Krystyna Zakrzewska

Parvovirus B19 (B19V) is a human pathogen belonging to the Parvoviridae family. It is widely diffused in the population and responsible for a wide range of diseases, diverse in pathogenetic mechanisms, clinical course, and severity. B19V infects and replicates in erythroid progenitor cells (EPCs) in the bone marrow leading to their apoptosis. Moreover, it can also infect, in an abortive manner, a wide set of different cell types, normally non-permissive, and modify their normal physiology. Differences in the characteristics of virus–cell interaction may translate into different pathogenetic mechanisms and clinical outcomes. Joint involvement is a typical manifestation of B19V infection in adults. Moreover, several reports suggest, that B19V could be involved in the pathogenesis of some autoimmune rheumatologic diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), or vasculitis. This review provides basic information on the B19 virus, highlights characteristics of viral infection in permissive and non-permissive systems, and focuses on recent findings concerning the pathogenic role of B19V in rheumatologic diseases.

Rheumatology 2021; https://doi.org/10.1093/rheumatology/keab904

Objective: Emerging evidence demonstrates that excessive accumulation of senescent cells is associated with some chronic diseases and suggests a pathogenic role of cellular senescence in fibrotic processes, such as that occurring in ageing or in SSc. Recently we demonstrated that parvovirus B19 (B19V) activates normal human dermal fibroblasts and induces expression of different profibrotic/pro-inflammatory genes. This observation prompted us to investigate whether it is also able to induce fibroblast senescence as a potential pathogenetic mechanism in B19V-induced fibrosis. Methods: Primary cultures of fibroblasts were infected with B19V and analysed for the acquisition of senescence markers, such as morphological modifications, senescence-associated β-galactosidase (SA-β-gal) activity, DNA damage response and expression of senescence-associated secretory phenotype (SASP)-related factors. Results: We demonstrated that B19V-infected fibroblasts develop typical senescence features such as enlarged and flat-shaped morphology and SA-β-gal activity similar to that observed in SSc skin fibroblasts. They also developed an SASP-like phenotype characterized by mRNA expression and release of some pro-inflammatory cytokines, along with activation of the transcription factor nuclear factor κB. Moreover, we observed B19V-induced DNA damage with the comet assay: a subpopulation of fibroblasts from B19V-infected cultures showed a significantly higher level of DNA strand breaks and oxidative damage compared with mock-infected cells. An increased level and nuclear localization of γH2AX, a hallmark of DNA damage response, were also found. Conclusions: B19V-induced senescence and production of SASP-like factors in normal dermal fibroblasts could represent a new pathogenic mechanism of non-productive B19V infection, which may have a role in the fibrotic process.

Fibrosis is the most characteristic pathological hallmark of SSc, a connective tissue disease characterized by vascular and immunological abnormalities, inflammation and enhanced extracellular matrix production, leading to progressive fibrosis of skin and internal organs. We previously demonstrated that parvovirus B19 (B19V) can infect normal human dermal fibroblasts (NHDFs) and that B19V persists in SSc fibroblasts. In this study, we investigated whether parvovirus B19V is able to activate in vitro NHDFs and to induce in these cells some phenotypic features similar to that observed in the SSc fibroblasts. We preliminarily analysed the time course of B19V infection in cultured NHDFs, then we investigated the ability of B19V to induce cell migration, invasive phenotype and mRNA expression of some profibrotic and/or proinflammatory genes. We confirmed our previous findings that B19V infects NHDFs, but the infection is not productive. After incubation with B19V, NHDFs showed a significant increase of both migration and invasiveness, along with mRNA expression of different profibrotic genes (α-SMA, EDN-1, IL-6, TGF-β1 receptors 1 and 2, Col1α2), some genes associated with inflammasome platform (AIM2, IFI16, IL-1β, CASP-1) and genes for metalloprotease (MMP 2, 9 and 12). These data suggest that B19V can activate dermal fibroblasts and may have a role in the pathogenesis of fibrosis. B19V-induced fibroblast migration and invasiveness could be due to the B19V-associated MMP9 overexpression and activation. Moreover, the up-regulation of MMP12, typical of SSc, could link the B19V infection of fibroblasts to the anti-angiogenic process.

The association between human papillomavirus (HPV) infection and non-melanoma skin cancers (NMSCs) such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) is not yet fully understood. We analysed the prevalence and spectrum of cutaneous beta-HPV types and mucosal/genital HPV types in paired biopsies (tumour and corresponding perilesional skin) obtained from 50 BCC immunocompetent patients. A small group of SCC patients (n=9) was also included. We also evaluated some previously postulated risk factors for HPV infection in NMSC patients.

Background: PARV4 is a new member of the Parvoviridae family not closely related to any of the known human parvoviruses. Viremia seems to be a hallmark of PARV4 infection and viral DNA persistence has been demonstrated in a few tissues. Till now, PARV4 has not been associated with any disease and its prevalence in human population has not been clearly established. This study was aimed to assess the tissue distribution and the ability to persist of PARV4 in comparison to parvovirus B19 (B19V).Results: PARV4 and B19V DNA detection was carried out in various tissues of individuals without suspect of acute viral infection, by a real time PCR and a nested PCR, targeting the ORF2 and the ORF1 respectively. Low amount of PARV4 DNA was found frequently (>40%) in heart and liver of adults individuals, less frequently in lungs and kidneys (23,5 and 18% respectively) and was rare in bone marrow, skin and synovium samples (5,5%, 4% and 5%, respectively). By comparison, B19V DNA sequences were present in the same tissues with a higher frequency (significantly higher in myocardium, skin and bone marrow) except than in liver where the frequency was the same of PARV4 DNA and in plasma samples where B19V frequency was significantly lower than that of PARV4Conclusions: The particular tropism of PARV4 for liver and heart, here emerged, suggests to focus further studies on these tissues as possible target for viral replication and on the possible role of PARV4 infection in liver and heart diseases. Neither bone marrow nor kidney seem to be a common target of viral replication.

Background: Our previous reports suggested a possible association between parvovirus B19 (B19V) infection and systemic sclerosis (SSc), based on higher prevalence of B19V DNA in SSc patients in respect to controls. Methods: In the present study, to further evaluate the differences in the pattern of B19 infection in SSc, skin biopsies and bone marrow samples from patients and controls were analysed for B19V DNA detection, genotyping and viral expression. Results: B19V DNA was detected in skin biopsies from 39/49 SSc patients and from 20/28 controls. Bone marrow showed positive in 17/29 SSc patients, 5/21 haematological patients and 0/10 healthy controls. Genotype 1 was more frequent in skin and bone marrow from patients than from controls. Simultaneous persistence of 2 genotypes was detected in SSc skin and bone marrow samples, never in controls. Viral mRNA for capsid protein was detected in the skin of genotype 1-positive patients and not in control skins. Conclusion: The results outline some differences in the rate of persistence of B19V DNA, in the simultaneous persistence of 2 genotypes and in the pattern of viral expression among SSc patients and controls.