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Lövheim, H., Norman, T., Weidung, B., Olsson, J., Josefsson, M., Adolfsson, R., . . . Elgh, F. (2019). Herpes Simplex Virus, APOE ɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study. Journal of Alzheimer's Disease, 67(1), 211-220
Open this publication in new window or tab >>Herpes Simplex Virus, APOE ɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 1, p. 211-220Article in journal (Refereed) Published
Abstract [en]

Background: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer’s disease (AD) development.

Objective: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOE ɛ4) in a large population-based cohort with a long follow-up time.

Methods: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOE ɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared.

Results: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOE ɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOE ɛ4 for episodic memory decline (p < 0.001).

Conclusion: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOE ɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.

Place, publisher, year, edition, pages
IOS Press, 2019
Keywords
Alzheimer’s disease, APOE ɛ4, apolipoprotein E4, cognitive impairment, cohort study, dementia, epidemiological study, episodic memory, herpes simplex virus
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162728 (URN)10.3233/JAD-171162 (DOI)000457778000017 ()30636735 (PubMedID)
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-09-10Bibliographically approved
Olsson, J., Johansson, J., Honkala, E., Blomqvist, B., Kok, E., Weidung, B., . . . Elgh, F. (2019). Urea dilution of serum for reproducible anti-HSV1 IgG avidity index. BMC Infectious Diseases, 19, Article ID 164.
Open this publication in new window or tab >>Urea dilution of serum for reproducible anti-HSV1 IgG avidity index
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2019 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 19, article id 164Article in journal (Refereed) Published
Abstract [en]

Herpes simplex virus type 1 (HSV1), establishes life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe a protocol to generate a reliable and discriminative avidity index (AI) for anti-HSV1 IgG content in human sera. Human serum from two distinct cohorts; one a biobank collection (Betula) (n = 28), and one from a clinical diagnostics laboratory at Northern Sweden University Hospital (NUS) (n = 18), were assessed for presence of IgG antibodies against HSV1 by a commercially available ELISA-kit. Addition of urea at the incubation step reduces effective binding, and the ratio between urea treated sample and non-treated sample was used to express an avidity index (AI) for individual samples. AI score ranged between 43.2 and 73.4% among anti-HSV1 positive biobank sera. Clinical samples ranged between 36.3 and 74.9%. Reproducibility expressed as an intraclass correlation coefficient (ICC) was estimated at 0.948 (95% CI: 0.900-0.979) and 0.989 (95% CI 0.969-0.996) in the biobank and clinical samples, respectively. The method allows for AI scoring of anti-HSV1 IgG from individual human sera with a single measurement. The least significant change between two measurements at the p < 0.05 level was estimated at 5.4 and 3.2 points, respectively, for the two assessed cohorts.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Herpes simplex, IgG, Avidity, ELISA, Primary infection, Reactivated infection
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-157213 (URN)10.1186/s12879-019-3769-x (DOI)000459030400003 ()30764767 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Jonsson, S., Oda, H., Lundin, E., Olsson, J. & Idahl, A. (2018). Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors. Translational Oncology, 11(2), 546-551
Open this publication in new window or tab >>Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors
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2018 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 11, no 2, p. 546-551Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. METHODS: This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. RESULTS: Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. CONCLUSIONS: C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-148647 (URN)10.1016/j.tranon.2018.02.008 (DOI)000428690100041 ()29524832 (PubMedID)2-s2.0-85045732126 (Scopus ID)
Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2018-06-26Bibliographically approved
Lövheim, H., Olsson, J., Weidung, B., Johansson, A., Eriksson, S., Hallmans, G. & Elgh, F. (2018). Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer’s Disease Development. Journal of Alzheimer's Disease, 61, 939-945
Open this publication in new window or tab >>Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer’s Disease Development
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2018 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, p. 939-945Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies.

OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD.

METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses.

RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007).

CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

Keywords
Alzheimer’s disease, Herpes simplex virus, cytomegalovirus, dementia, nested case-control study
National Category
Medical and Health Sciences
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-143394 (URN)10.3233/JAD-161305 (DOI)000422845200010 ()29254081 (PubMedID)
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-08-31Bibliographically approved
Olsson, J., Kok, E., Adolfsson, R., Lövheim, H. & Elgh, F. (2017). Herpes virus seroepidemiology in the adult Swedish population. Immunity & Ageing, 14, Article ID 10.
Open this publication in new window or tab >>Herpes virus seroepidemiology in the adult Swedish population
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2017 (English)In: Immunity & Ageing, ISSN 1742-4933, E-ISSN 1742-4933, Vol. 14, article id 10Article in journal (Refereed) Published
Abstract [en]

Background: Herpes viruses establish a life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe the seroepidemiology of Herpes simplex type 1 (HSV1), Herpes simplex type 2 (HSV2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Human herpes virus type 6 (HHV6) in an adult Swedish population (35-95 years of age). Methods: Presence of antibodies against the respective viruses in serum from individuals in the Betula study was determined with an enzyme-linked immunosorbent assay (ELISA). Singular samples from 535 persons (53.9% women, mean age at inclusion 62.7 +/- 14.4 years) collected 2003-2005 were analyzed for the five HHVs mentioned above. In addition, samples including follow-up samples collected 1988-2010 from 3,444 persons were analyzed for HSV. Results: Prevalence of HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. Herpes virus infections were more common among women (p = 0.010) and a lower age-adjusted HSV seroprevalence was found in later birth cohorts (p < 0.001). The yearly incidence of HSV infection was estimated at 14.0/1000. Conclusion: Women are more often seropositive for HHV, especially HSV2. Age-adjusted seroprevalence for HSV was lower in later birth cohorts indicating a decreasing childhood and adolescent risk of infection.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
Herpes, Herpes simplex, Cytomegalovirus, Varicella zoster virus, Seroprevalence, Epidemiology
National Category
Geriatrics Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-136062 (URN)10.1186/s12979-017-0093-4 (DOI)000401191100001 ()28491117 (PubMedID)
Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2018-06-09Bibliographically approved
Olsson, J., Lövheim, H., Honkala, E., Karhunen, P. J., Elgh, F. & Kok, E. H. (2016). HSV presence in brains of individuals without dementia: the TASTY brain series. Disease Models and Mechanisms, 9(11), 1349-1355
Open this publication in new window or tab >>HSV presence in brains of individuals without dementia: the TASTY brain series
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2016 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 11, p. 1349-1355Article in journal (Refereed) Published
Abstract [en]

Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (A beta) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had A beta aggregations, most of those with A beta aggregations did not have HSV present in the brain tissue.

Keywords
Herpes simplex virus, Amyloid beta aggregations, Alzheimer's disease, PCR detection, Human brain tissue, Paraffin-embedded samples
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-129884 (URN)10.1242/dmm.026674 (DOI)000387581000011 ()27664135 (PubMedID)
Available from: 2017-01-16 Created: 2017-01-10 Last updated: 2018-06-09Bibliographically approved
Olsson, J., Davidsson, S., Unemo, M., Mölling, P., Andersson, S.-O., Andrén, O., . . . Elgh, F. (2012). Antibiotic susceptibility in prostate-derived Propionibacterium acnes isolates. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 120(10), 778-785
Open this publication in new window or tab >>Antibiotic susceptibility in prostate-derived Propionibacterium acnes isolates
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2012 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 10, p. 778-785Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to determine antibiotic susceptibility of Propionibacterium acnes isolates from prostate. Prostate-derived P. acnes isolates (n = 24, Umeå & Örebro, Sweden, 2007-2010) and a panel of control strains (n = 25, Sweden) collected from skin and deep infections were assessed for resistance to penicillin G, piperacillin-tazobactam, imipenem, gentamicin, azithromycin, erythromycin, vancomycin, ciprofloxacin, moxifloxacin, tetracycline, tigecycline, fusidic acid, clindamycin, rifampicin, linezolid, daptomycin, trimethoprim-sulfamethoxazole, and metronidazole. In addition, the isolates were tested for inducible clindamycin resistance. All prostate derived P. acnes isolates displayed wild-type distribution of MIC-values, without evidence of acquired resistance. In the reference panel, 5 of 25 isolates had acquired macrolide resistance with cross-resistance to azithromycin, clindamycin, and erythromycin. In addition, one of these isolates was resistant to tetracycline.

