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Larsson, Christer
Publications (10 of 18) Show all publications
Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Open this publication in new window or tab >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America, 2019
Keywords
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Kubler, A., Larsson, C., Luna, B., Andrade, B. B., Amaral, E. P., Urbanowski, M., . . . Bishai, W. R. (2016). Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. Journal of Infectious Diseases, 213(4), 618-627
Open this publication in new window or tab >>Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis
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2016 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 213, no 4, p. 618-627Article in journal (Refereed) Published
Abstract [en]

Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinoline (DPD), and urinary helical peptide, revealed that cavitation in tuberculosis leads to both type I collagen destruction and synthesis and that proteases other than MMP-1, MMP-13, and MMP-14 are involved, suggesting a key role for CTSK. We confirmed the importance of CTSK upregulation in human lung specimens, using immunohistochemical analysis, which revealed perigranulomatous staining for CTSK, and we showed that CTSK levels were increased in the serum of patients with tuberculosis, compared with those in controls (3.3 vs 0.3 ng/mL; P = .005).

Place, publisher, year, edition, pages
Oxford University Press, 2016
Keywords
tuberculosis, cathepsin K, rabbit, collagen, collagenolysis, RNAseq
National Category
Microbiology Immunology
Identifiers
urn:nbn:se:umu:diva-119672 (URN)10.1093/infdis/jiv458 (DOI)000372437700019 ()26416658 (PubMedID)
Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2018-06-07Bibliographically approved
Melo Filho, A., Drotz, S., Tsai, C.-J., Ragnvaldsson, D. & Larsson, C. (2015). Heat-killing of Legionella in biological sludge from a paper and pulp mill water treatment plant. Nordic Pulp & Paper Research Journal, 30(1), 121-125
Open this publication in new window or tab >>Heat-killing of Legionella in biological sludge from a paper and pulp mill water treatment plant
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2015 (English)In: Nordic Pulp & Paper Research Journal, ISSN 0283-2631, E-ISSN 2000-0669, Vol. 30, no 1, p. 121-125Article in journal (Refereed) Published
Abstract [en]

Paper and pulp mills use biological water treatment plants to reduce Chemical Oxygen Demand (COD) release to the environment. In the end of the process, microorganisms are concentrated into a biological sludge. Among the microbes thriving in these plants are Legionella, causing the Legionnaires disease. Combustion of the biological sludge produced at a plant results in unwanted downstream effects on the production and probably increased formation of nitrogen oxides (NOx) in the recovery boiler. Due to the disadvantages of combustion, the possibility to sterilize biological sludge has been investigated as a part of the continuously ongoing work at Metsa to improve occupational safety and reduce impact on the environment in a proactive way. A method to eradicate Legionellae in biological sludge would improve safety and ecological sustainability if the sludge instead is safely composted and used as e.g. soil fertilizer. Here we have assessed the time to death upon sludge heat treatment of a pathogenic L. pneumophila serogroup 1 strain, a L. longbeachae strain and the bacteria naturally occurring in biological sludge at the Metsa Board, Husum mill, Sweden. Time to death decreased with increasing temperatures up to 65 degrees C, where higher temperatures resulted in neglectable gain in time to death.

Keywords
Biological sludge, Biological water treatment, Legionella, Legionnaire's disease, Pontiac fever, NNIS PJ, 1984, JOURNAL OF APPLIED BACTERIOLOGY, V56, P349 alle T., 2014, Microb Ecol, amp G. J., 2010, EPIDEMIOLOGY AND INFECTION, V138, P15 gard K., 2005, Euro Surveill, V10, dege E., 2009, CLINICAL AND VACCINE IMMUNOLOGY, V16, P528 egersen P, 1999, SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH, V25, P291
National Category
Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-102390 (URN)000351668000015 ()
Available from: 2015-05-20 Created: 2015-04-23 Last updated: 2018-06-07Bibliographically approved
Luna, B., Kubler, A., Larsson, C., Foster, B., Bagci, U., Mollura, D. J., . . . Bishai, W. R. (2015). In Vivo Prediction of Tuberculosis-Associated Cavity Formation in Rabbits. The Journal of infectious diseases, 211(3), 481-485
Open this publication in new window or tab >>In Vivo Prediction of Tuberculosis-Associated Cavity Formation in Rabbits
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2015 (English)In: The Journal of infectious diseases, ISSN 1537-6613, Vol. 211, no 3, p. 481-485Article in journal (Refereed) Published
Abstract [en]

