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Tiensuu, T., Guerreiro, D. N., de Oliveira, A. H., O'Byrne, C. & Johansson, J. (2019). Flick of a switch: regulatory mechanisms allowing Listeria monocytogenes to transition from a saprophyte to a killer. Microbiology, 165(8), 819-833
Open this publication in new window or tab >>Flick of a switch: regulatory mechanisms allowing Listeria monocytogenes to transition from a saprophyte to a killer
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2019 (English)In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 165, no 8, p. 819-833Article, review/survey (Refereed) Published
Abstract [en]

In contrast to obligate intracellular pathogens that can remain in relatively stable host-associated environments, the soil-living bacterial pathogen Listeria monocytogenes has to sense and respond to physical and chemical cues in a variety of quite different niches. In particular, the bacterium has to survive the dramatic transition from its saprophytic existence to life within the host where nutritional stress, increased temperature, acidity, osmotic stress and the host defences present a new and challenging landscape. This review focuses on the sB and PrfA regulatory systems used by L. monocytogenes to sense the changing environment and implement survival mechanisms that help to overcome the disparate conditions within the host, but also to switch from a harmless saprophyte to an impressively effective pathogen.

Place, publisher, year, edition, pages
MICROBIOLOGY SOC, 2019
Keywords
Listeria monocytogenes, sigma B, PrfA, virulence, light-sensing
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-162311 (URN)10.1099/mic.0.000808 (DOI)000478025200002 ()31107205 (PubMedID)
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-09-03Bibliographically approved
Johansson, J. & Freitag, N. E. (2019). Regulation of Listeria monocytogenes Virulence. Microbiology Spectrum, 7(4)
Open this publication in new window or tab >>Regulation of Listeria monocytogenes Virulence
2019 (English)In: Microbiology Spectrum, ISSN 2165-0497, Vol. 7, no 4Article in journal (Refereed) Published
Abstract [en]

Whereas obligate human and animal bacterial pathogens may be able to depend upon the warmth and relative stability of their chosen replication niche, environmental bacteria such as Listeria monocytogenes that harbor the ability to replicate both within animal cells and in the outside environment must maintain the capability to manage life under a variety of disparate conditions. Bacterial life in the outside environment requires adaptation to wide ranges of temperature, available nutrients, and physical stresses such as changes in pH and osmolarity as well as desiccation. Following ingestion by a susceptible animal host, the bacterium must adapt to similar changes during transit through the gastrointestinal tract and overcome a variety of barriers associated with host innate immune responses. Rapid alteration of patterns of gene expression and protein synthesis represent one strategy for quickly adapting to a dynamic host landscape. Here, we provide an overview of the impressive variety of strategies employed by the soil-dwelling, foodborne, mammalian pathogen L. monocytogenes to straddle diverse environments and optimize bacterial fitness both inside and outside host cells.

Place, publisher, year, edition, pages
American Society for Microbiology, 2019
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-163702 (URN)10.1128/microbiolspec.GPP3-0064-2019 (DOI)000482711900019 ()31441398 (PubMedID)2-s2.0-85071468356 (Scopus ID)
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-10-16Bibliographically approved
Marinho, C. M., Dos Santos, P. T., Kallipolitis, B. H., Johansson, J., Ignatov, D., Guerreiro, D. N., . . . O'Byrne, C. P. (2019). The σB-dependent regulatory sRNA Rli47 represses isoleucine biosynthesis in Listeria monocytogenes through a direct interaction with the ilvA transcript. RNA Biology
Open this publication in new window or tab >>The σB-dependent regulatory sRNA Rli47 represses isoleucine biosynthesis in Listeria monocytogenes through a direct interaction with the ilvA transcript
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2019 (English)In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584Article in journal (Refereed) Epub ahead of print
Abstract [en]

