Trichodysplasia Spinulosa Polyomavirus Infection Occurs during Early Childhood with Intrafamilial Transmission, Especially from Mother to Child

Trichodysplasia spinulosa polyomavirus (TSPyV) has recently been identified as the probable etiological agent of trichodysplasia spinulosa, a rare and severe proliferative skin disorder observed in immunocompromized patients, especially children (Rouanet et al., 2016Rouanet J. Aubin F. Gaboriaud P. Berthon P. Feltkamp M.C. Bessenay L. et al.Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.Br J Dermatol. 2016; 174: 629-632Crossref PubMed Scopus (15) Google Scholar, van der Meijden et al., 2010van der Meijden E. Janssens R.W. Lauber C. Bouwes Bavinck J.N. Gorbalenya A.E. Feltkamp M.C. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.PLoS Pathogens. 2010; 6: e1001024Crossref PubMed Scopus (375) Google Scholar). Recent serological studies have indicated that TSPyV infection is common and that TSPyV seroprevalence increases rapidly with age from childhood to reach approximately 70–90% in adults in blood donors and in populations of hospitalized patients in Europe, Australia, and Japan (Chen et al., 2011Chen T. Mattila P.S. Jartti T. Ruuskanen O. Soderlund-Venermo M. Hedman K. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.J Infect Dis. 2011; 204: 1523-1526Crossref PubMed Scopus (61) Google Scholar, Fukumoto et al., 2015Fukumoto H. Li T.C. Kataoka M. Hasegawa H. Wakita T. Saeki H. et al.Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.J Clin Virol. 2015; 65: 76-82Crossref PubMed Scopus (16) Google Scholar, Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar, Sroller et al., 2016Sroller V. Hamsikova E. Ludvikova V. Musil J. Nemeckova S. Salakova M. Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.J Med Virol. 2016; 88: 1254-1261Crossref PubMed Scopus (31) Google Scholar, van der Meijden et al., 2013van der Meijden E. Bialasiewicz S. Rockett R.J. Tozer S.J. Sloots T.P. Feltkamp M.C. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.PLoS One. 2013; 8: e81078Crossref PubMed Scopus (84) Google Scholar). However, seroprevalence data are lacking for other populations, and the routes by which this virus is transmitted and acquired remain unknown. This work aims to obtain new insight into the modes of distribution and acquisition of TSPyV from family-based epidemiological analyses in African populations. This study was carried out on two populations from Cameroon, Central Africa, in which we previously reported epidemiological studies searching for intrafamilial transmission of human herpes virus-8 and Merkel cell polyomavirus (MCPyV) (Martel-Jantin et al., 2013Martel-Jantin C. Pedergnana V. Nicol J.T. Leblond V. Tregouet D.A. Tortevoye P. et al.Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.J Clin Virol. 2013; 58: 288-291Crossref PubMed Scopus (73) Google Scholar, Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). The first population, from Yaoundé, consisted mostly of children. The second consisted of villagers living in an isolated rural area of Southern Cameroon, Ntem, for which familial relationships with full pedigrees were established. This survey was performed with authorization from the local authorities. Each participant was provided with information about the study, and written informed consent was obtained from adults or from the parents of minors. The study received ethical clearance in Cameroon from the National Ethics Committee and in France from the Comité de Protection des Personnes and the Commission Nationale de l’Informatique et des Libertés. Specific antibodies against TSPyV were tested by ELISA, in which anti-VP1 antibodies were detected with TSPyV-like viral particles generated in insect cells, as previously described (Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar). These assays are type specific because no evidence of cross-reactivity has been reported between other polyomaviruses and TSPyV (Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar). Plasma samples were tested at a 1:100 dilution. In the first population, which comprised 450 individuals (sex ratio = 0.96, 312 children), the overall seroprevalence of antibodies against TSPyV-VP1 was 69.8%, with no significant difference (P > 0.05) between female (73.8%) and male (65.6%) participants. We further investigated the age at which the virus was acquired by focusing on young children. Seroprevalence was high, at about 70%, from birth until the age of 2 months (Figure 1a), similar to what is observed in women of childbearing age (∼80%). Seroprevalence then first decreased, reaching 30–40% at 13–36 months of age and then rapidly and steadily increased from 3 years, to reach about 70% in children at age 11 years. This pattern of seroprevalence is consistent with the presence of maternal antibodies in very young children. These maternal antibodies then progressively disappear, and infection is rapidly acquired in most children, beginning from the age of 1 to 3 years. In our second analysis, we specifically studied a familial sample of 527 individuals (sex ratio = 1.00) ages 1 to 92 years (median age = 18 years) from an isolated village, Ntem. The overall TSPyV seroprevalence was 84%, with no significant difference (P > 0.05) between female (85.2%) and male (83.7%) participants. Seroprevalence increased rapidly with age, from approximately 40% in children younger than 2 years to 85% in adults older than 20 years (Figure 1a). Various age-coding schemes were tested to account for this highly significant age effect, and the best fit was obtained for a model in which the logarithm of age was considered as a quantitative variable (P < 5.5 × 10–6). The 527 subjects were clustered into 65 families, each with 2–25 members, and the second step of the analysis was to estimate the familial aggregation of serological status for TSPyV (infected