Publications by authors named "Cecilia Johansson"

69 Publications

Neutrophils in respiratory viral infections.

Mucosal Immunol 2021 Mar 23. Epub 2021 Mar 23.

National Heart and Lung Institute, Imperial College London, London, UK.

Viral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.
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http://dx.doi.org/10.1038/s41385-021-00397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985581PMC
March 2021

Weight, height, weight change, and risk of incident atrial fibrillation in middle-aged men and women.

J Arrhythm 2020 Dec 23;36(6):974-981. Epub 2020 Jul 23.

Skellefteå Research Unit Department of Public Health and Clinical Medicine Umeå University Skellefteå Sweden.

Background: Anthropometric factors are reported to be risk factors for atrial fibrillation (AF), but it is unclear whether weight change in mid-life is associated with AF. We aimed to study the possible associations of weight, height, and weight change with the risk of incident AF in men and women.

Methods: Our study cohort included 108 417 persons (51% women) who participated in a population-based health examination in northern Sweden at 30, 40, 50, or 60 years of age. The health examination included weight and height measurement and collection of data regarding cardiovascular risk factors. Within this cohort, 40 275 participants underwent two health examinations with a 10-year interval. We identified cases with a first-ever diagnosis of AF through the Swedish National Patient Registry.

Results: During a total follow-up of 1 469 820 person-years, 5154 participants developed incident AF. The mean age at inclusion was 46.3 years, and mean age at AF diagnosis was 66.6 years. After adjustment for potential confounders, height, weight, body mass index (BMI), and body surface area (BSA) were positively associated with risk of incident AF in both men and women. Among participants who underwent two health examinations 10 years apart, 1142 persons developed AF. The mean weight change from baseline was a gain of 4.8%. Weight gain or weight loss was not significantly associated with risk of incident AF.

Conclusions: Height, weight, BMI, and BSA showed positive associations with risk of incident AF in both men and women. Midlife weight change was not significantly associated with AF risk.
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http://dx.doi.org/10.1002/joa3.12409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733566PMC
December 2020

Genomic and Phenotypic Characterisation of Isolates From a Waterborne Outbreak.

Front Cell Infect Microbiol 2020 29;10:594856. Epub 2020 Oct 29.

Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

infections are the leading cause of bacterial gastroenteritis. In Europe, over 246,000 cases are confirmed annually. Infections are often transmitted contaminated food, such as poultry products, but water may be the source of infection as well. The aim of this study was to characterise a selection of human isolates, together with a water isolate, from a waterborne outbreak in Norway in 2019, including human isolates from early, mid-, and late epidemic. The isolates were characterised with whole-genome sequencing, analysing the expression of putative virulence genes and demonstrating the pathogenic potential in an adhesion model using HT-29 cells. All isolates belonged to the multilocus sequence type 1701 and ST45 clonal complex. In the genomic analysis, the water isolate clustered somewhat separately from the human isolates. There was some variation between the human isolates, but the water isolate seemed to display the greatest pathogenic potential, demonstrated by the highest levels of virulence gene expression, adhesion to epithelial cells and IL-8 induction. These results suggest that the water isolate of the study has potential to cause human infections, and that some bacterial changes due to host or environmental adaptation, may occur during a waterborne epidemic. This is, to the best of our knowledge, the first study on isolates from a waterborne outbreak, including both human isolates and a water isolate, characterised with genomic and phenotypic approaches.
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http://dx.doi.org/10.3389/fcimb.2020.594856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658296PMC
October 2020

Rapidly Deployable Mouse Models of SARS-CoV-2 Infection Add Flexibility to the COVID-19 Toolbox.

Am J Respir Cell Mol Biol 2021 01;64(1):7-9

National Heart and Lung Institute Imperial College London London, United Kingdom.

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http://dx.doi.org/10.1165/rcmb.2020-0456EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780994PMC
January 2021

MAVS Deficiency Is Associated With a Reduced T Cell Response Upon Secondary RSV Infection in Mice.

Front Immunol 2020 6;11:572747. Epub 2020 Oct 6.

Respiratory Infections Section, St Mary's Campus, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Infections with respiratory syncytial virus (RSV) occurs repeatedly throughout life because sustained, protective memory responses fail to develop. Why this occurs is not known. During RSV infection the recognition of the virus the cytosolic RIG-I like receptors and signaling the adaptor protein MAVS is crucial for mounting an innate immune response. However, if this signaling pathway is important for T cell responses during primary infection and during re-infection is not fully elucidated. We describe a second peak of pro-inflammatory mediators during the primary immune response to RSV that coincides with the arrival of T cells into the lung. This second peak of cytokines/chemokines is regulated differently than the early peak and is largely independent of signaling MAVS. This was concurrent with mice mounting a strong T cell response to primary RSV infection, with robust IFN-γ; and Granzyme B production. However, after RSV re-infection, mice showed fewer CD4 and CD8 short term memory T cells and their capacity to produce IFN-γ; and Granzyme B, was decreased. In sum, cytosolic recognition of RSV is important not only for initiating innate anti-viral responses but also for generating or maintaining efficient, short term T cell memory responses.
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http://dx.doi.org/10.3389/fimmu.2020.572747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573121PMC
October 2020

MAVS Deficiency Is Associated With a Reduced T Cell Response Upon Secondary RSV Infection in Mice.