The facultative intracellular pathogen Listeria monocytogenes can persist and grow in a diverse range of environmental conditions, both outside and within its mammalian host. The alternative sigma factor Sigma B (sigma(B)) plays an important role in this adaptability and is critical for the transition into the host. While some of the functions of the sigma(B) regulon in facilitating this transition are understood the role of sigma(B)-dependent small regulatory RNAs (sRNAs) remain poorly characterized. In this study, we focused on elucidating the function of Rli47, a sigma(B)-dependent sRNA that is highly induced in the intestine and in macrophages. Using a combination of in silico and in vivo approaches, a binding interaction was predicted with the Shine-Dalgarno region of the ilvA mRNA, which encodes threonine deaminase, an enzyme required for branched-chain amino acid biosynthesis. Both ilvA transcript levels and threonine deaminase activity were increased in a deletion mutant lacking the rli47 gene. The Delta rli47 mutant displayed a shorter growth lag in isoleucine-depleted growth media relative to the wild-type, and a similar phenotype was also observed in a mutant lacking sigma(B). The impact of the Delta rli47 on the global transcription profile of the cell was investigated using RNA-seq, and a significant role for Rli47 in modulating amino acid metabolism was uncovered. Taken together, the data point to a model where Rli47 is responsible for specifically repressing isoleucine biosynthesis as a way to restrict growth under harsh conditions, potentially contributing to the survival of L. monocytogenes in niches both outside and within the mammalian host.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Listeria monocytogenes, Rli47, Sigma B, Isoleucine biosynthesis, ilvA, sRNA, Threonine deaminase
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-161849 (URN)10.1080/15476286.2019.1632776 (DOI)000475257200001 ()31242083 (PubMedID)
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08
Olsson, J., Johansson, J., Honkala, E., Blomqvist, B., Kok, E., Weidung, B., . . . Elgh, F. (2019). Urea dilution of serum for reproducible anti-HSV1 IgG avidity index. BMC Infectious Diseases, 19, Article ID 164.
Open this publication in new window or tab >>Urea dilution of serum for reproducible anti-HSV1 IgG avidity index
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2019 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 19, article id 164Article in journal (Refereed) Published
Abstract [en]

Herpes simplex virus type 1 (HSV1), establishes life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe a protocol to generate a reliable and discriminative avidity index (AI) for anti-HSV1 IgG content in human sera. Human serum from two distinct cohorts; one a biobank collection (Betula) (n = 28), and one from a clinical diagnostics laboratory at Northern Sweden University Hospital (NUS) (n = 18), were assessed for presence of IgG antibodies against HSV1 by a commercially available ELISA-kit. Addition of urea at the incubation step reduces effective binding, and the ratio between urea treated sample and non-treated sample was used to express an avidity index (AI) for individual samples. AI score ranged between 43.2 and 73.4% among anti-HSV1 positive biobank sera. Clinical samples ranged between 36.3 and 74.9%. Reproducibility expressed as an intraclass correlation coefficient (ICC) was estimated at 0.948 (95% CI: 0.900-0.979) and 0.989 (95% CI 0.969-0.996) in the biobank and clinical samples, respectively. The method allows for AI scoring of anti-HSV1 IgG from individual human sera with a single measurement. The least significant change between two measurements at the p < 0.05 level was estimated at 5.4 and 3.2 points, respectively, for the two assessed cohorts.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Herpes simplex, IgG, Avidity, ELISA, Primary infection, Reactivated infection
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-157213 (URN)10.1186/s12879-019-3769-x (DOI)000459030400003 ()30764767 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Quereda, J. J., Andersson, C., Cossart, P., Johansson, J. & Pizarro-Cerda, J. (2018). Role in virulence of phospholipases, listeriolysin O and listeriolysin S from epidemic Listeria monocytogenes using the chicken embryo infection model. Veterinary research (Print), 49, Article ID 13.
Open this publication in new window or tab >>Role in virulence of phospholipases, listeriolysin O and listeriolysin S from epidemic Listeria monocytogenes using the chicken embryo infection model
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2018 (English)In: Veterinary research (Print), ISSN 0928-4249, E-ISSN 1297-9716, Vol. 49, article id 13Article in journal (Refereed) Published
Abstract [en]

