Intrauterine infection of human parvovirus B19 pathogenesis inducing hydrops fetalis

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Abstract

Human parvovirus B19 is a small single-stranded DNA virus etiologically related to a wide variety of human illnesses including erythema infectiosum (fifth disease) in children and hydrops fetalis and fetal death in pregnant women. The main target of B19 infection is human erythroid progenitor cells and the pathogenesis of hydrops fetalis has been attributed to the unique tropism of B19 for erythroid lineage cells and the cytotoxic effect on the infected cells. However, the relationship between outbreaks of erythema infectiosum and the incidence of hydrops fetalis caused by parvovirus B19 infection in utero has not been studied. Furthermore, the mechanism of B19- induced cytotoxicity has not been studied in detail. 1. Epidemiological studies To clarify the risk of hydrops fetalis in intrauterine B19 infection, sera of pregnant women with hydrops fetalis and B19 infection were examined for B19 IgG and IgM and for B19 DNA. Thirteen of the 175 cases of hydrops fetalis were found to be caused by intrauterine B19 infection and 12 of the 13 cases clustered in two periods of outbreaks of erythema infectiosum in the community. Furthermore, nine out of 48 women infected by B19 during pregnancy resulted in adverse fetal effects including hydrops fetalis and early abortion. The fetal death rate among them was 15%, far higher than the calculated 1% among the general population. B19 infection at 16 weeks' gestation or earlier was suggested to be critical for adverse fetal outcome. These results show an apparent relationship between hydrops fetalis and parvovirus outbreaks in the community, suggesting the necessity of serological screening of women of childbearing age for B19. 2. Experimental studies The evidences of apoptosis of erythroid cells infected by B19 both in vitro and in vivo were shown by pathological and biological methods and the mechanism of apoptosis was analyzed by immunohistochemical method. In electron microscopic study, cells containing viral crystalline arrays exhibited nuclear degeneration, extreme margination of the nuclear heterochromatin, and clumping of heterochromatins, which are typical features of cells undergoing individual programmed cell death. Erythroid cells infected in vitro and in vivo were positive for TUNEL immunostaining. Neither FAS/FAS ligand system nor perforin/granzyme system was associated with induction of apoptosis in B19 infection. Caspase-3/CPP32 seemed to play an important role in the apoptosis pathyway by B19. These results indicated that erythroblast cells in fetal tissues of intrauterine B19 infection were killed through apoptosis directly induced by B19, which is a main cause of hydrops fetalis and still birth. 3. Prevention and treatment Commercially available immunoglobulin preparations possessed neutralizing activity against in vitro infection, which suggests a possibility of passive immunization against B19 intrauterine infection. Overexpression of Bcl-2 and a caspase-3 inhibitor blocked apoptosis induced by expression of the cytotoxic protein of B19, NS1, suggesting a possible application of fetal therapy for hydrops fetalis by intrauterine B19 infection. A case of hydrops fetalis caused by B19 was rescued by intrauterine blood transfusions, which confirmed effectiveness of fetal therapy. These results indicate the possibility of future prevention strategies designed to inhibit the pathway form infection and consequent apoptosis induced by B19, and effective therapy of hydrops fetalis by genetic 'rescue' of severe anemia caused by apoptotic death of erythroid cells.

Original languageEnglish
Pages (from-to)569-580
Number of pages12
JournalActa Obstetrica et Gynaecologica Japonica
Volume50
Issue number8
Publication statusPublished - 1998 Aug

Keywords

  • Apoptosis
  • Hydrops fetalis
  • Intrauterine infection
  • Parvovirus B19

ASJC Scopus subject areas

  • Obstetrics and Gynaecology

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