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Tick-Borne Infections in Humans: Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 131 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1315
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-80260ISBN: 978-91-7519-852-1 (print)OAI: oai:DiVA.org:liu-80260DiVA: diva2:546340
Public defence
2012-09-07, Berzeliussalen, ingång 65, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2013-08-29Bibliographically approved
List of papers
1. Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum
Open this publication in new window or tab >>Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum
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2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 2, 322-328 p.Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis and human granulocytic ehrlichiosis are tick-borne diseases caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. Infection with A. phagocytophilum has been observed to induce immunosuppression and animal studies suggest that the bacteria might also have prolonged inhibitory effects on immune cells. The aim of this study was to investigate the cytokine secretion in patients exposed previously to A. phagocytophilum and currently infected with B. burgdorferi compared with patients infected with B. burgdorferi and seronegative for A. phagocytophilum. Eight patients with erythema migrans and antibodies against A. phagocytophilum, 15 patients with erythema migrans and negative A. phagocytophilum serology and 15 non-exposed healthy individuals were included in the study. Blood mononuclear cells were stimulated with Borrelia-antigen and the number of cytokine [interleukin (IL)-4, IL-5, IL-12, IL-13 and interferon (IFN)-γ]-secreting cells was detected by enzyme-linked immunospot (ELISPOT). This study shows that patients with a previous exposure to A. phagocytophilum and a current infection with B. burgdorferi have a lower number of Borrelia-specific cells secreting IL-12 compared to Ap seronegative patients infected with B. burgdorferi (P < 0·001), indicating impairment in the ability to mount strong Th1-responses. We suggest that this mirrors a reduced Th1 response caused by A. phagocytophilum which could influence the outcome of the Borrelia infection and, speculatively, may also have implications in other conditions.

Keyword
HGE, human granulocytic ehrlichiosis, interleukin-12, Lyme disease, tick-borne
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13801 (URN)10.1111/j.1365-2249.2005.02993.x (DOI)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2013-08-29Bibliographically approved
2. Cytotoxic mechanisms may play a role in the local immune response in the central nervous system in neuroborreliosis
Open this publication in new window or tab >>Cytotoxic mechanisms may play a role in the local immune response in the central nervous system in neuroborreliosis
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2011 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 232, no 1-2, 186-193 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
Keyword
Cytotoxic mechanisms, Neuroborreliosis, IL-17, Lyme borreliosis, Persisting symptoms
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67968 (URN)10.1016/j.jneuroim.2010.09.028 (DOI)000289493700025 ()
Available from: 2011-05-04 Created: 2011-05-04 Last updated: 2017-12-11Bibliographically approved
3. Aetiology of Tick-Borne Infections in an Adult Swedish Population: are Co-Infections with Multiple Agents Common?
Open this publication in new window or tab >>Aetiology of Tick-Borne Infections in an Adult Swedish Population: are Co-Infections with Multiple Agents Common?
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword
Epidemiology, Tick-borne infections, Tick-borne encephalitis, Lyme borreliosis, Human granulocytic anaplasmosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80257 (URN)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2012-08-23Bibliographically approved
4. Can ELISPOT Be Applied to A Clinical Setting as A Diagnostic Utility for Neuroborreliosis?
Open this publication in new window or tab >>Can ELISPOT Be Applied to A Clinical Setting as A Diagnostic Utility for Neuroborreliosis?
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2012 (English)In: Cells, ISSN 2073-4409, Vol. 13, no 48, 153-167 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Basel, Switzerland: MDPI AG, 2012
Keyword
Borrelia burgdorferi; neuroborreliosis; ELISPOT; cerebrospinal fluid; diagnostic test; sensitivity; specificity
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-80259 (URN)10.3390/cells1020153 (DOI)24710421 (PubMedID)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2015-10-23Bibliographically approved

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