| 1. |
- Appelgren, Daniel, et al.
(författare)
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Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections.
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (rs = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.
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| 2. |
- Carlströmer Berthén, Nellie, et al.
(författare)
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The AxBioTick Study: Borrelia Species and Tick-Borne Encephalitis Virus in Ticks, and Clinical Responses in Tick-Bitten Individuals on the Aland Islands, Finland
- 2023
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- The AxBioTick Study: Borrelia Species and Tick-Borne Encephalitis Virus in Ticks, and Clinical Responses in Tick-Bitten Individuals on the Aland Islands, Finlandby Nellie Carlströmer Berthén 1,2,*,† , Eszter Tompa 3,† , Susanne Olausson 1,2, Clara Nyberg 1, Dag Nyman 1,2, Malin Ringbom 1,4, Linda Perander 1,4, Joel Svärd 3, Per-Eric Lindgren 3,5, Pia Forsberg 3, Peter Wilhelmsson 3,5,‡, Johanna Sjöwall 3,6,‡ and Marika Nordberg 1,4,‡ 1Borrelia Research Group of the Aland Islands, 22100 Mariehamn, The Aland Islands, Finland2Bimelix AB, 22100 Mariehamn, The Aland Islands, Finland3Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linkoping University, 581 83 Linkoping, Sweden4The Aland Islands Healthcare Services, 22100 Mariehamn, The Aland Islands, Finland5Clinical Microbiology, Laboratory Medicine, County Hospital Ryhov, 551 85 Jonkoping, Sweden6Department of Infectious Diseases, Vrinnevi Hospital, 603 79 Norrkoping, Sweden*Author to whom correspondence should be addressed.†These authors contributed equally to the study.‡These authors contributed equally to the study.Microorganisms 2023, 11(5), 1100; https://doi.org/10.3390/microorganisms11051100Received: 30 March 2023 / Revised: 17 April 2023 / Accepted: 19 April 2023 / Published: 22 April 2023(This article belongs to the Special Issue Research on Ticks and Tick-Borne Pathogens)Download Browse Figures Versions NotesArticle Views585 AbstractThe AxBioTick study was initiated to investigate the prevalence of ticks and tick-borne pathogens and their impact on antibody and clinical responses in tick-bitten individuals on the Aland Islands. This geographical area is hyperendemic for both Lyme borreliosis (LB) and Tick-borne encephalitis (TBE). Blood samples and ticks were collected from 100 tick-bitten volunteers. A total of 425 ticks was collected, all determined to Ixodes ricinus using molecular tools. Of them 20% contained Borrelia species, of which B. garinii and B. afzelii were most common. None contained the TBE virus (TBEV). Blood samples were drawn in conjunction with the tick bite, and eight weeks later. Sera were analyzed for Borrelia- and TBEV-specific antibodies using an ELISA and a semiquantitative antibody assay. In total 14% seroconverted in Borrelia C6IgG1, 3% in TBEV IgG, and 2% in TBEV IgM. Five participants developed clinical manifestations of LB. The high seroprevalence of both Borrelia (57%) and TBEV (52%) antibodies are likely attributed to the endemic status of the corresponding infections as well as the TBE vaccination program. Despite the similar prevalence of Borrelia spp. detected in ticks in other parts of Europe, the infection rate in this population is high. The AxBioTick study is continuing to investigate more participants and ticks for co-infections, and to characterize the dermal immune response following a tick bite.
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| 3. |
- Nordberg, Marika, et al.
(författare)
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Aetiology of Tick-Borne Infections in an Adult Swedish Population : are Co-Infections with Multiple Agents Common?
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tickborne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (e38.0°C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM). A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical coinfection with Anaplasma phagocytophilum, based on serology. Both TBE cases had coinfections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.
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| 4. |
- Nordberg, Marika, et al.
(författare)
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Aetiology of tick-borne infections in an adult swedish population-are co-infections with multiple agents common
- 2014
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Ingår i: Open Journal of Clinical Diagnostics. - Scientific Research : Scientific Research Publishing, Inc.. - 2162-5816 .- 2162-5824. ; 4:1, s. 31-40
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Tidskriftsartikel (refereegranskat)abstract
- In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (≥38.0˚C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.
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| 5. |
- Nordberg, Marika, et al.
(författare)
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Can ELISPOT Be Applied to A Clinical Setting as A Diagnostic Utility for Neuroborreliosis?
