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Lindgren, H., Liu, X. & Sjöstedt, A. (2024). Francisella tularensis-specific antibody levels in sera from Swedish patients with suspected tularemia during a 13-year period. Frontiers in Cellular and Infection Microbiology, 14, Article ID 1381776.
Open this publication in new window or tab >>Francisella tularensis-specific antibody levels in sera from Swedish patients with suspected tularemia during a 13-year period
2024 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 14, article id 1381776Article in journal (Refereed) Published
Abstract [en]

Introduction: For a majority of tularemia patients, serology is the basis for the diagnosis. The aim of this study was to perform an analysis of the samples analyzed at a Swedish reference laboratory for the presence of Francisella tularensis-specific antibody levels in sera from individuals with suspected tularemia. Annual and monthly variations of the total number of samples and proportions of positive samples were analyzed, as well as the influence of age and gender.

Methods: We performed a retrospective analysis of the presence of F. tularensis-specific antibodies in serological samples from patients with suspected tularemia analyzed during the period 2010 - 2022 at the University Hospital of Umeå in Sweden, a national reference laboratory, by use of various statistical methods. In total, some 15,100 serum samples had been analyzed for the presence of IgG and IgM antibodies by ELISA during the 13-year period.

Results: Overall, there were higher number of samples with IgG positive or borderline titers, 2,522 and 921, respectively, than with IgM positive or borderline titers, 1,802 and 409, respectively. Repeated samples were obtained from some 1,930 individuals and approximately a third of the cases, which were initially seronegative, had seroconverted when resampled. Peak number of monthly samples were recorded in August and September, > 3,000. Annual numbers varied greatly and peak numbers were observed in 2015 and 2019, 1,832 and 2,250, respectively, whereas some other years the numbers were 700 – 800. There was also much variation in the annual and monthly percentages of positive samples and they varied between less than 10% to greater than 20%. The highest percentages of positive samples were recorded in September and October. IgG and IgM titers declined with age and these differences were highly significant for IgG titers, with decreasing average titers for each 20-year interval.

