages were reduced when lactate was present. Interestingly, glucose did not prevent the secretion of these cytokines. Taken together, our data suggest that lactate affects H. pylori adhesin gene expression and the host response upon infection.

National Category
Cell and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-213125 (URN)10.1038/s41598-022-24311-5 (DOI)000888057300033 ()36414643 (PubMedID)2-s2.0-85142261554 (Scopus ID)
Available from: 2022-12-20 Created: 2022-12-20 Last updated: 2022-12-20Bibliographically approved
Zuo, F., Somiah, T., Gebremariam, H. G. & Jonsson, A.-B. (2022). Lactobacilli Downregulate Transcription Factors in Helicobacter pylori That Affect Motility, Acid Tolerance and Antimicrobial Peptide Survival. International Journal of Molecular Sciences, 23(24), Article ID 15451.
Open this publication in new window or tab >>Lactobacilli Downregulate Transcription Factors in Helicobacter pylori That Affect Motility, Acid Tolerance and Antimicrobial Peptide Survival
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 24, article id 15451Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori infection triggers inflammation that may lead to gastritis, stomach ulcers and cancer. Probiotic bacteria, such as Lactobacillus, have been of interest as treatment options, however, little is known about the molecular mechanisms of Lactobacillus-mediated inhibition of H. pylori pathogenesis. In this work, we investigated the effect of Lactobacillus culture supernatants, so-called conditioned medium (CM), from two gastric isolates, L. gasseri and L. oris, on the expression of transcriptional regulators in H. pylori. Among the four known two-component systems (TCSs), i.e., ArsRS, FlgRS, CheAY and CrdRS, the flagellar regulator gene flgR and the acid resistance associated arsS gene were down-regulated by L. gasseri CM, whereas expression of the other TCS-genes remained unaffected. L. gasseri CM also reduced the motility of H. pylori, which is in line with reduced flgR expression. Furthermore, among six transcription factors of H. pylori only the ferric uptake regulator gene fur was regulated by L. gasseri CM. Deletion of fur further led to dramatically increased sensitivity to the antimicrobial peptide LL-37. Taken together, the results highlight that released/secreted factors of some lactobacilli, but not all, downregulate transcriptional regulators involved in motility, acid tolerance and LL-37 sensitivity of H. pylori.

Keywords
helicobacter, Lactobacillus, transcription factor, LL-37, motility
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-213810 (URN)10.3390/ijms232415451 (DOI)000902500600001 ()36555092 (PubMedID)2-s2.0-85144990765 (Scopus ID)
Available from: 2023-01-25 Created: 2023-01-25 Last updated: 2024-05-27Bibliographically approved
Wassing, G. M., Lidberg, K., Sigurlásdóttir, S., Frey, J., Schroeder, K., Ilehag, N., . . . Jonsson, A.-B. (2021). DNA Blocks the Lethal Effect of Human Beta-Defensin 2 Against Neisseria meningitidis. Frontiers in Microbiology, 12, Article ID 697232.
Open this publication in new window or tab >>DNA Blocks the Lethal Effect of Human Beta-Defensin 2 Against Neisseria meningitidis
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2021 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 697232Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is a gram-negative bacterium that often asymptomatically colonizes the human nasopharyngeal tract. These bacteria cross the epithelial barrier can cause life-threatening sepsis and/or meningitis. Antimicrobial peptides are one of the first lines of defense against invading bacterial pathogens. Human beta-defensin 2 (hBD2) is an antimicrobial peptide with broad antibacterial activity, although its mechanism of action is poorly understood. Here, we investigated the effect of hBD2 on N. meningitidis. We showed that hBD2 binds to and kills actively growing meningococcal cells. The lethal effect was evident after 2 h incubation with the peptide, which suggests a slow killing mechanism. Further, the membrane integrity was not changed during hBD2 treatment. Incubation with lethal doses of hBD2 decreased the presence of diplococci; the number and size of bacterial microcolonies/aggregates remained constant, indicating that planktonic bacteria may be more susceptible to the peptide. Meningococcal DNA bound hBD2 in mobility shift assays and inhibited the lethal effect of hBD2 in a dose-dependent manner both in suspension and biofilms, supporting the interaction between hBD2 and DNA. Taken together, the ability of meningococcal DNA to bind hBD2 opens the possibility that extracellular DNA due to bacterial lysis may be a means of N. meningitidis to evade immune defenses.

