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1.
Br J Dermatol ; 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38878280

ABSTRACT

BACKGROUND: The structured expression of several keratins in the skin is associated with differentiation status of the epidermal layers, whereas others are upregulated only during wound healing, in skin disorders and in cancers. One of these stress keratins, K17, is correlated with poor prognosis in various cancer types and its loss has been shown to decelerate tumour growth. K17 expression can also be detected in cutaneous squamous cell carcinomas (SCCs), where UV-irradiation and infection with cutaneous human papillomaviruses (HPVs) are important co-factors. It was previously reported that K17 is upregulated in papillomavirus (PV)-induced benign skin lesions in mice and induces an immunological status that is beneficial for tumour growth. OBJECTIVES: In order to investigate whether K17 upregulation is induced by PVs, we analysed K17 levels in skin tumour specimens of different animal models and humans. METHODS: Various immunofluorescence stainings were performed to identify K17 expression as well as levels of E-Cadherin, vimentin and CD271. Tissues were further analysed by PCRs, qPCRs and ELISA to control for PV activity. K17knockdown cells were generated and effects on viral life cycle were investigated by infection assays, qPCR and Western blotting. RESULTS: We could show that K17 is commonly expressed in skin tumours and that its presence is not directly linked to viral oncoprotein expression. Rather, K17 expression seems to be a marker of epithelial differentiation and its absence in tumour tissue is associated with an epithelial-to-mesenchymal transition. We further showed that the absence of K17 in skin tumours increases markers of cancer stem-like cells and negatively affects viral protein synthesis. CONCLUSIONS: Collectively, our data indicate that K17 expression is a common feature in skin tumourigenesis. While it is not primarily targeted by PV oncoproteins, our in vivo and in vitro data suggest that it is an important regulator of epithelial differentiation and thus may play a role in controlling viral protein synthesis.

2.
J Neurovirol ; 29(5): 588-597, 2023 10.
Article in English | MEDLINE | ID: mdl-37490185

ABSTRACT

Little is known about concomitant central nervous system (CNS) infections by more than one virus. Current diagnostics are based on molecular tests for particular pathogens making it difficult to identify multi-viral infections. In the present study, we applied DNA- and RNA-based next-generation sequencing metagenomics (mNGS) to detect viruses in cerebrospinal fluids from 20 patients with herpes simplex encephalitis. Coinfection was detected in one patient: sequences in cerebrospinal fluids matched enterovirus A (2.660 reads; 4% of recovered genome) and enterovirus B (1.571 reads; 13% of recovered genome). Subsequent PCR combined with serotyping allowed to identify human echovirus 6, a representative of enterovirus B. Several other mNGS hits (human pegivirus, Merkel cell polyomavirus, human papillomavirus type 5) were not considered to represent a genuine signal as they could not be confirmed by specific RT-PCR/PCR. HSV DNA, while being detectable by PCR in every patient, was detected by mNGS in only one. In conclusion, contaminations and false signals may complicate mNGS interpretation; however, the method can be useful in diagnostics of viral coinfections in CNS, particularly in the case of rare pathogens.


Subject(s)
Central Nervous System Infections , Coinfection , Encephalitis, Herpes Simplex , Virus Diseases , Humans , Encephalitis, Herpes Simplex/diagnosis , Polymerase Chain Reaction/methods , Enterovirus B, Human , DNA , High-Throughput Nucleotide Sequencing/methods
3.
Ann Neurol ; 91(1): 150-157, 2022 01.
Article in English | MEDLINE | ID: mdl-34724243

ABSTRACT

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.