Discussion: Collectively, the data demonstrate the marked annual and seasonal variations in tularemia sampling occurring in Sweden. Also, the proportion of positive samples increased during months and years with peak number of samples. Another notable finding was that average antibody titers decreased with increased age.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
age-related titers, annual distribution, monthly distribution, serological response, tularemia
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-223646 (URN)10.3389/fcimb.2024.1381776 (DOI)001203847700001 ()2-s2.0-85190392484 (Scopus ID)
Funder
Region Västerbotten, RV-939171Region Västerbotten, RV-941049
Available from: 2024-04-23 Created: 2024-04-23 Last updated: 2024-04-23Bibliographically approved
Nelson, C. A. & Sjöstedt, A. (2024). Tularemia: a storied history, an ongoing threat. Clinical Infectious Diseases, 78(Supplement_1), S1-S3
Open this publication in new window or tab >>Tularemia: a storied history, an ongoing threat
2024 (English)In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 78, no Supplement_1, p. S1-S3Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Oxford University Press, 2024
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-220880 (URN)10.1093/cid/ciad681 (DOI)001154832000011 ()38294109 (PubMedID)2-s2.0-85183724504 (Scopus ID)
Available from: 2024-02-15 Created: 2024-02-15 Last updated: 2024-02-15Bibliographically approved
Lindgren, H., Eneslätt, K., Golovliov, I., Gelhaus, C. & Sjöstedt, A. (2023). Analyses of human immune responses to Francisella tularensis identify correlates of protection. Frontiers in Immunology, 14, Article ID 1238391.
Open this publication in new window or tab >>Analyses of human immune responses to Francisella tularensis identify correlates of protection
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1238391Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is the etiological agent of the potentially severe infection tularemia. An existing F: tularensis vaccine, the live vaccine strain (LVS), has been used to protect at-risk personnel, but it is not licensed in any country and it has limited efficacy. Therefore, there is a need of a new, efficacious vaccine. The aim of the study was to perform a detailed analysis of the characteristics of the human immune response to F. tularensis, since this will generate crucial knowledge required to develop new vaccine candidates. Nine individuals were administered the LVS vaccine and peripheral blood mononuclear cells (PBMC) were collected before and at four time points up to one year after vaccination. The properties of the PBMC were characterized by flow cytometry analysis of surface markers and intracellular cytokine staining. In addition, the cytokine content of supernatants from F. tularensis-infected PBMC cultures was determined and the protective properties of the supernatants investigated by adding them to cultures with infected monocyte-derived macrophages (MDM). Unlike before vaccination, PBMC collected at all four time points after vaccination demonstrated F. tularensis-specific cell proliferation, cytokine secretion and cytokine-expressing memory cells. A majority of 17 cytokines were secreted at higher levels by PBMC collected at all time points after vaccination than before vaccination. A discriminative analysis based on IFN-γ and IL-13 secretion correctly classified samples obtained before and after vaccination. Increased expression of IFN-γ, IL-2, and MIP-1β were observed at all time points after vaccination vs. before vaccination and the most significant changes occurred among the CD4 transient memory, CD8 effector memory, and CD8 transient memory T-cell populations. Growth restriction of the highly virulent F. tularensis strain SCHU S4 in MDM was conferred by supernatants and protection correlated to levels of IFN-γ, IL-2, TNF, and IL-17. The findings demonstrate that F. tularensis vaccination induces long-term T-cell reactivity, including TEM and TTM cell populations. Individual cytokine levels correlated with the degree of protection conferred by the supernatants. Identification of such memory T cells and effector mechanisms provide an improved understanding of the protective mechanisms against F. tularensis. mechanisms against F. tularensis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
F. tularensis, human correlates of protection, immune response, memory cells, vaccination
National Category
Immunology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-215234 (URN)10.3389/fimmu.2023.1238391 (DOI)37781364 (PubMedID)2-s2.0-85173061344 (Scopus ID)
Funder
Region Västerbotten, RV-939171Region Västerbotten, RV-941049
Available from: 2023-10-16 Created: 2023-10-16 Last updated: 2024-01-17Bibliographically approved
Lindgren, H., Eklund, J., Eneslätt, K. & Sjöstedt, A. (2023). Kinetics of the serological response up to one year after tularemia. Frontiers in Cellular and Infection Microbiology, 12, Article ID 1072703.
Open this publication in new window or tab >>Kinetics of the serological response up to one year after tularemia
2023 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 12, article id 1072703Article in journal (Refereed) Published
Abstract [en]

Serological analysis is the predominant method used to diagnose tularemia, a zoonotic disease caused by the highly virulent bacterium F. tularensis. We determined F. tularensis-specific IgM and IgG antibody titers by an LPS-based ELISA assay on five occasions one to twelve months after onset of ulceroglandular tularemia in 19 individuals. Peak IgM antibody titers were observed at the one-month time point and peak IgG antibody titers at the two-month time point. Both IgG and IgM antibody levels declined linearly thereafter with rather similar kinetics. Compared to the average one-month antibody titers, average IgG titers were not significantly lower before the 12-month time point and IgM titers before the 4-month time point. All, but one average titer, were significantly increased compared to the cut-off of the assay. Average IgG and IgM titers were significantly lower for the group = 69 years old compared to the group < 69 years. Collectively, the data demonstrate a persistence of F. tularensis-specific IgM and IgG antibody titers for at least 12 months after ulceroglandular tularemia. Thus, low, but significantly elevated F. tularensis-specific antibody titers are of limited diagnostic value since they are not indicative of ongoing tularemia.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
elderly, kinetics, one year, serological response, tularemia
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-204159 (URN)10.3389/fcimb.2022.1072703 (DOI)000916140100001 ()2-s2.0-85146524901 (Scopus ID)
Funder
Region Västerbotten, RV-939171Region Västerbotten, RV-941049
Available from: 2023-01-30 Created: 2023-01-30 Last updated: 2023-09-05Bibliographically approved
Liu, X., Tabibzada, N., Lindgren, H. & Sjöstedt, A. (2023). Utility of Borrelia-specific IgM and IgG antibody titer determinations during a 12-year period: results from a clinical laboratory in Northern Sweden. Frontiers in Cellular and Infection Microbiology, 13, Article ID 1192038.
Open this publication in new window or tab >>Utility of Borrelia-specific IgM and IgG antibody titer determinations during a 12-year period: results from a clinical laboratory in Northern Sweden
2023 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 13, article id 1192038Article in journal (Refereed) Published
Abstract [en]