Keywords
Neisseria meningitidis, infection, hBD2, aggregation, eDNA
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-196515 (URN)10.3389/fmicb.2021.697232 (DOI)000673298600001 ()34276631 (PubMedID)
Available from: 2021-09-14 Created: 2021-09-14 Last updated: 2024-01-17Bibliographically approved
Sigurlásdóttir, S., Lidberg, K., Zuo, F., Newcombe, J., McFadden, J. & Jonsson, A.-B. (2021). Lactate-Induced Dispersal of Neisseria meningitidis Microcolonies Is Mediated by Changes in Cell Density and Pilus Retraction and Is Influenced by Temperature Change. Infection and Immunity, 89(10), Article ID e00296-21.
Open this publication in new window or tab >>Lactate-Induced Dispersal of Neisseria meningitidis Microcolonies Is Mediated by Changes in Cell Density and Pilus Retraction and Is Influenced by Temperature Change
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2021 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 89, no 10, article id e00296-21Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is the etiologic agent of meningococcal meningitis and sepsis. Initial colonization of meningococci in the upper respiratory tract epithelium is crucial for disease development. The colonization occurs in several steps and expression of type IV pili (Tfp) is essential for both attachment and microcolony formation of encapsulated bacteria. Previously, we have shown that host-derived lactate induces synchronized dispersal of meningococcal microcolonies. In this study, we demonstrated that lactate-induced dispersal is dependent on bacterial concentration but not on the quorum-sensing system autoinducer-2 or the two-component systems NarP/NarQ, PilR/PilS, NtrY/NtrX, and MisR/MisS. Further, there were no changes in expression of genes related to assembly, elongation, retraction, and modification of Tfp throughout the time course of lactate induction. By using pilT and pptB mutants, however, we found that lactate-induced dispersal was dependent on PilT retraction but not on phosphoglycerol modification of Tfp even though the PptB activity was important for preventing reaggregation postdispersal. Furthermore, protein synthesis was required for lactate-induced dispersal. Finally, we found that at a lower temperature, lactate-induced dispersal was delayed and unsynchronized, and bacteria reformed microcolonies. We conclude that lactate-induced microcolony dispersal is dependent on bacterial concentration, PilT-dependent Tfp retraction, and protein synthesis and is influenced by environmental temperature.

Keywords
Neisseria meningitidis, lactate, microcolony dispersal
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-198551 (URN)10.1128/IAI.00296-21 (DOI)000708004000023 ()34125601 (PubMedID)
Available from: 2021-11-12 Created: 2021-11-12 Last updated: 2022-02-25Bibliographically approved
Wassing, G. M., Ilehag, N., Frey, J. & Jonsson, A.-B. (2021). Modulation of Human Beta-Defensin 2 Expression by Pathogenic Neisseria meningitidis and Commensal Lactobacilli. Antimicrobial Agents and Chemotherapy, 65(4), Article ID e02002-20.
Open this publication in new window or tab >>Modulation of Human Beta-Defensin 2 Expression by Pathogenic Neisseria meningitidis and Commensal Lactobacilli
2021 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 4, article id e02002-20Article in journal (Refereed) Published
Abstract [en]