Front Immunol 2020 6;11:572747. Epub 2020 Oct 6.

Respiratory Infections Section, St Mary's Campus, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Infections with respiratory syncytial virus (RSV) occurs repeatedly throughout life because sustained, protective memory responses fail to develop. Why this occurs is not known. During RSV infection the recognition of the virus the cytosolic RIG-I like receptors and signaling the adaptor protein MAVS is crucial for mounting an innate immune response. However, if this signaling pathway is important for T cell responses during primary infection and during re-infection is not fully elucidated. We describe a second peak of pro-inflammatory mediators during the primary immune response to RSV that coincides with the arrival of T cells into the lung. This second peak of cytokines/chemokines is regulated differently than the early peak and is largely independent of signaling MAVS. This was concurrent with mice mounting a strong T cell response to primary RSV infection, with robust IFN-γ; and Granzyme B production. However, after RSV re-infection, mice showed fewer CD4 and CD8 short term memory T cells and their capacity to produce IFN-γ; and Granzyme B, was decreased. In sum, cytosolic recognition of RSV is important not only for initiating innate anti-viral responses but also for generating or maintaining efficient, short term T cell memory responses.
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http://dx.doi.org/10.3389/fimmu.2020.572747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573121PMC
October 2020

Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection.

Science 2020 10;370(6513)

National Heart and Lung Institute, Imperial College London, London, UK.

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8 T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.
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http://dx.doi.org/10.1126/science.aba9301DOI Listing
October 2020

The missing pieces for better future predictions in subarctic ecosystems: A Torneträsk case study.

Ambio 2021 Feb 13;50(2):375-392. Epub 2020 Sep 13.

Department of Physical Geography and Ecosystem Science, Lund University, Sölvegatan 12, 223 62, Lund, Sweden.

Arctic and subarctic ecosystems are experiencing substantial changes in hydrology, vegetation, permafrost conditions, and carbon cycling, in response to climatic change and other anthropogenic drivers, and these changes are likely to continue over this century. The total magnitude of these changes results from multiple interactions among these drivers. Field measurements can address the overall responses to different changing drivers, but are less capable of quantifying the interactions among them. Currently, a comprehensive assessment of the drivers of ecosystem changes, and the magnitude of their direct and indirect impacts on subarctic ecosystems, is missing. The Torneträsk area, in the Swedish subarctic, has an unrivalled history of environmental observation over 100 years, and is one of the most studied sites in the Arctic. In this study, we summarize and rank the drivers of ecosystem change in the Torneträsk area, and propose research priorities identified, by expert assessment, to improve predictions of ecosystem changes. The research priorities identified include understanding impacts on ecosystems brought on by altered frequency and intensity of winter warming events, evapotranspiration rates, rainfall, duration of snow cover and lake-ice, changed soil moisture, and droughts. This case study can help us understand the ongoing ecosystem changes occurring in the Torneträsk area, and contribute to improve predictions of future ecosystem changes at a larger scale. This understanding will provide the basis for the future mitigation and adaptation plans needed in a changing climate.
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http://dx.doi.org/10.1007/s13280-020-01381-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782653PMC
February 2021

R848 or influenza virus can induce potent innate immune responses in the lungs of neonatal mice.

Mucosal Immunol 2021 01 23;14(1):267-276. Epub 2020 Jun 23.

Section of Respiratory Infections, National Heart and Lung Institute, Imperial College London, London, UK.

Innate immune responses are important to protect the neonatal lung, which becomes exposed to commensal and pathogenic microorganisms immediately after birth, at a time when both the lung and the adaptive immune system are still developing. How immune cells in the neonatal lung respond to innate immune stimuli, including toll-like receptor (TLR) agonists, or viruses, is currently unclear. To address this, adult and neonatal mice were intranasally administered with various innate immune stimuli, respiratory syncytial virus (RSV) or influenza virus and cytokine and chemokine levels were quantified. The neonatal lungs responded weakly to RSV and most stimuli but more strongly than adult mice to R848 and influenza virus, both of which activate TLR7 and the inflammasome. Notably, neonatal lungs also contained higher levels of cAMP, a secondary messenger produced following adenosine receptor signaling, than adult lungs and increased responsiveness to R848 was observed in adult mice when adenosine was coadministered. Our data suggest that the neonatal lung may respond preferentially to stimuli that coactivate TLR7 and the inflammasome and that these responses may be amplified by extracellular adenosine. Improved understanding of regulation of immune responses in the neonatal lung can inform the development of vaccine adjuvants for the young.
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http://dx.doi.org/10.1038/s41385-020-0314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116567PMC
January 2021

Alcohol consumption and risk of incident atrial fibrillation: A population-based cohort study.

