www.elsevier.comrlocateranireprosci
Bluetongue and equine viral arteritis viruses as
models of virus-induced fetal injury and abortion
N.J. MacLachlan
a,), A.J. Conley
b, P.C. Kennedy
a aDepartments of Pathology, Microbiology and Immunology, School of Veterinary Medicine, UniÕersity of California, 1126 Haring Hall, DaÕis, CA 95616, USA
b
Population Health and Reproduction, School of Veterinary Medicine, UniÕersity of California, DaÕis,
CA 95616, USA
Abstract
A number of viruses have the capacity to cross the placenta and infect the fetus to cause,
Ž .
among other potential outcomes, developmental defects teratogenesis , fetal death and abortion.
Ž .
Bluetongue virus BTV infection of fetal ruminants provides an excellent model for the study of virus-induced teratogenesis. This model has shown that only viruses modified by passage in cell culture, such as modified live virus vaccine strains, readily cross the ruminant placenta, and that the timing of fetal infection determines the outcome. Thus, cerebral malformations only occur after fetal infection at critical stages during development and the precise timing of fetal BTV infection determines the severity of the malformation present at birth. Fetal BTV infection also can result in fetal death, followed by abortion or resorption, growth retardation, or no obvious
Ž .
abnormalities, depending on age of the conceptus at infection. Equine arteritis virus EAV infection of the equine fetus causes fetal death and abortion but not teratogenesis. These two fetal viral infections are useful not only for the study of teratogenesis and fetal disease, but also to further characterize and compare the complex process that is responsible for normal induction of parturition in ruminants and horses.q2000 Elsevier Science B.V. All rights reserved.
Keywords: Bluetongue; Equine viral arteritis; Abortion; Teratogenesis
1. Introduction
The extended duration of pregnancy in domestic ruminants and horses facilitates fetal development in a highly insulated environment. Suboptimal reproductive performance is
)Corresponding author. Tel.:q1-530-752-1385; fax:q1-530-754-8124.
Ž .
E-mail address: njmaclachlan@ucdavis.edu N.J. MacLachlan .
0378-4320r00r$ - see front matterq2000 Elsevier Science B.V. All rights reserved. Ž .
common in these species. There are many causes of this reduced fertility; it can result from anything from lack of cyclic activity of the female to perinatal mortality. Insults that occur during the period of the fetus that result in fetal death and abortion, or teratogenesis, are best understood from the perspective of the normal embryology, gestational physiology, and the mechanism responsible for induction of parturition in each animal species.
A wide variety of agents, both infectious and non-infectious, are capable of crossing the placenta to cause fetal injury. Most maternal virus infections are not transmitted to the fetus, however, several viruses that infect domestic animals have the capacity to cross the placenta and to subsequently induce disease andror developmental defects
Žteratogenesis . Teratogenesis is the production of physical defects in offspring in utero..
The outcome of virus infection of the fetus depends on the susceptibility of the fetus to the infecting virus which, in turn, is a reflection of the gestational age of the fetus at exposure as well as the virulence characteristics of the infecting virus. The potential consequences of fetal viral infections include teratogenesis, fetal disease with or without abortion, growth retardation, persistent postnatal infection, or no obvious abnormality
ŽCatalano and Sever, 1971 . This review will describe and compare aspects of blue-.
Ž . Ž .
tongue virus BTV infection of the ruminant fetus and equine arteritis virus EAV infection of the equine fetus.
2. Maintenance of pregnancy and induction of parturition
Parturition normally must be timed so that fetal development and physiological
Ž .
preparation ensure optimal survival of progeny Rossdale et al., 1997 , a process that requires dialogue between the fetus and dam. The fetus either signals readiness for birth
Ž
to the uterus, or the placenta signals impending delivery to the fetus Thorburn et al.,
.
1991 . Whether or not parturition is best viewed as a release from the inhibitory effects of pregnancy on the myometrium rather than an active process mediated by uterine
Ž .
stimulants Lopez-Bernal et al., 1995; Norwitz et al., 1999 , or more simply a change in balance of the two, is moot. Birth of the fetus is immediately preceded by a dramatic change in uterine reactivity and coordinated contractility that is sustained by oxytocin,
Ž
prostanoid and even proinflammatory cytokine secretion Pashen, 1984; Kelly, 1996;
.