Subject(s)
COVID-19/complications , Central Nervous System Infections/cerebrospinal fluid , Central Nervous System Infections/virology , RNA, Viral/cerebrospinal fluid , Adult , Aged , Aged, 80 and over , COVID-19/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/virology , Female , Germany , Humans , Male , Middle Aged , SARS-CoV-2 , Post-Acute COVID-19 Syndrome
4.
J Low Genit Tract Dis ; 26(2): 122-126, 2022 Apr 01.
Article in English | MEDLINE | ID: mdl-35019900

ABSTRACT

OBJECTIVE: High-grade cervical intraepithelial neoplasia (CIN 3) still develops in some vaccinated women despite established effectiveness of prophylactic human papillomavirus (HPV) vaccination. The purpose of this study was to define characteristics of women with CIN 3 after HPV vaccination referred to a gynecological dysplasia unit. MATERIALS AND METHODS: Retrospective analysis of HPV-vaccinated women with CIN 3 in a single German center. Between July 2018 and September 2020, 791 women were referred to our university hospital-based dysplasia unit for colposcopic evaluation of abnormal cytological findings. Human papillomavirus vaccination status was retrieved. Human papillomavirus typing was performed in lesional biopsies and cervical swabs. RESULTS: Nine women were identified who had previously been vaccinated with the quadrivalent HPV vaccine (Q-HPV) and were diagnosed with histologically confirmed CIN 3/high-grade squamous intraepithelial lesion. The Q-HPV had been administered between 12 and 28 years of age and 1-13 years before CIN 3 diagnosis. Nine different high-risk (HR)-HPV types were found in the CIN 3 biopsies, 6 monoinfections (twice HPV 16, once HPV 18, HPV 31, HPV 52, HPV 58, respectively) and 3 dual infections (HPV 33 + 52, HPV 51 + 52, HPV 53 + 66). Seven of these 9 HR-HPV types are not covered by Q-HPV, but only 2 CIN 3 lesions carried HR-HPV types not included in the nonavalent HPV vaccine. CONCLUSIONS: It is important to implement vaccination recommendations and administer HPV vaccination as early as possible in HPV-naive individuals. Because not all HR-HPV types are covered by the available HPV vaccines, other types may still cause CIN 3/high-grade squamous intraepithelial lesion. This requires further screening after vaccination, especially in women who were previously vaccinated with the bivalent or the quadrivalent HPV vaccine.


Subject(s)
Alphapapillomavirus , Papillomavirus Infections , Papillomavirus Vaccines , Squamous Intraepithelial Lesions , Uterine Cervical Dysplasia , Uterine Cervical Neoplasms , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Papillomaviridae , Papillomavirus Infections/complications , Papillomavirus Infections/diagnosis , Papillomavirus Infections/prevention & control , Retrospective Studies , Tertiary Care Centers , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Dysplasia/pathology
5.
Int J Mol Sci ; 23(21)2022 Nov 02.
Article in English | MEDLINE | ID: mdl-36362165

ABSTRACT

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.


Subject(s)
Condylomata Acuminata , Diterpenes , Keratosis, Actinic , Papillomavirus Infections , Skin Abnormalities , Warts , Humans , Papillomavirus Infections/complications , Papillomavirus Infections/drug therapy , Condylomata Acuminata/drug therapy , Diterpenes/pharmacology , Diterpenes/therapeutic use , Keratosis, Actinic/drug therapy , Papillomaviridae , Necrosis
6.
Hautarzt ; 73(6): 426-433, 2022 Jun.
Article in German | MEDLINE | ID: mdl-35482045

ABSTRACT

Of the 15 currently known human polyomaviruses (HPyV), eight have been found on healthy skin. Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7, and to a lesser extent Saint Louis polyomavirus (STLPyV) are considered part of the human cutaneous virome. The most important cutaneous polyomavirus, MCPyV, causes the majority of Merkel cell carcinomas (MCC). MCC is a rare but very aggressive malignant skin tumor that affects both immunocompetent and immunosuppressed patients. A steady increase in incidence rates of this skin tumor has been observed in recent decades. MCC occurs primarily on sunlight-exposed skin of fair-skinned individuals. Risk factors for MCC development include immunosuppression and advanced age. In immunocompromised individuals, primary infection with trichodysplasia spinulosa-associated polyomavirus (TSPyV) can cause the very rare skin disease trichodysplasia spinulosa (TS). Keratin spines (spicules), mainly in the center of the face, clinically characterize this disease. Skin lesions associated with further HPyV have been described exclusively in immunocompromised individuals. For HPyV6 and HPyV7, cases of epithelial proliferation and pruritic dyskeratotic dermatitis have been published. HPyV9 and New Jersey polyomavirus (NJPyV-13) were each found in different skin lesions of individual patients. The role of these polyomaviruses in the development of the skin lesions is still unclear.