- 2012
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Ingår i: Cells. - Basel, Switzerland : MDPI AG. - 2073-4409. ; 13:48, s. 153-167
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this prospective study was to investigate the diagnostic performance of Borrelia (Bb)-induced interferon (IFN)-γ secretion detected by ELISPOT modified to be feasible for clinical laboratories as a supplementary test to the laboratory diagnosis of Lyme neuroborreliosis (LNB) in an endemic setting. Between 2002 and 2004, patients with symptoms of suspected clinical LNB were included in a study conducted on the Åland islands in the Finnish archipelago, which is a hyper-endemic area for Lyme borreliosis (LB). Fourteen patients with confirmed LNB and 103 patients with non-LNB were included, and the numbers of spontaneous and Bb-induced IFN-γ-secreting cells were assayed by the ELISPOT test. The ELISPOT assay showed a weak diagnostic performance with a sensitivity of 36% and a specificity of 82%. The findings in this study show that this ELISPOT-assay modified to be feasible in clinical routine laboratories is not useful as a supplementary diagnostic tool in the laboratory diagnosis of patients with clinically suspected LNB.
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| 6. |
- Nordberg, Marika, et al.
(författare)
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Cytotoxic mechanisms may play a role in the local immune response in the central nervous system in neuroborreliosis
- 2011
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Ingår i: Journal of Neuroimmunology. - : Elsevier Science B.V., Amsterdam.. - 0165-5728 .- 1872-8421. ; 232:1-2, s. 186-193
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Tidskriftsartikel (refereegranskat)abstract
- Aiming to investigate the role of cytotoxic mechanisms in neuroborreliosis (NB), the cytokines IL-2, IL-7, IL-10, IL-12p70, IL-15, GM-CSF and the Th17-cytokine IL-17 were analyzed in cerebrospinal fluid (CSF) and plasma from NB-patients. NB-patients showed increased levels in CSF compared to controls of all analyzed cytokines except IL-15 but not in plasma. Blood lymphocytes from three NB-patients showed functional cytotoxicity in response to autologous Borrelia-infected macrophages. The findings support a role for cytotoxic mechanisms in the local immune response in NB and in addition suggest an increase of IL-17.
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| 7. |
- Nordberg, Marika
(författare)
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Tick-Borne Infections in Humans : Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tick-borne infectious agents, B. burgdorferi, A. phagocytophilum and the TBE-virus, can all cause clinical disease in humans and may all initially give rise to myalgia, arthralgia, headache and fever. The clinical manifestations of the infections range from subclinical or mild to severe, in some cases with a postinfectious sequel, and mixed infections may occur, confusing the clinical picture.The aim of this thesis was to investigate the occurrence and co-existence of these infections in a Scandinavian context. A further aim was to study aspects of the immunopathogenesis of B. burgdorferi infection and possible effects on the immune response when previously exposed to A. phagocytophilum. Finally, an attempt was made to improve the laboratory diagnosis of Lyme neuroborreliosis (LNB).In a prospective clinical study, patients were recruited based on two independent inclusion criteria; 1) patients with unspecific symptoms or fever, and 2) patients with erythema migrans (EM). Among 206 patients, we found 186 cases of Lyme borreliosis (LB) (174 with EM), 18 confirmed and two probable cases of human granulocytic anaplasmosis (HGA), and two cases of Tick-borne encephalitis (TBE). Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a subclinical co-infection with A. phagocytophilum, based on serology. Both TBE cases had co-infections, one with B. burgdorferi and one with A. phagocytophilum.In another investigation, IL-12p70 secretion in patients with current LB was compared in patients with or without previous A. phagocytophilum infection. Patients with serological evidence of previous exposure to A. phagocytophilum had a lower B. burgdorferi-induced IL-12p70 secretion. Since IL-12p70 induces the Th1 response, this finding indicates a reduced Th1 response, possibly caused by A. phagocytophilum. In a separate study, we showed that patients with LNB had increased levels of cytokines associated with cytotoxicity in cerebrospinal fluid (CSF), including the recently described cytokine IL-17.Since it is known that the adaptive immune system, especially the T cells, is activated during an infection with B. burgdorferi, a modified ELISPOT assay using cells from CSF was evaluated to be a useful complementary test in diagnosing LNB. However, we found that the diagnostic performance was too weak in our setting, and we could not recommend it for use in clinical laboratories at this stage.In conclusion, tick-borne co-infections are probably quite common in Sweden. Our HGA cases were most often discovered as co-infections with LB and would probably have been missed during a routine consultation. They presented with mild symptoms and often without fever, which in previous reports has been part of the disease definition.The immune response in LNB was shown to be compartmentalized to the target organ, also in terms of cytokine response. Furthermore, we found indications of possible long-term effects of A. phagocytophilum infection, demonstrated as a reduced IL-12p70 secretion in patients with ongoing LB. This could be a disadvantage when mounting a Th1 response to infection with B. burgdorferi. If this is so, the inter-play of these infectious agents in co-infections or consecutive infections may be of importance to clinical outcome.