Antimicrobial peptides (AMPs) play an important role in the defense against pathogens by targeting and killing invading microbes. Some pathogenic bacteria have been shown to negatively regulate AMP expression, while several commensals may induce AMP expression. The expression of certain AMPs, such as human betadefensin 2 (hBD2), can be induced via nuclear factor NF-kappa B, which, in turn, is negatively controlled by tumor necrosis factor alpha-induced protein 3 (TNFAIP3, or A20). In this work, we examined the expression of hBD1 and hBD2 during coincubation of pharyngeal epithelial cells with pathogenic Neisseria meningitidis and commensal lactobacilli. The Lactobacillus strains induced hBD2 expression in human pharyngeal cells, while the pathogen N. meningitidis did not. In coincubation experiments, meningococci were able to dampen the AMP expression induced by lactobacilli. We found that N. meningitidis induced the NF-kappa B inhibitor A20. Further, RNA silencing of A20 resulted in increased hBD2 expression after meningococcal infection. Since it is known that induction of A20 reduces NF-kappa B activity and thus hBD2 levels, meningococcal-mediated A20 induction could be a way for the pathogen to dampen AMP expression. Finally, treatment of N. meningitidis and lactobacilli with synthetic hBD2 reduced N. meningitidis viability more efficiently than Lactobacillus reuteri, explaining why maintaining low AMP levels is important for the survival of the pathogen.

Keywords
Neisseria meningitidis, hBD2, Lactobacillus, NF-kappa B, A20, Neisseria, meningococcus
National Category
Biological Sciences Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-193111 (URN)10.1128/AAC.02002-20 (DOI)000630326800073 ()33468461 (PubMedID)
Available from: 2021-05-14 Created: 2021-05-14 Last updated: 2022-02-25Bibliographically approved
Sigurlásdóttir, S., Wassing, G. M., Zuo, F., Arts, M. & Jonsson, A.-B. (2019). Deletion of D-Lactate Dehydrogenase A in Neisseria meningitidis Promotes Biofilm Formation Through Increased Autolysis and Extracellular DNA Release. Frontiers in Microbiology, 10, Article ID 422.
Open this publication in new window or tab >>Deletion of D-Lactate Dehydrogenase A in Neisseria meningitidis Promotes Biofilm Formation Through Increased Autolysis and Extracellular DNA Release
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2019 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, article id 422Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is a Gram-negative bacterium that asymptomatically colonizes the human nasopharyngeal mucosa. Pilus-mediated initial adherence of N. meningitidis to the epithelial mucosa is followed by the formation of three-dimensional aggregates, called microcolonies. Dispersal from microcolonies contributes to the transmission of N. meningitidis across the epithelial mucosa. We have recently discovered that environmental concentrations of host cell-derived lactate influences N. meningitidis microcolony dispersal. Here, we examined the ability of N. meningitidis mutants deficient in lactate metabolism to form biofilms. A lactate dehydrogenease A (idhA) mutant had an increased level of biofilm formation. Deletion of IdhA increased the N. meningitidis cell surface hydrophobicity and aggregation. In this study, we used FAM20, which belongs to clonal complex ST-11 that forms biofilms independently of extracellular DNA (eDNA). However, treatment with DNase I abolished the increased biofilm formation and aggregation of the ldhA-delicient mutant, suggesting a critical role for eDNA. Compared to wild-type, the IdhA-deficient mutant exhibited an increased autolytic rate, with significant increases in the eDNA concentrations in the culture supernatants and in biofilms. Within the IdhA mutant biofilm, the transcription levels of the capsule, pilus, and bacterial lysis genes were downregulated, while norB, which is associated with anaerobic respiration, was upregulated. These findings suggest that the absence of IdhA in N. meningitidis promotes biofilm formation and aggregation through autolysis-mediated DNA release.