Interpretation of serological findings in suspected Lyme borreliosis (LB) is challenging and IgM reactivities may have low predictive value. Therefore, if used indiscriminately, there is a risk for incorrect diagnosis of LB. To evaluate the usefulness of IgM titer determination, we performed a study of the prevalence of Borrelia-specific antibodies in serological samples from patients with suspected LB analyzed during the period 2010 - 2021 at the University Hospital of Umeå in Sweden. In total, 19,335 samples had been analyzed for the presence of IgG and IgM antibodies. Overall, there were higher percentages of IgM positive or borderline titers, 1,847 (9.6%) and 905 (4.7%), respectively, than IgG positive or borderline titers, 959 (5.0%) and 406 (2.1%), respectively. Peak number of samples were recorded 2012 - 2013, exceeding 1,800, whereas there were around 1,200 during 2020 - 2021. The peak number of positive IgG and/or positive IgM samples were observed during the period 2015 - 2017 with close to, or above 400, and concomitantly, the proportion of IgG positive samples increased markedly. For IgG positive samples, the increase followed a positive linear time trend (P< 0.001). Peak monthly numbers were observed during August, September, and October. This seasonal increase was significant for the IgG positive group (P< 0.05), but not for the IgM positive/IgG negative group. Repeated samples were obtained from 3,188 individuals and of the initial samples 2,817 were (88%) IgG negative and 2,315 (72%) were IgM negative and of these, 130 (4%) showed IgG seroconversion and 300 (9%) IgM seroconversion. Collectively, the data demonstrate that IgG and/or IgM positive samples represented a minority of all samples, even when repeated sampling had occurred, and IgM positive samples were much more common than IgG positive samples. Thus, the accuracy of the clinical suspicion was low and this will lead to a low predictive value of the analysis, in particular of IgM. These findings question the use of IgM titer determination as a routine analysis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
IgG, IgM, kinetics 2, lyme borreliosis, serological response
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-212431 (URN)10.3389/fcimb.2023.1192038 (DOI)37465761 (PubMedID)2-s2.0-85165217968 (Scopus ID)
Available from: 2023-07-27 Created: 2023-07-27 Last updated: 2023-07-27Bibliographically approved
Ul Mushtaq, A., Ådén, J., Alam, A., Sjöstedt, A. & Gröbner, G. (2022). Backbone chemical shift assignment and dynamics of the N-terminal domain of ClpB from Francisella tularensis type VI secretion system. Biomolecular NMR Assignments, 16, 75-79
Open this publication in new window or tab >>Backbone chemical shift assignment and dynamics of the N-terminal domain of ClpB from Francisella tularensis type VI secretion system
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2022 (English)In: Biomolecular NMR Assignments, ISSN 1874-2718, E-ISSN 1874-270X, Vol. 16, p. 75-79Article in journal (Refereed) Published
Abstract [en]

The Hsp100 family member ClpB is a protein disaggregase which solubilizes and reactivates stress-induced protein aggregates in cooperation with the DnaK/Hsp70 chaperone system. In the pathogenic bacterium Francisella tularensis, ClpB is involved in type VI secretion system (T6SS) disassembly through depolymerization of the IglA-IglB sheath. This leads to recycling and reassembly of T6SS components and this process is essential for the virulence of the bacterium. Here we report the backbone chemical shift assignments and 15N relaxation-based backbone dynamics of the N-terminal substrate-binding domain of ClpB (1-156).

Place, publisher, year, edition, pages
Springer, 2022
Keywords
15N relaxation, ClpB chaperone, Francisella tularensis, NMR resonance assignment, Type VI secretion system
National Category
Structural Biology
Identifiers
urn:nbn:se:umu:diva-191275 (URN)10.1007/s12104-021-10062-3 (DOI)000739320300001 ()34985724 (PubMedID)2-s2.0-85122286521 (Scopus ID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Available from: 2022-01-13 Created: 2022-01-13 Last updated: 2023-03-24Bibliographically approved
Nadeem, A., Berg, A., Pace, H., Alam, A., Toh, E., Ådén, J., . . . Wai, S. N. (2022). Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae. eLIFE, 11, Article ID e73439.
Open this publication in new window or tab >>Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae
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2022 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e73439Article in journal (Refereed) Published
Abstract [en]