Most human listeriosis outbreaks are caused by Listeria monocytogenes evolutionary lineage I strains which possess four exotoxins: a phosphatidylinositol-specific phospholipase C (PlcA), a broad-range phospholipase C (PlcB), listeriolysin O (LLO) and listeriolysin S (LLS). The simultaneous contribution of these molecules to virulence has never been explored. Here, the importance of these four exotoxins of an epidemic lineage I L. monocytogenes strain (F2365) in virulence was assessed in chicken embryos infected in the allantoic cavity. We show that LLS does not play a role in virulence while LLO is required to infect and kill chicken embryos both in wild type transcriptional regulator of virulence PrfA -(PrfAWT) and constitutively active PrfA (PrfA*) backgrounds. We demonstrate that PlcA, a toxin previously considered as a minor virulence factor, played a major role in virulence in a PrfA* background. Interestingly, GFP transcriptional fusions show that the plcA promoter is less active than the hly promoter in vitro, explaining why the contribution of PlcA to virulence could be observed more importantly in a PrfA* background. Together, our results suggest that PlcA might play a more important role in the infectious lifecycle of L. monocytogenes than previously thought, explaining why all the strains of L. monocytogenes have conserved an intact copy of plcA in their genomes.

Place, publisher, year, edition, pages
BioMed Central, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-145143 (URN)10.1186/s13567-017-0496-4 (DOI)000424675000001 ()29409521 (PubMedID)
Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2018-06-09Bibliographically approved
Kulén, M., Lindgren, M., Hansen, S., Cairns, A. G., Grundström, C., Begum, A., . . . Almqvist, F. (2018). Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes. Journal of Medicinal Chemistry, 61(9), 4165-4175
Open this publication in new window or tab >>Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4165-4175Article in journal (Refereed) Published
Abstract [en]

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-148830 (URN)10.1021/acs.jmedchem.8b00289 (DOI)000432204800027 ()29667825 (PubMedID)2-s2.0-85046422455 (Scopus ID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-28Bibliographically approved
Vdovikova, S., Luhr, M., Szalai, P., Skalman, L. N., Francis, M. K., Lundmark, R., . . . Wai, S. N. (2017). A Novel Role of Listeria monocytogenes Membrane Vesicles in Inhibition of Autophagy and Cell Death. Frontiers in Cellular and Infection Microbiology, 7, Article ID 154.
Open this publication in new window or tab >>A Novel Role of Listeria monocytogenes Membrane Vesicles in Inhibition of Autophagy and Cell Death
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2017 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 7, article id 154Article in journal (Refereed) Published
Abstract [en]

Bacterial membrane vesicle (MV) production has been mainly studied in Gram-negative species. In this study, we show that Listeria monocytogenes, a Gram-positive pathogen that causes the food-borne illness listeriosis, produces MVs both in vitro and in vivo. We found that a major virulence factor, the pore-forming hemolysin listeriolysin O (LLO), is tightly associated with the MVs, where it resides in an oxidized, inactive state. Previous studies have shown that LLO may induce cell death and autophagy. To monitor possible effects of LLO and MVs on autophagy, we performed assays for LC3 lipidation and LDH sequestration as well as analysis by confocal microscopy of HEK293 cells expressing GFP-LC3. The results revealed that MVs alone did not affect autophagy whereas they effectively abrogated autophagy induced by pure LLO or by another pore-forming toxin from Vibrio cholerae, VCC. Moreover, Listeria monocytogenes MVs significantly decreased Torin1-stimulated macroautophagy. In addition, MVs protected against necrosis of HEK293 cells caused by the lytic action of LLO. We explored the mechanisms of LLO-induced autophagy and cell death and demonstrated that the protective effect of MVs involves an inhibition of LLO-induced pore formation resulting in inhibition of autophagy and the lytic action on eukaryotic cells. Further, we determined that these MVs help bacteria to survive inside eukaryotic cells (mouse embryonic fibroblasts). Taken together, these findings suggest that intracellular release of MVs from L. monocytogenes may represent a bacterial strategy to survive inside host cells, by its control of LLO activity and by avoidance of destruction from the autophagy system during infection.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2017
Keywords
Listeria monocytogenes, membrane vesicles, autophagy, listeriolysin O, pore-forming toxin
National Category
Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-136187 (URN)10.3389/fcimb.2017.00154 (DOI)000400405800001 ()28516064 (PubMedID)
Available from: 2017-07-07 Created: 2017-07-07 Last updated: 2018-06-09Bibliographically approved
Krajewski, S. S., Isoz, I. & Johansson, J. (2017). Antibacterial and antivirulence effect of 6-N-hydroxylaminopurine in Listeria monocytogenes. Nucleic Acids Research, 45(4), 1914-1924
Open this publication in new window or tab >>Antibacterial and antivirulence effect of 6-N-hydroxylaminopurine in Listeria monocytogenes
2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 4, p. 1914-1924Article in journal (Refereed) Published
Abstract [en]