Keywords
Neisseria meningitidis, lactate dehydrogenase, eDNA, autolysis, biofilm
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-167499 (URN)10.3389/fmicb.2019.00422 (DOI)000460286700001 ()30891026 (PubMedID)
Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2024-01-17Bibliographically approved
Gebremariam, H. G., Qazi, K. R., Somiah, T., Pathak, S. K., Sjölinder, H., Sverremark Ekström, E. & Jonsson, A.-B. (2019). Lactobacillus gasseri Suppresses the Production of Proinflammatory Cytokines in Helicobacter pylori-Infected Macrophages by Inhibiting the Expression of ADAM17. Frontiers in Immunology, 10, Article ID 2326.
Open this publication in new window or tab >>Lactobacillus gasseri Suppresses the Production of Proinflammatory Cytokines in Helicobacter pylori-Infected Macrophages by Inhibiting the Expression of ADAM17
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2019 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 2326Article in journal (Refereed) Published
Abstract [en]

The ability of Helicobacter pylori to evade the host immune system allows the bacterium to colonize the host for a lifetime. Long-term infection with H. pylori causes chronic inflammation, which is the major risk factor for the development of gastric ulcers and gastric cancer. Lactobacilli are part of the human microbiota and have been studied as an adjunct treatment in H. pylori eradication therapy. However, the molecular mechanisms by which lactobacilli act against H. pylori infection have not been fully characterized. In this study, we investigated the anti-inflammatory effects of Lactobacillus strains upon coincubation of host macrophages with H. pylori. We found that Lactobacillus gasseri Kx110A1 (L. gas), a strain isolated from a human stomach, but not other tested Lactobacillus species, blocked the production of the proinflammatory cytokines TNF and IL-6 in H. pylori-infected macrophages. Interestingly, L. gas also inhibited the release of these cytokines in LPS or LTA stimulated macrophages, demonstrating a general anti-inflammatory property. The inhibition of these cytokines did not occur through the polarization of macrophages from the M1 (proinflammatory) to M2 (anti-inflammatory) phenotype or through the altered viability of H. pylori or host cells. Instead, we show that L. gas suppressed the release of TNF and IL-6 by reducing the expression of ADAM17 (also known as TNF-alpha-converting enzyme, TACE) on host cells. Our findings reveal a novel mechanism by which L. gas prevents the production of the proinflammatory cytokines TNF and IL-6 in host macrophages.

Keywords
Helicobacter pylori, infection, inflammation, Lactobacillus, ADAM17
National Category
Immunology in the medical area Microbiology in the medical area Biological Sciences
Identifiers
urn:nbn:se:su:diva-176743 (URN)10.3389/fimmu.2019.02326 (DOI)000496978900001 ()31636639 (PubMedID)
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2024-01-17Bibliographically approved
Zuo, F., Appaswamy, A., Gebremariam, H. G. & Jonsson, A.-B. (2019). Role of Sortase A in Lactobacillus gasseri Kx110A1 Adhesion to Gastric Epithelial Cells and Competitive Exclusion of Helicobacter pylori. Frontiers in Microbiology, 10, Article ID 2770.
Open this publication in new window or tab >>Role of Sortase A in Lactobacillus gasseri Kx110A1 Adhesion to Gastric Epithelial Cells and Competitive Exclusion of Helicobacter pylori
2019 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, article id 2770Article in journal (Refereed) Published
Abstract [en]

We have previously shown that Lactobacillus gasseri Kx110A1, a human stomach isolate, can colonize mouse stomach and reduce the initial colonization of Helicobacter pylori. Here, we investigated the role of sortase-dependent proteins (SDPs) involved in these functions by the construction of a mutant for srtA, the gene encoding the housekeeping sortase that covalently anchors SDPs to the cell surface. The srtA mutant showed a decrease in hydrophobicity and autoaggregation under acidic conditions, indicating the effect of SDPs on cell surface properties. Correspondingly, the srtA mutant lost the capacity to adhere to gastric epithelial cells, thus resulting in an inability to provide a physical barrier to prevent H. pylori adherence. These results indicate that sortase A is a key determinant of the cell surface properties of L. gasseri Kx110A1 and contributes to Lactobacillus-mediated exclusion of H. pylori. Understanding the molecular mechanisms by which lactobacilli antagonize H. pylori might contribute to the development of novel therapeutic strategies that take advantage of health-promoting bacteria and reduce the burden of antibiotic resistance.