The α-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. We demonstrate a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation induces tube-like structures in acidic endosomal compartments of epithelial cells in vitro. The present study unravels the dynamics of tubular growth, which occurs in a pH-, lipid-, and concentration-dependent manner. Within acidified organelle lumens or when incubated with cells in acidic media, MakA forms oligomers and remodels membranes into high-curvature tubes leading to loss of membrane integrity. A 3.7 Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. MakA forms a pinecone-like spiral with a central cavity and a thin annular lipid bilayer embedded between the MakA transmembrane helices in its active α-PFT conformation. Our study provides insights into a novel tubulation mechanism of an α-PFT protein and a new mode of action by a secreted bacterial toxin.

Place, publisher, year, edition, pages
eLife Sciences Publications, Ltd, 2022
Keywords
Vibrio cholerae, MakA, lipid
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-192300 (URN)10.7554/eLife.73439 (DOI)2-s2.0-85124321786 (Scopus ID)
Funder
Swedish Research Council, 2018–02914Swedish Research Council, 2016–05009Swedish Research Council, 2019–01720Swedish Research Council, 2016–06963Swedish Research Council, 2019–02011Swedish Cancer Society, 2017–419Swedish Cancer Society, 2020–711The Kempe Foundations, JCK-1728The Kempe Foundations, SMK-1756.2The Kempe Foundations, SMK-1553The Kempe Foundations, JCK-1724The Kempe Foundations, SMK-1961Knut and Alice Wallenberg FoundationFamiljen Erling-Perssons Stiftelse
Available from: 2022-02-08 Created: 2022-02-08 Last updated: 2024-01-12Bibliographically approved
Ozanic, M., Marecic, V., Knezevic, M., Kelava, I., Stojková, P., Lindgren, L., . . . Santic, M. (2022). The type IV pili component PilO is a virulence determinant of Francisella novicida. PLOS ONE, 17(1 1), Article ID e0261938.
Open this publication in new window or tab >>The type IV pili component PilO is a virulence determinant of Francisella novicida
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2022 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 1 1, article id e0261938Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a highly pathogenic intracellular bacterium that causes the disease tularemia. While its ability to replicate within cells has been studied in much detail, the bacterium also encodes a less characterised type 4 pili (T4P) system. T4Ps are dynamic adhesive organelles identified as major virulence determinants in many human pathogens. In F. tularensis, the T4P is required for adherence to the host cell, as well as for protein secretion. Several components, including pilins, a pili peptidase, a secretin pore and two ATPases, are required to assemble a functional T4P, and these are encoded within distinct clusters on the Francisella chromosome. While some of these components have been functionally characterised, the role of PilO, if any, still is unknown. Here, we examined the role of PilO in the pathogenesis of F. novicida. Our results show that the PilO is essential for pilus assembly on the bacterial surface. In addition, PilO is important for adherence of F. novicida to human monocyte-derived macrophages, secretion of effector proteins and intracellular replication. Importantly, the pilO mutant is attenuated for virulence in BALB/c mice regardless of the route of infection. Following intratracheal and intradermal infection, the mutant caused no histopathology changes, and demonstrated impaired phagosomal escape and replication within lung liver as well as spleen. Thus, PilO is an essential virulence determinant of F. novicida.

Place, publisher, year, edition, pages
Public Library of Science, 2022
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-192161 (URN)10.1371/journal.pone.0261938 (DOI)000792720400017 ()2-s2.0-85123542882 (Scopus ID)
Funder
Swedish Research Council, 2020-01362Region Västerbotten, RV-939171The Kempe Foundations, JCK-1624
Available from: 2022-02-04 Created: 2022-02-04 Last updated: 2023-09-05Bibliographically approved
Nadeem, A., Nagampalli, R., Toh, E., Alam, A., Myint, S. L., Heidler, T., . . . Persson, K. (2021). A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion. Proceedings of the National Academy of Sciences of the United States of America, 118(47), Article ID e2111418118.
Open this publication in new window or tab >>A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 47, article id e2111418118Article in journal (Refereed) Published
Abstract [en]

