A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus.

In human cytomegalovirus (HCMV), tropism to epithelial and endothelial cells is dependent upon a pentameric complex (PC). Given the structure of the placenta, the PC is potentially an important neutralizing antibody target antigen against congenital infection. The guinea pig is the only small animal model for congenital CMV. Guinea pig cytomegalovirus (GPCMV) potentially encodes a UL128-131 HCMV PC homolog locus (GP128-GP133). In transient expression studies, GPCMV gH and gL glycoproteins interacted with UL128, UL130 and UL131 homolog proteins (designated GP129 and GP131 and GP133 respectively) to form PC or subcomplexes which were determined by immunoprecipitation reactions directed to gH or gL. A natural GP129 C-terminal deletion mutant (aa 107-179) and a chimeric HCMV UL128 C-terminal domain swap GP129 mutant failed to form PC with other components. GPCMV infection of a newly established guinea pig epithelial cell line required a complete PC and a GP129 mutant virus lacked epithelial tropism and was attenuated in the guinea pig for pathogenicity and had a low congenital transmission rate. Individual knockout of GP131 or 133 genes resulted in loss of viral epithelial tropism. A GP128 mutant virus retained epithelial tropism and GP128 was determined not to be a PC component. A series of GPCMV mutants demonstrated that gO was not strictly essential for epithelial infection whereas gB and the PC were essential. Ectopic expression of a GP129 cDNA in a GP129 mutant virus restored epithelial tropism, pathogenicity and congenital infection. Overall, GPCMV forms a PC similar to HCMV which enables evaluation of PC based vaccine strategies in the guinea pig model.

Vertically transmitted herpesvirus infections.

The importance of recognizing perinatally acquired herpes simplex virus infections is now well understood and recently, increased attention has been devoted by clinicians to the problem of perinatally acquired cytomegalovirus infections. Less commonly, other members of the herpesvirus family may also be transmitted from mother to infant in the perinatal period, causing disease. Future developments of the management of herpesvirus infections will include greater roles for antiviral therapies and vaccines. Expanded use of oral nucleoside antiviral therapies in pregnancy has engendered uncertainty in how best to screen, monitor, and treat women at risk of transmitting the infection. Vaccines against herpesviruses have progressed in clinical trials, and the imminent licensing of such vaccines will further complicate clinical management decisions. As potential therapeutic agents become available, better understanding and recognition of risk factors, and awareness of the clinical presentation of perinatally acquired herpesvirus infections, will be required to maximize satisfactory pregnancy outcomes.

Developmental disorders of the mouse brain induced by murine cytomegalovirus: animal models for congenital cytomegalovirus infection.

Developmental disorders induced by congenital cytomegalovirus (CMV) infection mainly involve the central nervous system. The type and degree of the brain disorders seems to depend on infection time during gestation, virulence, route of infection and viral susceptible cells in each embryonal stage. Since transplacental transmission has been reported not to occur with murine CMV (MCMV), we developed mouse models for congenital CMV infection by surgical injection of MCMV into the mouse conceptus or embryo at different gestational stages. For the early stage, the mouse embryos were not infected with MCMV even after injecting the virus into the blastocysts, which were developed in the pseudo-pregnant mothers or cultured in vitro. Isolated whole mouse embryos of day 7.5 of gestation (E7.5), adsorbed with a high titer of MCMV and cultured for 3 days, were susceptible to MCMV infection. Therefore, the mouse embryo acquires the susceptibility around this period. Microphthalmia and cerebral atrophy were induced in mouse embryos after injection of MCMV into the conceptus on E8.5. Viral antigen-positive cells were widely distributed in the mesenchyme around the oral and nasal cavities and in the mesenchyme around the brain, especially the endothelial cells of vessels and the perivascular mesodermal cells, then infection extends to the eyes, brain or choroid plexus. This finding suggests that mesenchymal infection may be the critical step in disrupting organogenesis, resulting in brain disorders. For the late stage, mouse embryos were infected with MCMV by injecting the virus into the cerebral ventricles on E15.5. Brains of the offspring showed massive necrosis with gliomesodermal proliferation in the cerebral cortex. Viral antigen-positive cells were observed in laminar array in the lesion-free cortex and the hippocampus, suggesting that the infected cells migrate in association with the lamina formation. Immunohistochemical double-staining showed that brain cells susceptible to MCMV infection may be mainly neuronal and endothelial cells, resulting in cerebral atrophy with reduction of neuronal cells and cystic lesions, presumably due to ischemic vascular changes.

Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease.

We present data on 10 patients from 5 families with a condition of microcephaly, intracranial calcification, and a clinical course resembling congenital TORCH infection. Repeatedly, negative TORCH investigations are a prerequisite for the identification of this disorder and the value of disturbed liver function and thrombocytopenia as aids to diagnosis is emphasised. Several similar families with recurrence of the disease in sibships are identified in the literature and the genetic implications of our observations are considered.

[Infections with herpesvirus 6--really only "exanthema subitum"? Part 2: Rare or unknown disease pictures]. / Infektionen mit dem Herpesvirus 6--wirklich nur "Exanthema subitum"? Teil 2: Seltene oder unbekannte Krankheitsbilder.

