immunization usually confers protective immunity. Thus, females undergoing their first pregnancy are most at risk to infection with endemic viruses, whereas pregnant animals
of all ages usually are susceptible to epizootic virus infections that periodically spread through the population.
3.2. Ontogeny of fetal immunity The placenta of the large domestic species does not allow the passage of maternal
immunoglobulins to the fetus, whereas the fetal membranes of small domestic carnivores allow such transfer of maternal antibody to the fetus. The fetus is clearly capable of
Ž .
mounting an active acquired immune response humoral and cellular to a variety of agents thus, in the absence of significant placental injury, immunoglobulins, found in
fetal fluids of the large domestic species, are produced by the fetus itself. Immunity, Ž
. Ž
both innate cytokines, complement, phagocytic function, etc. and acquired humoral .
and cellular , develops sequentially in the fetus during gestation so domestic animals are born with functional, if not fully mature, innate and acquired immune defense mecha-
Ž .
nisms Arvin, 1997; Osburn et al., 1982 . The pregnant uterus usually allows the fetus to develop in a sterile environment, but the fetus is at considerable risk to in utero virus
infections when they occur because of the inherent slowness of the acquired immune response. Thus, a virus that is able to cross the placenta to infect the fetus can cause
extensive damage before immune clearance occurs.
3.3. Stage of gestation Susceptibility of the conceptus to the deleterious effects of virus infections often is
inversely proportional to fetal age, although a number of viruses cause fetal death and abortion regardless of fetal age. Teratogenic agents typically exert their effect only
Ž .
during a narrow ‘‘window’’ of susceptibility Schofield and Cotran, 1994 , and the fetus is especially susceptible to teratogenic agents during the period when organogenesis
occurs. Rapidly dividing populations of stem cells are present at this time, which are both fragile and highly susceptible to selected virus infections.
4. BTV infection of the fetal ruminant
4.1. Introduction Bluetongue is a virus disease of wild and domestic ruminants that is transmitted by
Ž .
hematophagous Culicoides insects Walton and Osburn, 1992 . The disease was first Ž
. described in South Africa Hutcheon, 1902 , but BTV infection is endemic in temperate
Ž .
and tropical areas throughout most of the world Gibbs and Griner, 1994 . The incidence of clinical disease, however, does not consistently correlate with the distribution of
BTV, and viruses and vectors in different regions of the world are quite distinct. The expression of bluetongue disease reflects a complex interaction of predisposing factors
that includes susceptibility of the ruminant host, virulence of the infecting virus, and
Ž .
vector competence of the local insect population Barratt-Boyes and MacLachlan, 1995 . Continued cycling of BTV between vector insects and susceptible ruminant populations
is critical to perpetuation of the virus in nature because infection is not contagious and vertical transmission of virus in ruminants is unimportant to the epidemiology of BTV
Ž .
infection MacLachlan et al., 1989 . 4.2. BTV-induced teratogenesis in fetal ruminants
Spontaneous, authentic cases of BTV-induced abortion and fetal malformation occur sporadically, and the pathogenesis of BTV-induced hydranencephaly has been reported
in both cattle and sheep. Teratogenic defects attributable to BTV infection were first described in sheep after a modified live, chick-embryo propagated BTV vaccine was
Ž .
introduced in California Schultz and Delay, 1955 . The use of this vaccine in pregnant ewes resulted in an extensive outbreak of fetal anomalies characterized by cerebral
malformations of varying severity that produced ‘‘dummy lambs’’. Field observations indicated that ovine fetuses were most susceptible during the fifth and sixth weeks of
gestation. Brains from affected lambs exhibited meningoencephalitis and cavitating
Ž .
lesions in the subcortical white matter and cerebellum Cordy and Schultz, 1967 . Acute necrotizing meningoencephalitis that progressed to hydranencephaly and subcortical
cysts was detected in some 20 of the fetuses born to ewes vaccinated on the 40th day Ž
. of gestation Griner et al., 1964 . Similarly, fetuses experimentally inoculated with the
BTV vaccine at 50–59 days of gestation developed a severe necrotizing encephalopathy and retinopathy, which manifest as hydranencephaly and retinal dysplasia at birth
Ž .
Young and Cordy, 1964; Richards and Cordy, 1967; Silverstein et al., 1971 . In contrast, fetuses inoculated at 75 days of gestation developed considerably milder and
more focal lesions, which manifest as cerebral cysts at birth. The virus replicates in neuronal and glial precursor cells that populate the subependymal plate prior to their
migration to form the cerebral cortex. Fetal infection at gestation day 40 destroys both neuronal and glial cell precursors, thus, the cerebral hemispheres do not form, whereas
infection at 75 days of gestation produces less severe damage because much of the cerebral cortex already is populated. Glial cells and neurons largely are resistant to
infection after their migration from the subependymal plate into the cerebral cortex, thus
Ž .
the age-dependence of the lesion Osburn et al., 1971 . Spontaneous occurrence of similar abnormalities has also been described in cattle, but
interestingly only in the US and South Africa, countries in which modified live virus Ž
. vaccines have been used Richards et al., 1971; Barnard and Pienaar, 1976 . Recent
studies with Australian strains of BTV and pregnant sheep have shown that BTV crosses the placenta to induce teratogenesis only after it has been altered by adaption to cell
Ž .
culture Flanagan and Johnson, 1995 . Vaccine strains of BTV, therefore, are likely responsible for spontaneous cases of BTV-induced CNS malformation in both sheep and
cattle. BTV-induced cerebral malformation in calves range from brains with thin-walled cerebral hemispheres, cerebral cysts and dilated lateral ventricles to those in which the
cerebral hemispheres are represented only by fluid-filled sacs. Brain stem structures usually remain but the cerebellum may also be represented only by a fluid-filled sac in
fetuses that were infected early in gestation. The pathogenesis of BTV-induced hydra-
Ž nencephaly in cattle is analogous to that in sheep MacLachlan and Osburn, 1983;
. MacLachlan et al., 1985 . The severity of the cerebral malformation is inversely
proportional to the gestational age of the fetus at infection. Fetuses inoculated very early Ž
. in gestation between 70 and 85 days of gestation , if they survived infection, had the
Ž .
most severe CNS malformations hydranencephaly, cerebellar destruction at birth,
whereas fetuses inoculated within a few weeks of parturition had mild encephalitis but Ž
. no malformations Waldvogel et al., 1992 . The critical period would appear to range
from approximately 70 to 130 days of gestation, with fetuses inoculated at the later stage of this period having only cerebral cysts and dilated lateral ventricles.
4.3. BTV-induced abortion in ruminants BTV infection of both fetal cattle and sheep can occasionally result in abortion, but
teratogenesis is more common. Although definitive studies are lacking, it is likely that BTV-induced abortion utilizes the same pathway as for normal delivery. However, fetal
death also may, depending on the stage of gestation and the source of hormonal control of pregnancy result in the expulsion of the uterine contents. It is to be emphasized that
pregnant sheep and cattle can abort in the absence of any fetal infection or disease, presumably as a direct consequence of maternal stress.
5. EAV infection of the equine fetus