Vibrio cholerae, responsible for outbreaks of cholera disease, is a highly motile organism by virtue of a single flagellum. We describe how the flagellum facilitates the secretion of three V. cholerae proteins encoded by a hitherto-unrecognized genomic island. The proteins MakA/B/E can form a tripartite toxin that lyses erythrocytes and is cytotoxic to cultured human cells. A structural basis for the cytolytic activity of the Mak proteins was obtained by X-ray crystallography. Flagellum-facilitated secretion ensuring spatially coordinated delivery of Mak proteins revealed a role for the V. cholerae flagellum considered of particular significance for the bacterial environmental persistence. Our findings will pave the way for the development of diagnostics and therapeutic strategies against pathogenic Vibrionaceae.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-191257 (URN)10.1073/pnas.2111418118 (DOI)000727697700014 ()34799450 (PubMedID)2-s2.0-85121209218 (Scopus ID)
Funder
Swedish Research Council, 2016-05009Swedish Research Council, 2018-02914Swedish Research Council, 2019-01720Swedish Research Council, 2007-08673The Kempe Foundations, SMK-1756.2The Kempe Foundations, SMK-1553The Kempe Foundations, JCK-1728Swedish Cancer Society, 2017-419The Kempe Foundations, SMK-1961Swedish Research Council
Available from: 2022-01-12 Created: 2022-01-12 Last updated: 2023-05-11Bibliographically approved
Chin, C.-Y., Zhao, J., Llewellyn, A. C., Golovliov, I., Sjöstedt, A., Zhou, P. & Weiss, D. S. (2021). Francisella FlmX broadly affects lipopolysaccharide modification and virulence. Cell Reports, 35(11), Article ID 109247.
Open this publication in new window or tab >>Francisella FlmX broadly affects lipopolysaccharide modification and virulence
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 11, article id 109247Article in journal (Refereed) Published
Abstract [en]

The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the surprising convergence of these pathways through FlmX, an uncharacterized protein in the intracellular pathogen Francisella. FlmX is in the flippase family, which includes proteins that traffic lipid-linked envelope components across membranes. flmX deficiency causes defects in lipid A modification, core remodeling, and O-antigen addition. We find that an F. tularensis mutant lacking flmX is >1,000,000-fold attenuated. Furthermore, FlmX is required to resist the innate antimicrobial LL-37 and the antibiotic polymyxin. Given FlmX's central role in LPS modification and its conservation in intracellular pathogens Brucella, Coxiella, and Legionella, FlmX may represent a novel drug target whose inhibition could cripple bacterial virulence and sensitize bacteria to innate antimicrobials and antibiotics.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
cationic antimicrobial peptide, flippase, lipid A, lipopolysaccharide, polymyxin resistance
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-186362 (URN)10.1016/j.celrep.2021.109247 (DOI)000661869600009 ()34133919 (PubMedID)2-s2.0-85107905377 (Scopus ID)
Funder
NIH (National Institute of Health), AI098800, I01 BX002788Swedish Research Council, 2013-4581, 2013-8621
Available from: 2021-07-23 Created: 2021-07-23 Last updated: 2024-01-17Bibliographically approved
Projects
Eutrophication as a selection factor for the occurrence of predation-resistant and potentially pathogenic bacteria in aquatic environments [2008-1443_Formas]; Umeå UniversityThe roles of and relationships between iron regulation, resistance to reactive oxygen species and the virulence of Francisella tularensis [2009-03496_VR]; Umeå UniversityA type VI secretion system of Francisella tularensis - defining the functions of its components and their contribution to virulence [2009-05026_VR]; Umeå UniversityMechanisms effectuating killing of Francisella tularensis with a special focus on reactrive oxygen species and iron and their relationship to vaccine-mediated protection [2012-03469_VR]; Umeå UniversityA model for prediction of tularemia outbreaks and the relevance of climate change for future outbreaks [2012-1070_Formas]; Umeå UniversityDelineating immune-subversive mechanisms of Francisella tularensis and utilizing them as therapeutic targets [2013-08621_VR]; Umeå UniversityMechanisms of type VI secretion and its utility as therapeutic target [2013-04581_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0768-8405

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