Eur J Intern Med 2020 06 6;76:50-57. Epub 2020 Mar 6.

Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, 931 86 Skellefteå, Sweden.

Aims: Atrial fibrillation (AF) is a common tachyarrhythmia. High alcohol consumption is associated with increased AF risk. It remains unclear whether lower levels of alcohol consumption are also associated with AF risk, and whether the association differs between men and women. In this study, we investigated the association between low to moderate levels of alcohol consumption and AF risk in men and women.

Methods: We performed a population-based cohort study of 109,230 health examination participants in northern Sweden. Data regarding alcohol intake were obtained using a questionnaire administered at the health examination. Incident AF cases were identified from the Swedish National Patient Registry.

Results: AF was diagnosed in 5,230 individuals during a total follow-up of 1,484,547 person-years. Among men, AF risk increased over quartiles of weekly alcohol consumption (P for trend 0.001). Men with alcohol consumption in the highest quartile (≥4.83 standard drinks [each drink containing 12 gs of ethanol] per week; SDW) had a HR of 1.21 (95% CI 1.09-1.34) for AF compared to men in the lowest quartile (<0.90 SDW). In men, problem drinking was also associated with an increased AF risk (HR: 1.24; 95% CI: 1.10-1.39). Among women, AF risk was not significantly associated with alcohol consumption (P for trend 0.09 for decreasing risk of AF over quartiles of weekly alcohol consumption) or problem drinking (HR: 1.00; 95% CI 0.70-1.42).

Conclusion: Self-reported alcohol consumption and problem drinking were associated with an increased risk of AF among men, but not in women.
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http://dx.doi.org/10.1016/j.ejim.2020.02.022DOI Listing
June 2020

Neutrophils do not impact viral load or the peak of disease severity during RSV infection.

Sci Rep 2020 01 24;10(1):1110. Epub 2020 Jan 24.

National Heart and Lung Institute, Imperial College London, London, UK.

Lung and airway neutrophils are a hallmark of severe disease in infants with respiratory syncytial virus (RSV)-induced lower respiratory tract infections. Despite their abundance in the lungs during RSV infection of both mice and man, the role of neutrophils in viral control and in immune pathology is not clear. Here, antibody mediated neutrophil depletion was used to investigate the degree to which neutrophils impact the lung immune environment, the control of viral replication and the peak severity of disease after RSV infection of mice. Neutrophil depletion did not substantially affect the levels of inflammatory mediators such as type I interferons, IL-6, TNF-α or IL-1β in response to RSV. In addition, the lack of neutrophils did not change the viral load during RSV infection. Neither neutrophil depletion nor the enhancement of lung neutrophils by administration of the chemoattractant CXCL1 during RSV infection affected disease severity as measured by weight loss. Therefore, in this model of RSV infection, lung neutrophils do not offer obvious benefits to the host in terms of increasing anti-viral inflammatory responses or restricting viral replication and neutrophils do not contribute to disease severity.
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http://dx.doi.org/10.1038/s41598-020-57969-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981203PMC
January 2020

Chemokine regulation of inflammation during respiratory syncytial virus infection.

F1000Res 2019 31;8. Epub 2019 Oct 31.

National Heart and Lung Institute, Imperial College London, London, UK.

Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections especially in infants, immunocompromised individuals and the elderly and is the most common cause of infant hospitalisation in the developed world. The immune responses against RSV are crucial for viral control and clearance but, if dysregulated, can also result in immunopathology and impaired gas exchange. Lung immunity to RSV and other respiratory viruses begins with the recruitment of immune cells from the bloodstream into the lungs. This inflammatory process is controlled largely by chemokines, which are small proteins that are produced in response to innate immune detection of the virus or the infection process. These chemokines serve as chemoattractants for granulocytes, monocytes, lymphocytes and other leukocytes. In this review, we highlight recent advances in the field of RSV infection and disease, focusing on how chemokines regulate virus-induced inflammation.
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http://dx.doi.org/10.12688/f1000research.20061.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823903PMC
June 2020

Differences in virulence gene expression between human blood and stool clade 1 ST828CC isolates.

Gut Pathog 2019 1;11:42. Epub 2019 Aug 1.

1Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: colonise the gastrointestinal tract of warm-blooded animals and are major enteropathogens in humans. is less common than and accounts for about 10% of the total number of infections although the two species seem to share many virulence determinants. bacteraemia is rare, estimated to occur in less than 1% of the infections, and the exact mechanisms regulating the progression of the infection from the gastrointestinal tract to the blood stream are unclear. Here, we looked at the contribution of to infections and further compared various virulence traits in clade 1 blood and stool isolates.

Results: We assessed the numbers of and among typed isolates in the PubMLST database and found that accounted for 25.9% of blood isolates, but only 8.9% of the stool isolates. Phylogenetic analysis of 128 clade 1 whole genome sequences deposited to NCBI revealed no specific clustering of the human blood, stool or animal isolates. Of the six isolates chosen for phenotypic analyses, stool isolates adhered significantly better to human HT-29 colon cancer cells than the blood isolates, while there was no difference in induced IL-8 levels between the isolates. Furthermore, the stool isolates had two- to fourfold higher RNA expression levels of the , and virulence genes than the blood isolates. Finally, we looked at the gene structure of the and toxin genes and found numerous nucleotide additions and deletions disrupting the open reading frames. In contrast to 58% isolates of animal origin, only 38% and 32% of human blood and stool isolates, respectively, had all three genes intact, a prerequisite to produce functional toxins.

Conclusions: This study reveals interesting differences between clade 1 isolates of human and animal origin on one hand, and also between human blood and stool isolates, on the other. The results suggest that might downregulate and/or inactivate various virulence determinants as the isolates pass from the animal host to the human gastrointestinal tract and enter the human blood stream.
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http://dx.doi.org/10.1186/s13099-019-0322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669978PMC
August 2019

Neutrophil recruitment and activation are differentially dependent on MyD88/TRIF and MAVS signaling during RSV infection.

Mucosal Immunol 2019 09 29;12(5):1244-1255. Epub 2019 Jul 29.

National Heart and Lung Institute, Imperial College London, St Mary's Hospital, Norfolk Place, London, W2 1PG, UK.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections, especially in infants. Lung neutrophilia is a hallmark of RSV disease but the mechanism by which neutrophils are recruited and activated is unclear. Here, we investigate the innate immune signaling pathways underlying neutrophil recruitment and activation in RSV-infected mice. We show that MyD88/TRIF signaling is essential for lung neutrophil recruitment while MAVS signaling, leading to type I IFN production, is necessary for neutrophil activation. Consistent with that notion, administration of type I IFNs to the lungs of RSV-infected Mavs mice partially activates lung neutrophils recruited via the MyD88/TRIF pathway. Conversely, lack of neutrophil recruitment to the lungs of RSV-infected Myd88/Trif mice can be corrected by administration of chemoattractants and those neutrophils become fully activated. Interestingly, Myd88/Trif mice did not have increased lung viral loads during RSV infection, suggesting that neutrophils are dispensable for viral control. Thus, two distinct pathogen sensing pathways collaborate for neutrophil recruitment and full activation during RSV infection.
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http://dx.doi.org/10.1038/s41385-019-0190-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778055PMC
September 2019

and are cytotoxic to human cells due to high expression of alpha-hemolysin Hla.

Virulence 2019 12;10(1):502-510

a Clinical Microbiology, Department of Medical Sciences , Uppsala University , Uppsala , Sweden.

and are newly identified species of the -related complex. as occurring globally and showing significant prevalence and comparable infection and morbidity rates compared to , is becoming clinically important. Whole genome sequencing has revealed the presence of several virulence genes but the molecular mechanisms of infection and virulence are largely unknown. Here, we studied the effect of a previously characterized clinical isolate on human cells . The clinical isolate, together with the type strain MSHR1132T and the type strain FSA084T, had a cytotoxic effect on the cells, which showed necrotic cell death after a few hours of treatment. The protein causing the cytotoxic effect was purified and identified by mass spectrometry as alpha-hemolysin, Hla, which is awell-known pore-forming toxin in . The cytotoxic effect could be blocked with an antibody against Hla. showed 12-15 fold higher expression levels of at the RNA level and 4-6 fold higher expression levels at the protein level compared to . The higher expression levels of were supported by higher RNA levels of the regulatory factors and . Also, the RNAIII component of the accessory gene regulator (agr) quorum sensing system was 8,000-10,000 fold higher in the isolates compared to . This is the first study on the effect of on ahuman cell line and strengthens the idea of significant virulence of .
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http://dx.doi.org/10.1080/21505594.2019.1620062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550535PMC
December 2019

Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans.

J Allergy Clin Immunol 2019 07 16;144(1):342-345.e7. Epub 2019 Apr 16.

Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602583PMC
July 2019

Clade 3 Isolates Induce Rapid Cell Death .

Appl Environ Microbiol 2019 03 20;85(5). Epub 2019 Feb 20.

Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

bacteria are major human enteropathogens. shows less genetic diversity than and clusters into three clades, of which clade 1 includes most human and farm animal isolates, while environmental isolates mainly belong to clades 2 and 3. Recently, we sequenced the whole genomes of eight clade 2 and 3 isolates cultivated from water, and here we studied their interaction with human HT-29 colon cancer cells compared to that of clinical clade 1 isolates. All clade 3 isolates already caused cell necrosis 1 to 2 h after inoculation, whereas none of the clade 1 and 2 isolates analyzed induced cell death. Isolates from clades 2 and 3 adhered to epithelial cells better than clade 1 isolates, but all isolates induced similar levels of interleukin-8 (IL-8). Alignment and phylogenetic analysis of the translated putative virulence genes , , , , and revealed clade-specific protein sequence variations, with clade 1 and 2 sequences being more closely related and clade 3 sequences being further apart, in general. Moreover, when RNA levels were measured, clade 3 isolates showed significantly lower levels of expression of , , and than clade 2 isolates, while expression levels were higher in clade 3 isolates. The cytolethal distending toxin genes were also expressed in clades 2 and 3, although there was no difference between clades. Our findings demonstrate differences between the effects of clade 1, 2, and 3 isolates on human cells and suggest that clade 3 might be more virulent than clade 2 due to the observed cytotoxicity. is a common zoonotic cause of gastroenteritis in humans worldwide. The majority of infections are caused by clade 1 isolates, whereas infections due to clade 2 and 3 isolates are rare. Whether this depends on a low prevalence of clade 2 and 3 isolates in reservoirs important for human infections or their lower ability to cause human disease is unknown. Here, we studied the effects of clade 2 and 3 isolates on a human cell line. These isolates adhered to human cells to a higher degree than clinical clade 1 isolates. Furthermore, we could show that clade 3 isolates rapidly induced cell death, suggesting differences in the virulence of The exact mechanism of cell death remains to be revealed, but selected genes showed interesting clade-specific expression patterns.
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http://dx.doi.org/10.1128/AEM.02993-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384112PMC
March 2019

Which methods are appropriate for the detection of and is it worthwhile to distinguish from ?

Infect Drug Resist 2018 21;11:2335-2344. Epub 2018 Nov 21.

Department of Medical Sciences, Clinical Microbiology, Uppsala University, Uppsala, Sweden,

Purpose: To further analyze a clinical isolate originally identified as methicillin-resistant (MRSA) using whole-genome sequencing and comparative genomics.

Materials And Methods: Classical diagnostic methods such as cultivation, biochemical tests, and PCR were supplemented with whole-genome sequencing and comparative genomics, to identify the isolate.

Results: The isolate was phenotypically similar to MRSA. However, the presence of the gene could not be confirmed using PCR, while it was positive for the gene. Whole-genome sequencing correctly identified the isolate as . The isolate possessed several resistance genes, such as , (β-lactam antibiotics) and (trimethoprim). The gene differed from that of MRSA. Six phylogenetic distinct clusters were identified by average nucleotide identity (ANI) analysis of all available whole-genome sequences. Our isolate, RK308, clustered with those isolated in Europe and Asia.

Conclusion: Due to the invasive potential, the multi-drug resistance and the similarity to MRSA, should be included in the MRSA screening. Due to the divergent genome compared to MRSA, new PCR approaches have to be developed to avoid an unnoticed spreading of .
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http://dx.doi.org/10.2147/IDR.S179390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254542PMC
November 2018

Survival of Campylobacter jejuni and Campylobacter coli water isolates in lake and well water.

APMIS 2018 Sep;126(9):762-770

Department of Medical Sciences, Clinical Microbiology, Uppsala University, Uppsala, Sweden.

The role of water for transmission of Campylobacter jejuni and C. coli to humans might be underestimated, as factors important for bacterial viability in water are largely unknown. We have studied water survival of seven C. jejuni and eight C. coli isolates originally isolated from Swedish waters, together with selected reference strains, over eight days at 4 °C in the dark in untreated water collected from a local lake and a private well. To study seasonality, lake water samples were collected during spring and autumn. Samples for culturable bacterial counts were taken on days 2, 4, 6, and 8 and compared to the start inoculum. For C. jejuni, a significantly better survival was observed in autumn than in spring lake water. Furthermore, C. jejuni had a significantly better survival than C. coli in autumn lake and well water samples; the rate of culturability loss was almost double for C. coli in autumn lake water. These findings contribute to a better understanding on the seasonality of waterborne Campylobacter infections and the general predominance of C. jejuni.
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http://dx.doi.org/10.1111/apm.12879DOI Listing
September 2018

Characterization of Swedish Campylobacter coli clade 2 and clade 3 water isolates.