Subject(s)
Carcinoma, Merkel Cell , Merkel cell polyomavirus , Polyomavirus Infections , Polyomavirus , Skin Neoplasms , Humans , Polyomavirus Infections/epidemiology , Skin
7.
Hautarzt ; 71(12): 1000-1006, 2020 Dec.
Article in German | MEDLINE | ID: mdl-32820361

ABSTRACT

Lichen planus is a chronic inflammatory, immunologically mediated mucocutaneous dermatosis. Lichen planus mucosae predominantly affects the oral cavity. Various trigger factors such as bacterial or viral infections, drugs or physical stimuli are discussed in the development of the disease. An association with human papillomavirus infections has also been described, but is not sufficiently proven. Lichen planus mucosae is considered as a premalignant condition, but the malignant transformation rate is low. The risk of malignant transformation is significantly increased in patients with oral lichen planus who smoke, drink alcohol or have hepatitis C. We describe two patients with locally advanced squamous cell carcinoma that developed on a longstanding oral lichen planus. Both cases were successfully treated with radical tumor resection, subsequent tissue reconstruction, and adjuvant radiation/radiochemotherapy.


Subject(s)
Carcinoma, Squamous Cell , Lichen Planus, Oral , Lichen Planus , Mouth Neoplasms , Precancerous Conditions , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/therapy , Humans , Lichen Planus/diagnosis , Lichen Planus, Oral/diagnosis , Precancerous Conditions/diagnosis
8.
Emerg Infect Dis ; 25(8): 1600-16002, 2019 08.
Article in English | MEDLINE | ID: mdl-31310208

ABSTRACT

Cutavirus was previously found in cutaneous melanoma. We detected cutavirus DNA in only 2/185 melanoma biopsies and in 0/52 melanoma metastases from patients in Germany. Viral DNA was localized in the upper epidermal layers. Swab specimens from healthy skin were cutavirus positive for 3.8% (9/237) of immunocompetent and 17.1% (35/205) of HIV-positive men.


Subject(s)
Melanoma/epidemiology , Melanoma/etiology , Parvoviridae Infections/complications , Parvovirus , Biopsy , DNA, Viral , Germany/epidemiology , Humans , Melanoma/diagnosis , Neoplasm Staging , Parvoviridae Infections/virology , Skin Neoplasms/diagnosis , Skin Neoplasms/epidemiology , Skin Neoplasms/etiology , Viral Load , Melanoma, Cutaneous Malignant
10.
Hautarzt ; 70(12): 964-968, 2019 Dec.
Article in German | MEDLINE | ID: mdl-31342101

ABSTRACT

An atypical variant of hand-foot-mouth disease (HFMD) has sporadically been reported in recent years, with outbreaks in Europe, Asia, the USA and South America. A new lineage of Coxsackie virus A6 has been identified as the causative agent, a virus-type belonging to the group of enteroviruses. HFMD is transmitted through droplet infection or through faecal-oral transmission. The disease may begin with a prodromal stage and is often accompanied by fever and malaise. Typical skin findings include a papular and vesiculobullous exanthema that might be accompanied by confluent blisters (bullae), crusting, and ulceration. In contrast to "classic" HFMD, predilection sites include the dorsal aspects of the hands and feet, forearms, lower legs, neck and trunk. Oral lesions may be present, but are less often seen compared to "classic" HFMD. The course of the disease is self-limiting, with complete resolution usually within 7-14 days after disease onset. The treatment of atypical HFMD is usually symptomatic. A diagnosis of atypical HFMD might be challenging due to the polymorphous presentation of the disease. This review describes a rarely reported but more frequently diagnosed viral condition.


