Abstract
Background: The human bocavirus (HBoV) is known to persist latently in the infected host cells and seems to replicate its DNA via the DNA damage response system, which is frequently defect in tumors and correlates with microsatellite instability (MSI). Because HBoV is able to persist in the infected tissues, induces pro-fibrotic and pro- cancerogenic cytokines in vivo and in vitro, and is detected in colorectal and lung tumors, the virus may be involved in cancerogenesis at least as a cofactor. Recently it was shown that the adenotonsillar tissue is an important site of HBoV1 persistence and replication. Considering the background that approximately 60% of oropharyngeal cancers were thought to be attributable to a HPV infection, a co-participation of HBoV in terms of a chronic virus infection might play a role in the cancerogenesis of tonsil tumors.Methods: Formalin-fixed, paraffin-embedded tonsil tumor samples were screened for HBoV and HPV DNA. Positive tissue sections were afterward subjected to fluorescence in situ hybridization (FISH) analysis to identify HBoV and HPV infected cells. By use of an in vitro cell culture model with primary tonsil fibroblasts, keratinocytes, and lymphocytes infected by HBoV we tried to find the target cells of virus replication. MSI testing was based on a previously published protocol using a de-multiplexed PCR followed by fluorescent detection of PCR products in a capillary sequencing device.Results: In total 62 of 103 (60, 19%) of the tonsil squamous cell carcinomas tested positive for HBoV DNA and 66 of 103 (66%) samples were identified as HPV positive. The FISH analysis revealed both double infection of HPV and HBoV in the same cells as well as single infections of both viruses within the tumor tissue. Twenty-two of 62 HBoV positive tumors tested HPV negative, 40 of 62 tissue sections were HBoV and HPV positive. We analyzed 21 out of the 62 HBoV positive tumors for MSI. Of those four tonsils displayed MSI in at least 1 of 10 microsatellite markers.Conclusion: Our findings support the hypothesis that human bocavirus infections as a cofactor may have an impact on tumor development in tonsils, although it still remains possible that HBoV solely displays a tumor tropism.
Highlights
Since the identification of human bocavirus 1 in nasopharyngeal aspirates in 2005, evidence is increasing that the HBoV1, belonging to the Bocaparvovirus genus of the Parvoviridae family, is associated with respiratory tract infections and gastrointestinal infections (Allander et al, 2005; Huang et al, 2012)
62 of 103 (60.19%) of tonsil squamous cell carcinomas and 7 of 20 (35%) of chronically inflamed tonsils tested positive for HBoV DNA by the RespiFinder Smart22 PCR (Figure 1A)
In contrast we found virus persistence in different cells in 13 of 40 co-infected tumor samples (32.5%) which means that FITC signals and rhodamine red signals were spread as distinct separated signals all over the tumor sections
Summary
Since the identification of human bocavirus 1 in nasopharyngeal aspirates in 2005, evidence is increasing that the HBoV1, belonging to the Bocaparvovirus genus of the Parvoviridae family, is associated with respiratory tract infections and gastrointestinal infections (Allander et al, 2005; Huang et al, 2012). Previous studies suggest that HBoV is associated with some lung and colorectal tumors and prove that the bocavirus persistence is increased in cancer patients (Schildgen et al, 2013). It is known that HBoV persists in adenotonsillar tissue, which is considered as the major replication site in vivo by some researchers (Clement et al, 2009). The human bocavirus (HBoV) is known to persist latently in the infected host cells and seems to replicate its DNA via the DNA damage response system, which is frequently defect in tumors and correlates with microsatellite instability (MSI). Because HBoV is able to persist in the infected tissues, induces pro-fibrotic and pro- cancerogenic cytokines in vivo and in vitro, and is detected in colorectal and lung tumors, the virus may be involved in cancerogenesis at least as a cofactor. Considering the background that approximately 60% of oropharyngeal cancers were thought to be attributable to a HPV infection, a co-participation of HBoV in terms of a chronic virus infection might play a role in the cancerogenesis of tonsil tumors
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