Microbiologyopen 2018 08 9;7(4):e00583. Epub 2018 Feb 9.

Department of Medical Sciences, Clinical Microbiology, Uppsala University, Uppsala, Sweden.

Campylobacter jejuni and Campylobacter coli are important bacterial enteropathogens. Poultry is the best-known reservoir for Campylobacter infection but natural bodies of water have also been shown to be important pathways for transmission. Campylobacter can survive in cold water but most of the studies have focused on C. jejuni only. In this paper, we take a closer look at the biology and water survival strategies of C. coli. Eight C. coli isolates cultivated from raw (incoming) surface water at water plants in Sweden were characterized using whole-genome sequencing and phenotypical assays. Phylogenetic analysis assigned the Swedish water isolates to clades 2 and 3, known to include C. coli of environmental origin. In addition, 53 earlier published sequences of C. coli clade 2 and 3 from environmental waters were included for in silico analyses. Generally, clade 2 isolates had larger genomes, which included a functional tricarballylate utilization locus, while clade 3 isolates contained different genes involved in oxidative stress as well as putative virulence factors. The Swedish water isolates of clade 2 formed large, blurry bacterial colonies on agar, whereas clade 3 colonies were smaller. All Swedish isolates were motile, but clade 3 isolates formed larger motility zones on soft agar, and none of these isolates produced biofilm. Although water survival varied between the analyzed isolates, there were hardly any clade-specific significant differences. Our results highlight the diversity of C. coli in general, and show differences in metabolic capabilities and ways to handle oxidative stress between clade 2 and 3 water isolates.
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http://dx.doi.org/10.1002/mbo3.583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079167PMC
August 2018

Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice.

PLoS Pathog 2018 01 4;14(1):e1006821. Epub 2018 Jan 4.

Section of Virology, Department of Medicine, Imperial College London, London, United Kingdom.

The highly pathogenic avian influenza (HPAI) H5N1 influenza virus has been a public health concern for more than a decade because of its frequent zoonoses and the high case fatality rate associated with human infections. Severe disease following H5N1 influenza infection is often associated with dysregulated host innate immune response also known as cytokine storm but the virological and cellular basis of these responses has not been clearly described. We rescued a series of 6:2 reassortant viruses that combined a PR8 HA/NA pairing with the internal gene segments from human adapted H1N1, H3N2, or avian H5N1 viruses and found that mice infected with the virus with H5N1 internal genes suffered severe weight loss associated with increased lung cytokines but not high viral load. This phenotype did not map to the NS gene segment, and NS1 protein of H5N1 virus functioned as a type I IFN antagonist as efficient as NS1 of H1N1 or H3N2 viruses. Instead we discovered that the internal genes of H5N1 virus supported a much higher level of replication of viral RNAs in myeloid cells in vitro, but not in epithelial cells and that this was associated with high induction of type I IFN in myeloid cells. We also found that in vivo during H5N1 recombinant virus infection cells of haematopoetic origin were infected and produced type I IFN and proinflammatory cytokines. Taken together our data infer that human and avian influenza viruses are differently controlled by host factors in alternative cell types; internal gene segments of avian H5N1 virus uniquely drove high viral replication in myeloid cells, which triggered an excessive cytokine production, resulting in severe immunopathology.
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http://dx.doi.org/10.1371/journal.ppat.1006821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771632PMC
January 2018

Genomic and phenotypic characteristics of Swedish C. jejuni water isolates.

PLoS One 2017 7;12(12):e0189222. Epub 2017 Dec 7.

Department of Medical Sciences, Clinical Microbiology, Uppsala University, Uppsala, Sweden.

Campylobacter jejuni is the most common cause of bacterial gastroenteritis. Major reservoirs are warm-blooded animals, poultry in particular, but Campylobacter can also be transmitted via water. In this paper, we have taken a closer look at the biology and potential virulence of C. jejuni water isolates. Seven C. jejuni isolates from incoming surface water at water plants in Sweden were characterized with whole genome sequencing and phenotypical testing. Multi locus sequence typing analysis revealed that these isolates belonged to groups known to include both common (ST48CC) and uncommon (ST1275CC, ST683, ST793 and ST8853) human pathogens. Further genomic characterization revealed that these isolates had potential for arsenic resistance (due to presence of arsB gene in all isolates), an anaerobic dimethyl sulfoxide oxidoreductase (in three isolates) and lacked the MarR-type transcriptional regulator gene rrpB (in all but one isolate) earlier shown to be involved in better survival under oxidative and aerobic stress. As putative virulence factors were concerned, there were differences between the water isolates in the presence of genes coding for cytolethal distending toxin (cdtABC), Type VI secretion system and sialylated LOS, as well as in biofilm formation. However, all isolates were motile and could adhere to and invade the human HT-29 colon cancer cell line in vitro and induce IL-8 secretion suggesting potential to infect humans. This is, to the best of our knowledge, the first study where C. jejuni water isolates have been characterized using whole genome sequencing and phenotypical assays. We found differences and shared traits among the isolates but also potential to infect humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720728PMC
December 2017

Type I interferon is required for T helper (Th) 2 induction by dendritic cells.