The emerging development of antibiotic resistant bacteria calls for novel types of antibacterial agents. In this work we examined the putative antibacterial effect of purine analogs in Listeria monocytogenes. We show that, among several tested purine analogs, only 6-N-hydroxylaminopurine (6-N-HAP) reduces the viability of the Gram-positive pathogenListeria monocy-togenes. As in Bacillus subtilis, 6-N-HAP terminates expression at guanine riboswitches in L. monocyto-genes hence preventing expression of their downstream genes. However, we show that the bacteriocidal effect of the compound was unlinked to the terminated expression at the guanine riboswitches. When further examining the antimicrobial effect, we observed that 6-N-HAP acts as a potent mutagen in L. monocytogenes, by increasing the mutation rate and inducing the SOS-response. Also, addition of 6N-HAP decreased virulence gene expression by reducing both the levels and activity of the virulence regulator PrfA.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-133203 (URN)10.1093/nar/gkw1308 (DOI)000396055400037 ()
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2018-06-09Bibliographically approved
Ignatov, D. & Johansson, J. (2017). RNA-mediated signal perception in pathogenic bacteria. Wiley Interdisciplinary Reviews-RNA, 8(6), Article ID e1429.
Open this publication in new window or tab >>RNA-mediated signal perception in pathogenic bacteria
2017 (English)In: Wiley Interdisciplinary Reviews-RNA, ISSN 1757-7004, Vol. 8, no 6, article id e1429Article, review/survey (Refereed) Published
Abstract [en]

Bacterial pathogens encounter several different environments during an infection, many of them possibly being detrimental. In order to sense its surroundings and adjust the gene expression accordingly, different regulatory schemes are undertaken. With these, the bacterium appropriately can differentiate between various environmental cues to express the correct virulence factor at the appropriate time and place. An attractive regulator device is RNA, which has an outstanding ability to alter its structure in response to external stimuli, such as metabolite concentration or alterations in temperature, to control its downstream gene expression. This review will describe the function of riboswitches and thermometers, with a particular emphasis on regulatory RNAs being important for bacterial pathogenicity.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-141475 (URN)10.1002/wrna.1429 (DOI)000412915800003 ()28792118 (PubMedID)
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-06-09Bibliographically approved
Krajewski, S. S., Ignatov, D. & Johansson, J. (2017). Two Are Better Than One: Dual Targeting of Riboswitches by Metabolite Analogs. Cell Chemical Biology, 24(5), 535-537
Open this publication in new window or tab >>Two Are Better Than One: Dual Targeting of Riboswitches by Metabolite Analogs
2017 (English)In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 24, no 5, p. 535-537Article in journal, Editorial material (Refereed) Published
Abstract [en]

In this issue of Cell Chemical Biology, Wang et al. (2017) examine the effect of the novel synthetic molecule ribocil-C and the natural compound roseoflavin in Gram-positive pathogens. In methicillin-resistant Staphylococcus aureus (MRSA), ribocil-C and roseoflavin target two autonomous riboswitches simultaneously, thereby inhibiting de novo synthesis and uptake of riboflavin.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-136335 (URN)10.1016/j.chembiol.2017.05.004 (DOI)000402418300002 ()28525764 (PubMedID)
Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-0904-497x

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