Subject(s)
Exanthema , Hand, Foot and Mouth Disease , Skin Diseases, Vesiculobullous , Disease Outbreaks , Europe , Exanthema/etiology , Hand, Foot and Mouth Disease/complications , Hand, Foot and Mouth Disease/pathology , Humans , Skin Diseases, Vesiculobullous/pathology
15.
Med Microbiol Immunol ; 206(2): 93-103, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27832373

ABSTRACT

Human papillomaviruses (HPVs) are an acknowledged cause of a subset of oropharyngeal cancers, especially of tonsillar cancer. Similar to HPV, some human polyomaviruses (HPyVs), such as Merkel cell polyomavirus (MCPyV), have an oncogenic potential. Recently, several novel HPyVs have been discovered. The aim of our study was to determine viral DNA prevalence and viral DNA load of 13 different HPyVs in benign and malignant tonsillar tissue and to compare the data with those found for HPV. A total of 78 biopsies of palatine tonsils with a histologic diagnosis of non-malignant disease (chronic tonsillitis, tonsillar hyperplasia, n = 40) or tonsillar squamous cell carcinoma (n = 38) were included in the study. HPyV DNA prevalence and viral load were determined by virus-specific quantitative real-time PCRs. JCPyV (1/40, 2.5%) and WUPyV (3/40, 7.5%) were only found in non-malignant tonsillar tissue. HPyV7 and HPyV10 were only detected in one (2.6%) and seven (18.4%) of the 38 cancer biopsies, respectively. Both MCPyV (8/38, 21.1 vs. 4/40, 10.0%) and HPyV6 (2/38, 5.3 vs. 1/40, 2.5%) were found more frequently in cancer samples than in non-malignant tissue, but the differences were not significant. BKPyV, KIPyV, TSPyV, HPyV9, STLPyV, HPyV12 and NJPyV were not discovered in any of the samples. HPyV loads found in HPyV DNA-positive biopsies were very low with no difference between non-malignant and malignant samples (median load <0.0001 HPyV DNA copies per beta-globin gene copy, respectively). In contrast to HPyV, high-risk HPV types (HPV16/HPV18) were found significantly more frequently in tonsillar cancers than in non-malignant tonsillar tissue (17/38, 44.7 vs. 2/40, 5.0%, p < 0.001). Furthermore, high-risk HPV DNA loads were significantly higher in the cancer compared to the non-malignant samples (median load 11.861 vs. 7 × 10-6 HPV DNA copies per beta-globin gene copy, p = 0.012). While both HPV and HPyV may persist in tonsillar tissue, our data on HPyV DNA prevalence and load do not support a role of HPyV in tonsillar carcinogenesis, neither alone nor as co-infecting agents of HPV.


Subject(s)
Palatine Tonsil/pathology , Palatine Tonsil/virology , Papillomaviridae , Papillomavirus Infections/complications , Papillomavirus Infections/virology , Polyomavirus Infections/complications , Polyomavirus Infections/virology , Polyomavirus , Tonsillar Neoplasms/epidemiology , Tonsillar Neoplasms/etiology , Adult , Aged , Biopsy , Carcinoma , DNA, Viral , Female , Humans , Hyperplasia , Male , Middle Aged , Papillomaviridae/genetics , Polyomavirus/genetics , Prevalence , Retrospective Studies , Risk Factors , Tonsillar Neoplasms/diagnosis , Tumor Virus Infections/complications , Tumor Virus Infections/virology , Viral Load , Young Adult
16.
Med Microbiol Immunol ; 205(6): 595-602, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27601062