or noninfected). Although the correlation between spouses (i.e., the father and mother of the family) could be estimated, it was not significant, because almost all adults were seropositive. We estimated the following three familial correlations: father-child, mother-child and child-child. Figure 1b shows the results of the familial odds ratio (OR) estimations with the second-order estimating equations approach, adjusted for age, as previously described (Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). A highly significant correlation was found between mother and children (OR = 7.28, 95% confidence interval [CI] = 2.02–26.25, P = 0.002), and a similar trend, although not nominally significant, was observed between father and children (OR = 3.19, 95% CI = 0.97–10.51, P = 0.06). We further investigated the mother-children correlation by testing if the risk of infection in children may depend on TSPyV antibody levels in infected mothers. No correlation between the TSPyV antibody levels of infected mothers (as measured by the ELISA optical density) and the proportion of seropositive children was found (see Supplementary Table S1 online). Finally, TSPyV serological status was significantly correlated (P = 0.01) between siblings, with an OR of 1.95 (95% CI = 1.16–3.27). Furthermore, the OR was higher for pairs in which the two siblings were closer in age (age difference of less than 7 years, to give a balanced number of child-child pairs in each subgroup), in which it reached 2.44 (95% CI = 1.16–5.82, P = 0.02), than for sibling pairs with an age difference of 7 years or greater (OR = 1.28, 95% CI = 0.45–3.37, P > 0.05). This study clearly shows the high seroprevalence of antibodies directed against TSPyV in children and adults living in Central Africa. This confirms and extends to Africa previous findings of a high level of serological evidence of TSPyV exposure in young children living in Europe, Australia, and Japan (Chen et al., 2011Chen T. Mattila P.S. Jartti T. Ruuskanen O. Soderlund-Venermo M. Hedman K. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.J Infect Dis. 2011; 204: 1523-1526Crossref PubMed Scopus (61) Google Scholar, Fukumoto et al., 2015Fukumoto H. Li T.C. Kataoka M. Hasegawa H. Wakita T. Saeki H. et al.Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.J Clin Virol. 2015; 65: 76-82Crossref PubMed Scopus (16) Google Scholar, Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar, Sroller et al., 2016Sroller V. Hamsikova E. Ludvikova V. Musil J. Nemeckova S. Salakova M. Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.J Med Virol. 2016; 88: 1254-1261Crossref PubMed Scopus (31) Google Scholar, van der Meijden et al., 2013van der Meijden E. Bialasiewicz S. Rockett R.J. Tozer S.J. Sloots T.P. Feltkamp M.C. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.PLoS One. 2013; 8: e81078Crossref PubMed Scopus (84) Google Scholar). Moreover, our epidemiological data indicate that most primary TSPyV infections (at least 50 to 70% of these infections) occurred during early childhood, after the disappearance of specific maternal antibodies. This indicates that mother-fetus transmission is not a major route of TSPyV transmission. Lastly, the correlations in serological status for TSPyV infection observed within families strongly suggest that TSPyV is transmitted from parents to children, especially from the mother, and also between siblings (in particular when they are close in age). In addition, the antibody levels in infected mothers did not influence the risk of infection in their children. This pattern is quite similar to that found in this population for human herpes virus-8 and for MCPyV, which are thought to be transmitted through close contacts involving saliva and skin, respectively (Martel-Jantin et al., 2013Martel-Jantin C. Pedergnana V. Nicol J.T. Leblond V. Tregouet D.A. Tortevoye P. et al.Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.J Clin Virol. 2013; 58: 288-291Crossref PubMed Scopus (73) Google Scholar, Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). To date, TSPyV has been detected on the skin and in nasopharynx, tonsils, stools, cerebrospinal fluid, and urine samples (Rockett et al., 2013Rockett R.J. Sloots T.P. Bowes S. O'Neill N. Ye S. Robson J. et al.Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid.PLoS One. 2013; 8: e62764Crossref PubMed Scopus (47) Google Scholar, Sadeghi et al., 2014Sadeghi M. Aaltonen L.M. Hedman L. Chen T. Soderlund-Venermo M. Hedman K. Detection of TS polyomavirus DNA in tonsillar tissues of children and adults: evidence for site of viral latency.J Clin Virol. 2014; 59: 55-58Crossref PubMed Scopus (33) Google Scholar, Urbano et al., 2016Urbano P.R. Nali L.H. Bicalho C.S. Pierrotti L.C. David-Neto E. Pannuti C.S. et al.New findings about trichodysplasia spinulosa-associated polyomavirus (TSPyV)—novel qPCR detects TSPyV-DNA in blood samples.Diagn Microbiol Infect Dis. 2016; 84: 123-124Crossref PubMed Scopus (12) Google Scholar). This suggests that these sites may act as reservoirs and could play a role in viral dissemination. Overall, our analyses strongly suggest that TSPyV can be transmitted within families through close interpersonal contacts, particularly between mother to child and between young siblings. The authors state no conflict of interest. This work was supported by the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (grant no. ANR-10-LABX-62-IBEID), by the Institut Pasteur in Paris. CMJ was supported by the Ministère de l’Enseignement Supérieur et de la Recherche of France and Paris Diderot University and JN was supported by a grant from the Région Centre, France. We thank the Institut de Recherche pour le Développement and the Centre Pasteur du Cameroun for their collaboration in the field work carried out in Cameroon. Download .pdf (.06 MB) Help with pdf files Supplementary Table S1