EMBO J 2017 08 17;36(16):2404-2418. Epub 2017 Jul 17.

Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from mice were incapable of initiating Th2 responses These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.
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http://dx.doi.org/10.15252/embj.201695345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556270PMC
August 2017

Differentially methylated embryonal Fyn-associated substrate (EFS) gene as a blood-specific epigenetic marker and its potential application in forensic casework.

Forensic Sci Int Genet 2017 07 19;29:165-173. Epub 2017 Apr 19.

Department of Pharmacy and Forensic Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, UK.

DNA methylation patterns have the ability to reveal the activities of genes within a certain tissue at a particular time point. Tissue-specific DNA methylation patterns have been previously investigated for their applicability in the identification of forensically relevant body fluids, however there is still a lack in robust markers. While following a genome-wide scale investigation has a great potential to reveal useful tissue-specific changes, a gene-targeted approach can also lead to significant outcomes, especially in genomic locations not included in the genome-wide experiments. In this study, the potential of the candidate embryonal Fyn-associated substrate (EFS) gene for the positive identification of whole blood was investigated. For this purpose, the methylation profile of a selected genomic region containing a total of 10 CpG sites was analysed in 124 individuals via bisulfite pyrosequencing. Volunteers donated various forensically relevant tissues, including whole blood, saliva, seminal fluid, vaginal fluid and menstrual secretion. Whole blood showed the highest levels of DNA methylation (mean=0.67), while semen samples were found to be very low methylated (mean=0.06). The remaining tissues demonstrated partial mean methylation levels; more specifically, saliva - 0.43, vaginal fluid - 0.22 and menstrual blood - 0.22. One out of the 10 analysed CpG sites, CpG4, showed to be more robust, resulting in not only the highest methylation difference between blood and the rest of the tissues, but also the lowest inter-individual methylation difference. The proposed pyrosequencing assay was found to be accurate, linear and reproducible. Lastly, the method's applicability to forensic casework was assessed via the analysis of very old bloodstains stored up to 18 years, blood DNA samples stored long-term up to 9 years, mixed stains as well as other 'forensic-like' samples. In the majority of cases the expected methylation ratios were obtained indicating a stable DNA methylation pattern, however caution is necessary when analysing low quantity and/or quality samples due to potential stochastic effects. Future validation experiments can shed more light into the usefulness of EFS locus as a promising blood-specific epigenetic marker.
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http://dx.doi.org/10.1016/j.fsigen.2017.04.010DOI Listing
July 2017

Type I Interferons as Regulators of Lung Inflammation.

Front Immunol 2017 10;8:259. Epub 2017 Mar 10.

Section of Respiratory Infections, National Heart and Lung Institute, Imperial College London , London , UK.

Immune responses to lung infections must be tightly regulated in order to permit pathogen eradication while maintaining organ function. Exuberant or dysregulated inflammation can impair gas exchange and underlies many instances of lung disease. An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are antiviral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses. However, type I IFNs have also recently been found to be central to the initiation of lung inflammatory responses, by inducing recruitment and activation of immune cells. This helps control virus burden but can cause detrimental immunopathology and contribute to disease severity. Furthermore, there is now increasing evidence that type I IFNs are not only induced after viral infections but also after infection with bacteria and fungi. The pro-inflammatory function of type I IFNs in the lung opens up the possibility of immune modulation directed against this antiviral cytokine family. In this review, the initiation and signaling of type I IFNs as well as their role in driving and maintaining lung inflammation will be discussed.
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http://dx.doi.org/10.3389/fimmu.2017.00259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344902PMC
March 2017

Protective and Harmful Immunity to RSV Infection.

Annu Rev Immunol 2017 04 6;35:501-532. Epub 2017 Feb 6.

Respiratory Infections, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom; email:

Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
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http://dx.doi.org/10.1146/annurev-immunol-051116-052206DOI Listing
April 2017

Incidence, type of atrial fibrillation and risk factors for stroke: a population-based cohort study.

Clin Epidemiol 2017 24;9:53-62. Epub 2017 Jan 24.

Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Västerbotten, Sweden.