Keywords
sortase, sortase-dependent protein, lactobacillus, helicobacter pylori, host cell adhesion, competitive exclusion
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-177578 (URN)10.3389/fmicb.2019.02770 (DOI)000502958100001 ()31849907 (PubMedID)
Available from: 2020-01-15 Created: 2020-01-15 Last updated: 2024-01-17Bibliographically approved
Sigurlásdóttir, S., Engman, J., Eriksson, O. S., Saroj, S. D., Zguna, N., Lloris-Garcerá, P., . . . Jonsson, A.-B. (2017). Host cell-derived lactate functions as an effector molecule in Neisseria meningitidis microcolony dispersal. PLoS Pathogens, 13(4), Article ID e1006251.
Open this publication in new window or tab >>Host cell-derived lactate functions as an effector molecule in Neisseria meningitidis microcolony dispersal
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2017 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, no 4, article id e1006251Article in journal (Refereed) Published
Abstract [en]

The development of meningococcal disease, caused by the human pathogen Neisseria meningitidis, is preceded by the colonization of the epithelial layer in the nasopharynx. After initial adhesion to host cells meningococci form aggregates, through pilus-pilus interactions, termed microcolonies from which the bacteria later detach. Dispersal from microcolonies enables access to new colonization sites and facilitates the crossing of the cell barrier; however, this process is poorly understood. In this study, we used live-cell imaging to investigate the process of N. meningitidis microcolony dispersal. We show that direct contact with host cells is not required for microcolony dispersal, instead accumulation of a host-derived effector molecule induces microcolony dispersal. By using a host-cell free approach, we demonstrated that lactate, secreted from host cells, initiate rapid dispersal of microcolonies. Interestingly, metabolic utilization of lactate by the bacteria was not required for induction of dispersal, suggesting that lactate plays a role as a signaling molecule. Furthermore, Neisseria gonorrhoeae microcolony dispersal could also be induced by lactate. These findings reveal a role of host-secreted lactate in microcolony dispersal and virulence of pathogenic Neisseria.

National Category
Biological Sciences Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-144725 (URN)10.1371/journal.ppat.1006251 (DOI)000402555700005 ()
Available from: 2017-07-20 Created: 2017-07-20 Last updated: 2022-03-23Bibliographically approved
Saroj, S. D., Holmer, L., Berengueras, J. M. & Jonsson, A.-B. (2017). Inhibitory role of acyl homoserine lactones in hemolytic activity and viability of Streptococcus pyogenes M6 S165. Scientific Reports, 7, Article ID 44902.
Open this publication in new window or tab >>Inhibitory role of acyl homoserine lactones in hemolytic activity and viability of Streptococcus pyogenes M6 S165
2017 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 44902Article in journal (Refereed) Published
Abstract [en]

Streptococcus pyogenes an adapted human pathogen asymptomatically colonizes the nasopharynx, among other polymicrobial communities. However, information on the events leading to the colonization and expression of virulence markers subject to interspecies and host-bacteria interactions are limited. The interference of acyl homoserine lactones (AHLs) with the hemolytic activity and viability of S. pyogenes M6 S165 was examined. AHLs, with fatty acid side chains >= 12 carbon atoms, inhibited hemolytic activity by downregulating the expression of the sag operon involved in the production of streptolysin S. Inhibitory AHLs upregulated the expression of transcriptional regulator LuxR. Electrophoretic mobility shift assays revealed the interaction of LuxR with the region upstream of sagA. AHL-mediated bactericidal activity observed at higher concentrations (mM range) was an energydependent process, constrained by the requirement of glucose and iron. Ferrichrome transporter FtsABCD facilitated transport of AHLs across the streptococcal membrane. The study demonstrates a previously unreported role for AHLs in S. pyogenes virulence.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-142655 (URN)10.1038/srep44902 (DOI)000396836500001 ()28303956 (PubMedID)
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2022-09-15Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-4480-2940

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