Place, publisher, year, edition, pages
HOBOKEN, NJ USA: Wiley-Blackwell, 2012
Keywords
CHRONIC BACTERIAL PROSTATITIS, RANDOMIZED CONTROLLED-TRIAL, STERNAL WOUND INFECTIONS, PELVIC PAIN SYNDROME, CARDIAC-SURGERY, ANTIMICROBIAL RESISTANCE, CLINICAL PRESENTATION, TRACT-INFECTIONS, VULGARIS, MANAGEMENT
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-59682 (URN)10.1111/j.1600-0463.2012.02905.x (DOI)22958285 (PubMedID)
Available from: 2012-09-24 Created: 2012-09-24 Last updated: 2018-06-08Bibliographically approved
Olsson, J., Bergh Drott, J., Laurantzon, L., Laurantzon, O., Bergh, A. & Elgh, F. (2012). Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model. PLoS ONE, 7(12), e51434
Open this publication in new window or tab >>Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51434-Article in journal (Refereed) Published
Abstract [en]

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.

Place, publisher, year, edition, pages
Public library of science, 2012
Keywords
bacterial inflammation; mouse prostate; cancer; hyperplasia; carcinogenesis; pathogenesis; castration; specimens; proteins; cells
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-63922 (URN)10.1371/journal.pone.0051434 (DOI)000312290800058 ()
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2018-06-08Bibliographically approved
Davidsson, S., Söderquist, B., Elgh, F., Olsson, J., Andrén, O., Unemo, M. & Mölling, P. (2012). Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin. Anaerobe, 18(4), 392-399
Open this publication in new window or tab >>Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin
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2012 (English)In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed) Published
Abstract [en]

Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology. The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences. The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types. Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-56885 (URN)10.1016/j.anaerobe.2012.04.015 (DOI)22609518 (PubMedID)
Available from: 2012-06-28 Created: 2012-06-28 Last updated: 2018-06-08Bibliographically approved
Bergh Drott, J., Alexeyev, O., Bergström, P., Elgh, F. & Olsson, J. (2010). Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells. BMC Microbiology, 10, 126
Open this publication in new window or tab >>Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells
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2010 (English)In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 10, p. 126-Article in journal (Refereed) Published
Abstract [en]

Background: The immune stimulating bacterium Propionibacterium acnes is a frequent colonizer of benign and malignant prostate tissue. To understand the pathogenesis of the earliest phase of this infection, we examined the P. acnes triggered immune response in cultivated prostate epithelial cells.

Results: Prostate epithelial cells are triggered to secrete IL-6, IL-8 and GM-CSF when infected with P. acnes. The secretion of cytokines is accompanied by NFκB related upregulation of the secreted cytokines as well as several components of the TLR2-NFκB signaling pathway.

Conclusions: P. acnes has potential to trigger a strong immune reaction in the prostate glandular epithelium. Upon infection of prostate via the retrograde urethral route, the induced inflammatory reaction might facilitate bacterial colonization deeper in the prostate tissue where persistent inflammation may impact the development of prostate diseases as hyperplasia and/or malignancy.

Place, publisher, year, edition, pages
BioMed Central, 2010
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-41876 (URN)10.1186/1471-2180-10-126 (DOI)000277522700001 ()20420679 (PubMedID)
Available from: 2011-04-01 Created: 2011-04-01 Last updated: 2018-06-08Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-9094-319x

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