ABSTRACT

Data about the prevalence of human papillomaviruses (HPV) in African women with normal and abnormal cervical cytology are still scarce. Current HPV vaccines contain HPV types, which mainly represent the HPV epidemiology of industrial countries. As further developments of HPV vaccines are going on, it is necessary to regard regional differences in HPV type prevalence to ensure optimal protection by the vaccine. Vaginal swabs of Ghanaian pregnant women, routinely collected before delivery to rule out bacterial infections causing early onset sepsis, were screened for 12 high-risk (HR), 13 probably/possibly (pHR), and 18 low-risk (LR) HPV types. Most pregnant women come for delivery to the hospital. This was considered as appropriate possibility to have an unselected group of women. HPV DNA were detected in 55/165 women (33.3, 95 % CI 26.3-41.1 %). Thirty-four out of fifty-five (61.8, 95 % CI 47.7-74.3 %) of HPV-positive women were infected with HR and/or pHR HPV types. The five most prevalent HR or pHR HPV types were HPV-52 and HPV-67 (7 women each, 4.2, 95 % CI 1.9-8.9 %), HPV-53 (six women, 3.6, 95 % CI 1.5-8.1 %), HPV-45 (five women, 3.0, 95 % CI 1.1-7.3 %), and HPV-18 (four women, 2.4, 95 % CI 0.8-6.5 %), respectively. HPV-16 was found in two women only (1.2, 95 % CI 0.2-4.8 %). Future HPV vaccine research may devote special interest to HPV-67 and HPV-53 provided further studies confirm their high prevalence in the general population of Sub-Saharan African countries. The true carcinogenic potential of HPV-67, which is a member of species alpha9 including HPV-16, and so far categorized as pHR, should be clarified.


Subject(s)
Papillomaviridae/classification , Papillomaviridae/genetics , Papillomavirus Infections/epidemiology , Papillomavirus Infections/virology , Cross-Sectional Studies , Female , Ghana/epidemiology , Humans , Mass Screening , Molecular Typing , Papillomavirus Infections/prevention & control , Population Surveillance , Pregnancy , Prevalence , Risk Factors , Vaginal Smears
18.
Int J Cancer ; 136(5): E207-18, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25082736

ABSTRACT

HPV-related HNSCC generally have a better prognosis than HPV-negative HNSCC. However, a subgroup of HPV-positive tumors with poor prognosis has been recognized, particularly related to smoking, EGFR overexpression and chromosomal instability. Viral integration into the host genome might contribute to carcinogenesis, as is shown for cervical carcinomas. Therefore, all HPV16-positive HNSCC cell lines currently available have been carefully analyzed for viral and host genome parameters. The viral integration status, viral load, viral gene expression and the presence of aneusomies was evaluated in the cell lines UD-SCC-2, UM-SCC-047, UM-SCC-104, UPCI:SCC090, UPCI:SCC152, UPCI:SCC154 and 93VU147T. HPV integration was examined using FISH, APOT-PCR and DIPS-PCR. Viral load and the expression of the viral genes E2, E6 and E7 were determined via quantitative PCR. All cell lines showed integration-specific staining patterns and signals indicating transcriptional activity using FISH. APOT- and DIPS-PCR identified integration-derived fusion products in six cell lines and only episomal products for UM-SCC-104. Despite the observed differences in viral load and the number of viral integration sites, this did not relate to the identified viral oncogene expression. Furthermore, cell lines exhibited EGFR expression and aneusomy (except UPCI:SCC154). In conclusion, all HPV16-positive HNSCC cell lines showed integrated and/or episomal viral DNA that is transcriptionally active, although viral oncogene expression was independent of viral copy number and the number of viral integration sites. Because these cell lines also contain EGFR expression and aneusomy, which are parameters of poor prognosis, they should be considered suitable model systems for the development of new antiviral therapies.


Subject(s)
Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/genetics , Human papillomavirus 16/genetics , Oncogene Proteins, Viral/genetics , Papillomavirus Infections/genetics , Viral Load , Virus Integration/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , DNA, Viral/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Expression Profiling , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/virology , Human papillomavirus 16/isolation & purification , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Male , Middle Aged , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Polymerase Chain Reaction , Tumor Cells, Cultured
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