The human herpes virus 6 (HHV 6) may induce not only the wellknown condition of exanthem subitum, but also a number of more common (cf. Part 1) or rare, even previously unknown, clinical manifestations. Part 2 of this paper deals with the more rarely observed manifestations. These include complications of ARD (sinusitis, otitis media, bronchial pneumonia) hepatitis, encephalitis or Pfeiffer's disease (mononucleosis-like syndrome). In individuals with a relevant disposition (genetic HLA/DR type?) initiation or (re-)activation of rheumatoid arthritis (JCA = juvenile chronic arthritis) or chronic iridocyclitis may occur. Although, on account of the high prevalence of vaccination in our population (approximately 95%), prenatal infections are extremely rare, they may manifest in a severe "septic" form (fatalities have occurred) or may lead to neurological deficits (comparable with cytomegalovirus infection). To date, no specific therapy (e.g. gammaglobulin, virostatics) or reliable preventive measures (e.g. vaccination) are available.

Infección congénita por virus herpes simplex / Congenital infection due to herpes simplex virus

Se presentan 5 casos de probable infección herpética intrauterina; en 4 de ellos se comprobó clínicamente la presencia de herpes neonatal, observándose un caso localizado a piel, dos casos de herpes diseminado y un herpes neonatal con compromiso del sistema nervioso central. En los cuatro casos enfermos se descartó la posibilidad de infección postnatal o durante el parto, puesto que presentaron signos o síntomas de la enfermedad antes de transcurrir 24 horas de vida. En ellos se plantea la posibilidad de infección transcervical o transplacentaria. Todos los recién nacidos fueron tratados con aciclovir endovenoso por 10 días, evolucionando bien 3 de ellos; los otros 2 fallecen; uno a los 9 días y el otro a los 2 meses de vida por encefalitis y secuelas neurológicas severas, respectivamente

Should we expand the TORCH complex? A description of clinical and diagnostic aspects of selected old and new agents.

Physicians faced with a newborn infant with signs and symptoms of perinatal infection must consider a multitude of diseases, and may need to embark on a complex differential diagnosis. As stated by Alford in 1967, "neonatal diagnoses of infections acquired in utero, natally and postnatally, are inherently difficult." Twenty years later, this statement is still true. In this review, the diagnostic problems encountered in the evaluation of a suspected perinatal infection have been discussed, as have the complexities of the evaluation process for the original four TORCH agents, as well as for three additional agents. From our point of view, the usefulness of the TORCH acronym has been to focus attention on perinatal infections. Its main drawback has been the resultant overuse of TORCH titers ignoring the complexity of the diagnostic process. Ideally, the TORCH concept serves two functions. It continues to remind us of the multiplicity of pathogens that can cause perinatal infection, and it underscores the need for thorough diagnostic evaluation for these challenging infections. We believe that this is an appropriate expansion of the TORCH complex, and we anticipate that this expanded TORCH complex will continue to grow.

Herpesvirus infections in pregnancy: risks to embryo, fetus, and neonate.

Gestational herpesvirus infections can significantly alter the outcome of pregnancy. Potential hazards to the embryo, fetus, or neonate are numerous and depend on several variables, including the specific virus involved, gestational timing of infection, and whether the infection is primary or recurrent in nature. This article reviews the epidemiology and clinical manifestations of maternal, fetal, and neonatal herpesvirus infections, methods for establishing an accurate etiologic diagnosis, and prevention strategies, including prospects for prenatal diagnosis of these infections.

Perinatal viral infections.

In comparison to older children and adults, neonates are immunologically incompetent. They are susceptible to infections caused by a variety of microorganisms, including bacteria, fungi and viruses. These infectious agents may be acquired by neonates either prenatally, during the intrapartum period or postnatally. The purpose of this review is to emphasize the potential impact of viral infections contracted by neonates at the time of delivery or within the neonatal period. The viruses reviewed include the herpes group of viruses (cytomegalovirus, herpes simplex viruses and varicella-zoster virus), type B hepatitis virus, human immunodeficiency virus, respiratory viruses, enteroviruses, rotavirus and human papilloma virus. For each virus the potential sources and incidence of the infection, the common manifestations of the illness, and possible means of prevention and therapy are discussed. Although infections caused by bacteria tend to be more clinically dramatic and more immediately life-threatening, it is emphasized that infections caused by viruses are common and associated with substantial long-term morbidity. Perinatal viral infections need to be recognized as early in life as possible so that their natural history can be more completely defined and any possible intervention made.

Infecciones congénitas y neonatales por virus herpes / Congenital and neonatal infections by herpes virus

En el presente trabajo se realiza una revisión de la patogenia de diversas infecciones congénitas y neonatales causadas por virus herpes en humanos, estableciendo las variaciones existentes entre los síndromes, y los aspectos de la infección estudiada en diversas especies animales. Asimismo, se analiza la semejanza que guardan los síndromes desde el punto de vista de las características de los agentes causales y las posibilidades de enriquecer el conocimiento del problema a través de modelos animales

Epstein-Barr virus infections during pregnancy. A prospective study and review of the literature.

Susceptibility to Epstein-Barr virus (EBV) infection in 1,729 pregnant women was evaluated by screening for EBV antibodies. Fifty-eight subjects (3.4%) had no detectable EBV antibody and were presumably susceptible. Of the 54 women who agreed to participate in this study, none acquired EBV antibody during pregnancy. Our results are in general agreement with some published reports that primary EBV infection during pregnancy is rare. The role of EBV in congenital infections and perinatal morbidity remains to be defined.

Human newborns are deficient in natural killer activity.

The peripheral blood natural killer (NK) activity of newborns was found to be significantly less than that of adults. In mixing experiments newborn cells inhibited adult NK activity in only one of nine instances. Interferon treatment in vitro increased newborn NK activity to an even greater degree than adult NK activity. These findings imply that diminished newborn NK activity is due not to inhibitory cells or lack of pre-NK cells but rather to deficient in vivo activation of pre-NK cells. This deficiency may be a major factor in the increased susceptibility of newborns to certain virus infections.