The presence of cavitary lesions in patients with tuberculosis poses a significant clinical concern due to the risk of infectivity and the risk of antibiotic treatment failure. We describe 2 algorithms that use noninvasive positron emission tomography (PET) and computed tomography (CT) to predict the development of cavitary lesions in rabbits. Analysis of the PET region of interest predicted cavitary disease with 100% sensitivity and 76% specificity, and analysis of the CT region of interest predicted cavitary disease with 83.3% sensitivity and 76.9% specificity. Our results show that restricting our analysis to regions with high [(18)F]-fluorodeoxyglucose uptake provided the best combination of sensitivity and specificity.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-93715 (URN)10.1093/infdis/jiu449 (DOI)000350221500018 ()25117755 (PubMedID)
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-06-07Bibliographically approved
Kübler, A., Luna, B., Larsson, C., Ammerman, N. C., Andrade, B. B., Orandle, M., . . . Bishai, W. R. (2015). Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.. Journal of Pathology, 235(3), 431-444
Open this publication in new window or tab >>Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
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2015 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 3, p. 431-444Article in journal (Refereed) Published
Abstract [en]

Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>10(7) CFU/g) far greater than those found in matched granulomatous tissue (10(5) CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R(2) =0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p < 0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1-99.8%, NPV=85.6%; 95%CI 77.0-91.9%).

Keywords
tuberculosis, matrix metalloproteinase, computed tomography, cavity
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-93713 (URN)10.1002/path.4432 (DOI)000347709000006 ()25186281 (PubMedID)
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-06-07Bibliographically approved
Elbir, H., Larsson, P., Normark, J., Upreti, M., Korenberg, E., Larsson, C. & Bergström, S. (2014). Genome Sequence of the Asiatic Species Borrelia persica. Genome Announcements, 2(1), Article ID e01127-13.
Open this publication in new window or tab >>Genome Sequence of the Asiatic Species Borrelia persica
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2014 (English)In: Genome Announcements, ISSN 2169-8287, E-ISSN 2169-8287, Vol. 2, no 1, article id e01127-13Article in journal (Refereed) Published
Abstract [en]

We report the complete genome sequence of Borrelia persica, the causative agent of tick-borne relapsing fever borreliosis on the Asian continent. Its genome of 1,784,979 bp contains 1,850 open reading frames, three ribosomal RNAs, and 32 tRNAs. One clustered regularly interspaced short palindromic repeat (CRISPR) was detected.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-93716 (URN)10.1128/genomeA.01127-13 (DOI)24407639 (PubMedID)
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-06-07Bibliographically approved
Larsson, C., Luna, B., Ammerman, N. C., Maiga, M., Agarwal, N. & Bishai, W. R. (2012). Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments. PLoS ONE, 7(7), e37516
Open this publication in new window or tab >>Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e37516-Article in journal (Refereed) Published
Abstract [en]

The seven WhiB proteins of Mycobacterium tuberculosis (M.tb) are widely believed to be redox-sensing transcription factors due to their binding of iron-sulfur clusters and similarities to DNA binding proteins. Here, we explored the nature of this hypothesized relationship. We exposed M.tb to physiologic conditions such as gradual hypoxia, nitric oxide (NO), cyclic AMP and in vivo conditions, and measured transcription of the whiB genes. We found whiB3 to be induced both by hypoxia and NO, whiB7 to be induced in macrophage-like cells, and whiB4 to be induced in mouse lung. Cyclic AMP induced whiB1,-2, -4, -6 and -7. Our data indicate that the M.tb whiB genes are induced independently by various stimuli which may add versatility to their suggested redox-sensing properties.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-61865 (URN)10.1371/journal.pone.0037516 (DOI)000306956300004 ()22829866 (PubMedID)
Funder
Swedish Research Council
Note

This work was supported by The Swedish Research Council (VR) www.vr.se, the Swedish Society for Medical Research (SSMF) www.ssmf.se, and the National Institute of Health (NIH) www.nih.gov AI36973 and AI37856.

Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2018-06-08Bibliographically approved
Lundqvist, J., Larsson, C., Nelson, M., Andersson, M., Bergström, S. & Persson, C. (2010). Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis. Infection and Immunity, 78(5), 1924-1930
Open this publication in new window or tab >>Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis
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2010 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, no 5, p. 1924-1930Article in journal (Refereed) Published
Abstract [en]

About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia can be misdiagnosed with malaria due to similar manifestations and geographic distribution of the two diseases. More alarmingly, high prevalence of concomitant infections with malaria and RF Borrelia has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response towards the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, co-infected animals had higher fatality rate and shorter time to death than both malaria and RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF Borrelia infection. Our study highlights the importance of investigating concomitant infections in vivo to elucidate the immune responses that are involved in the clinical outcome.

Place, publisher, year, edition, pages
American Society for Microbiology, 2010
National Category
Immunology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-32816 (URN)10.1128/IAI.01082-09 (DOI)000276778700013 ()20145098 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-26 Last updated: 2018-06-08Bibliographically approved
Toledo-Arana, A., Anda, P., Escudero, R., Larsson, C., Bergström, S. & Benach, J. (2010). Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever. Journal of Clinical Microbiology, 48(7), 2484-2489
Open this publication in new window or tab >>Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever
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2010 (English)In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 48, no 7, p. 2484-2489Article in journal (Refereed) Published
Abstract [en]

Multilocus sequence analysis (MLSA) was used to clarify the taxonomic status of a virulent Borrelia organism previously isolated from patients with relapsing fever and from ticks in Spain that is designated the Spanish relapsing fever (SRF) Borrelia. This species has been used extensively in experimental infection models because of its continued virulence. Seven genes were amplified to analyze the phylogenetic relationships among several Spanish isolates of SRF Borrelia and other relapsing fever Borrelia species. The genes targeted in this study included rrs and flaB, which have commonly been used in phylogenetic studies; the rrf-rrl intergenic spacer (IGS), which is highly discriminatory; and four additional genes, p66, groEL, glpQ, and recC, which are located on the chromosome and which have therefore evolved in a clonal way. The species included in this study were Borrelia duttonii, B. recurrentis, B. crocidurae, and B. hispanica as Old World Borrelia species and B. turicatae and B. hermsii as New World Borrelia species. The results obtained by MLSA of the SRF Borrelia on the basis of 1% of the genomic sequence data analyzed confirmed that the SRF Borrelia isolates are B. hispanica. However, the prototype isolates of B. hispanica used in this study have an uncertain history and display unique phenotypic characteristics that are not shared with the SRF Borrelia. Therefore, we propose to use strain SP1, isolated from a relapsing fever patient in 1994 in southern Spain, as the type strain for B. hispanica.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-43202 (URN)10.1128/JCM.00541-10 (DOI)000279318700024 ()
Available from: 2011-04-22 Created: 2011-04-22 Last updated: 2018-12-04Bibliographically approved
Larsson, C., Lundqvist, J., van Rooijen, N. & Bergström, S. (2009). A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice. PLoS Neglected Tropical Diseases, 3(9), e522
Open this publication in new window or tab >>A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice
2009 (English)In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 3, no 9, p. e522-Article in journal (Refereed) Published
Abstract [en]

Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.

Place, publisher, year, edition, pages
PLoS, Public Library of Science, 2009
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-32839 (URN)10.1371/journal.pntd.0000522 (DOI)19787030 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-29 Last updated: 2018-06-08Bibliographically approved
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