Purpose: The aims of this study were to estimate the incidence of atrial fibrillation and atrial flutter (AF), to assess the presence of provoking factors and risk factors for stroke and systemic embolism, and to determine the type of AF in patients with first-diagnosed AF.

Patients And Methods: This cohort study was performed in northern Sweden between January 1, 2011 and December 31, 2012. Diagnosis registries were searched for the International Classification of Diseases-10 code for AF (I48) to identify cases of incident AF. All AF diagnoses were electrocardiogram-verified. Data pertaining to provoking factors, type of AF and presence of risk factors for stroke and systemic embolism according to the CHADS-VASc score were obtained from medical records.

Results: The incidence of AF in the entire population was 4.0 per 1,000 person-years. The incidence was 27.5 per 1,000 person-years in patients aged ≥80 years. A total of 21% of all patients had a provoking factor in association with the first-diagnosed episode of AF. The CHADS-VASc score was 2 or higher in 81% of the patients. Permanent AF was the most common type of AF (29%).

Conclusion: There was a considerable increase in the incidence of AF with age, and a provoking factor was found in one-fifth. The most common type of AF was permanent AF. Four in five patients had a CHADS-VASc score of 2 or more.
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http://dx.doi.org/10.2147/CLEP.S122916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283072PMC
January 2017

Respiratory syncytial virus infection: an innate perspective.

F1000Res 2016 21;5:2898. Epub 2016 Dec 21.

Respiratory Infections Section, St Mary's campus, National Heart and Lung Institute, Imperial College London, London, W2 1PG, UK.

Respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in children and adults. However, infection with this virus sometimes leads to severe lower respiratory disease and is the major cause of infant hospitalisations in the developed world. Several risk factors such as baby prematurity and congenital heart disease are known to predispose towards severe disease but previously healthy, full-term infants can also develop bronchiolitis and viral pneumonia during RSV infection. The causes of severe disease are not fully understood but may include dysregulation of the immune response to the virus, resulting in excessive recruitment and activation of innate and adaptive immune cells that can cause damage. This review highlights recent discoveries on the balancing act of immune-mediated virus clearance versus immunopathology during RSV infection.
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http://dx.doi.org/10.12688/f1000research.9637.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224685PMC
December 2016

Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons.

J Innate Immun 2016 16;8(5):452-63. Epub 2016 Jul 16.

Respiratory Infections Section, St. Mary's Campus, National Heart and Lung Institute, Imperial College London, London, UK.

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections. Immunity to RSV is initiated upon detection of the virus by pattern recognition receptors, such as RIG-I-like receptors. RIG-I-like receptors signal via MAVS to induce the synthesis of proinflammatory mediators, including type I interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. Alveolar macrophages (AMs) are amongst the first cells to encounter invading viruses and the ones producing type I IFNs. However, it is unclear whether IFNs act to prevent AMs from serving as vehicles for viral replication. In this study, primary AMs from MAVS (Mavs-/-)- or type I IFN receptor (Ifnar1-/-)-deficient mice were exposed to RSV ex vivo. Wild-type (wt) AMs but not Mavs-/- and Ifnar1-/- AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/- and Ifnar1-/- AMs accumulated more RSV proteins than wt AMs, but the infection was abortive. Thus, RIG-I-like receptor-MAVS and IFNAR signalling are important for the induction of proinflammatory mediators from AMs upon RSV infection, but this signalling is not central for controlling viral replication. The ability to restrict viral replication makes AMs ideal sensors of RSV infection and important initiators of immune responses in the lung.
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http://dx.doi.org/10.1159/000446824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322584PMC
October 2017

Changing Arctic snow cover: A review of recent developments and assessment of future needs for observations, modelling, and impacts.

Ambio 2016 Sep 17;45(5):516-37. Epub 2016 Mar 17.

Department of Physical Geography and Ecosystem Science, Lund University, Sölvegatan 12, 223 62, Lund, Sweden.

Snow is a critically important and rapidly changing feature of the Arctic. However, snow-cover and snowpack conditions change through time pose challenges for measuring and prediction of snow. Plausible scenarios of how Arctic snow cover will respond to changing Arctic climate are important for impact assessments and adaptation strategies. Although much progress has been made in understanding and predicting snow-cover changes and their multiple consequences, many uncertainties remain. In this paper, we review advances in snow monitoring and modelling, and the impact of snow changes on ecosystems and society in Arctic regions. Interdisciplinary activities are required to resolve the current limitations on measuring and modelling snow characteristics through the cold season and at different spatial scales to assure human well-being, economic stability, and improve the ability to predict manage and adapt to natural hazards in the Arctic region.
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http://dx.doi.org/10.1007/s13280-016-0770-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980315PMC
September 2016