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| 8. |
- Ocias, Lukas Frans, et al.
(författare)
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Emerging tick-borne pathogens in the Nordic countries: A clinical and laboratory follow-up study of high-risk tick-bitten individuals
- 2020
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Ingår i: Ticks and Tick-borne Diseases. - : ELSEVIER GMBH. - 1877-959X .- 1877-9603. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite the presence of several microorganisms, other than Borrelia burgdorferi sensu lato (Bbsl) and TBE virus, in Ixodes ricinus ticks from the Nordic countries, data is lacking on their pathogenic potential in humans. In this study, we wanted to investigate the aetiology and clinical manifestations of tick-transmitted infections in individuals seeking medical care following a tick-bite. The sampling frame was participants of a large-scale, prospective, multi-centre, follow-up study of tick-bitten volunteers recruited in Sweden, Finland and Norway in the years 2007-2015. Participants who sought medical care during the three-month follow-up period and from whom blood samples were collected during this healthcare visit (n=92) were tested, using PCR, for exposure to spotted fever group (SFG) Rickettsia spp., Anaplasma phagocytophilum and Babesia spp. Moreover, 86 of these individuals had two serum samples, collected three months apart, tested serologically for six tick-borne microorganisms. The selected organisms-Bbsl, SFG rickettsiae, Anaplasma phagocytophilum, TBE virus, Babesia microti and Bartonella henselae-have all been detected in field-collected ticks from the Nordic countries. Medical records were reviewed and questionnaires were completed to determine clinical manifestations. We found Lyme borreliosis to be the most common tick-transmitted infection as seen in 46 (54%) of the 86 participants with available medical records. Among the 86 participants with paired sera, serological or molecular evidence of recent exposure to other microorganisms than Bbsl could be demonstrated in eight (9%). Five participants (6%) exhibited serological evidence of recent concomitant exposure to more than one tick-borne microorganism. Clinical presentations were mild with one exception (TBE). In conclusion, our data suggest a low risk of infection with tick-borne microorganisms, other than Bbsl, in immunocompetent tick-bitten persons from the examined regions, a low occurrence of co-infection and mostly mild or no overt clinical signs of infection in immunocompetent persons exposed to the studied agents.
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| 9. |
- Sandholm, Kerstin, et al.
(författare)
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Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis : Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- An optimal eradication of spirochetes in Lyme borreliosis depends on the early immune response, including the potent actions of the complement system. We here assessed possible differences between two Borrelia burgdorferi genospecies in their ability to activate complement, and the consequences of complement activation in terms of phagocytosis and induction of cytokines.Early local complement activation was assessed immunohistochemically in skin biopsies from patients with erythema migrans (EM) caused by B. afzelii or B. garinii. Complement activation, phagocytosis and early cytokine and chemokine release were studied in vitro by incubating clinical isolates of B. afzelii (K78 from a human skin biopsy) and B. garinii (LU59 from human cerebrospinal fluid) in human whole blood.B. afzelii and B. garinii were detected in skin biopsies from EM and deposition of C3-fragments and IgG was found adjacent to the spirochetes. In vitro, B. garinii LU59 induced higher complement activation (measured as the generation of C3a and C5b-9), while B. afzelii K78 recruited more factor H. Phagocytosis by granulocytes and monocytes was demonstrated to be largely dependent on complement activation since phagocytosis was substantially reduced by addition of the C3 inhibitor compstatin or a C5a receptor antagonist. The early cytokine and chemokine release in human blood in response to live spirochetes revealed a rapid and pronounced pro-inflammatory response, mainly associated with the Th1- and Th17-types.We conclude that complement is activated locally in the skin in EM, and that B. garinii LU59 activates complement more than B. afzelii K78. Complement activation is pivotal for efficient phagocytosis of Borrelia spirochetes, especially in early infection before specific antibodies are produced. Both B. garinii LU59 and B. afzelii K78 induce proinflammatory cytokines rapidly, but no clear differences were seen between the two genospecies in this respect.
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| 10. |
- Sjöwall, Johanna, et al.
(författare)
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Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3, s. 0018220-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.
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