Nathanielsz et al., 1997; Mitchell et al., 1998 . The specific sequence of events differs between species, and species-specific differences in the mechanisms of pregnancy maintenance and induction of parturition influence the occurrence of abortion in different animal species. Furthermore, abortigenic viral infections cause premature expulsion of the fetus by either stimulating the normal delivery process or by inhibiting the maintenance of pregnancy, whereas normal gestation must be sustained for develop-mental defects to occur in fetuses in infected with teratogenic viruses
Placental steroids are mediators of pregnancy and of the parturition process. All placental mammals appear to require progesterone for the establishment and
mainte-Ž .
nance of pregnancy Geisert and Conley, 1998 . Uterine quiescence is maintained in
Ž
large part by the high concentrations of progesterone in uterine tissues Weems et al.,
.
the relative importance of each varies with species. The relative contributions of the corpus luteum and placenta as sources of progesterone can also change as gestation advances, thus placental production of progesterone can, by itself, sustain pregnancy in
Ž .
the ewe and mare late in gestation Casida and Warwick, 1945; Holtan et al., 1979 . This is important because disruption of placental progesterone production in these species, as occurs with death of the fetus, will quickly lead to fetal expulsion in the latter half of pregnancy. In contrast, fetal expulsion is delayed in those species, that depend on the corpus luteum as the principal source of progesterone throughout gestation. The balance between placental production and metabolism of progesterone is of considerable importance to the maintenance of pregnancy and induction of parturition, and this
Ž .
balance may differ between species Conley and Mason, 1990 and so influence occurrence of abortion.
Estrogen is also an important modulator of uterine activity through its influence on
Ž .
prostaglandin synthesis and levels of oxytocin receptors Zeeman et al., 1997 . Thus, an increase in estrogen or a decrease in the ratio of progesterone to estrogen at the level of the myometrium signals maternal preparation for parturition. In contrast, fetal prepara-tion involves an activaprepara-tion of the pituitary–adrenal axis and an increase in fetal cortisol
Ž .
synthesis Wood and Cudd, 1997 . The fetal cortisol surge precedes birth in both the ovine and equine fetus, and the secretion of cortisol by the sheep fetus appears to initiate
Ž .
the parturition cascade Norwitz et al., 1999 . A sharp rise in the secretion of fetal cortisol induces the expression of placental enzymes in the sheep, both 17a-hydroxylase
Ž .
and aromatase cytochromes P450 France et al., 1988 , which promote a pre-partum
Ž .
burst in placental estrogen synthesis Liggins, 1989 . The process of parturition is less clear in the mare. Like the sheep, the perinatal equine fetus experiences activation of the adrenal cortex with increased secretion of cortisol, and recent evidence indicates that
Ž .
progesterone levels decline immediately prior to birth Silver, 1994 . Fetal
administra-Ž .
tion of ACTH can induce parturition in the pregnant mare Ousey et al., 1998 , whereas maternal dexamethasone administration is relatively ineffective. Much remains to be determined regarding the initiation of parturition in the mare, and the interaction and metabolism of progesterone and estrogen, but it is clear that there is an increase in
Ž
uterine responsiveness to certain agents that precedes fetal expulsion Leadon et al.,
.
1982 . The influence of fetal viral infections on levels of these various modulators is virtually uncharacterized.
3. Fetal viral infections: predisposing factors
3.1. Maternal immunity
The fetus is afforded protection by the host defense mechanisms of its dam and by the placenta, because viruses first must infect the pregnant dam before they gain access
Ž .
to the fetus Arvin, 1997 . Maternal viremia is a critical prerequisite to fetal infection, and the risk of transplacental transmission of some viral infections is proportional to
Ž .
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 .
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
ŽYoung 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 .
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
5.1. Introduction
Ž .
EAV was first isolated in 1953 in the US Doll et al., 1957 . The virus can cause abortion of pregnant mares, interstitial pneumonia in foals, and a generalized influenza-like illness in adult horses that is characterized by fever, peripheral edema, and nasal
Ž .
discharge Huntington et al., 1990; Timoney and McCollum, 1993 . Outbreaks of equine viral arteritis have been reported in both North America and Europe, and serological surveys indicate that the virus is widespread. Although confirmed occurrences of clinical viral arteritis have increased in recent years, the majority of infections are subclinical and asymptomatic infection is especially prevalent among Standardbred and the
Warm-Ž .
blood breeds of horses Timoney and McCollum, 1993 . The pathogenesis of EAV infection of the horse has been described. After respiratory infection, the virus first replicates in pulmonary macrophages, it then proliferates in macrophages and endothe-lial cells in the lungs and bronchial lymph nodes, and then it rapidly spreads in the
Ž
circulation to infect endothelial cells and macrophages throughout the body McCollum
.
et al., 1971; MacLachlan et al., 1996 . Although endothelial cells and macrophages are the principal sites of virus replication, selected epithelial cells, mesothelium, and smooth
Ž
muscle cells of the media of arteries and the myometrium may also be infected Henson
.
and Crawford, 1974; Wada et al., 1994 . Although EAV infection of pregnant mares can result in abortion, the pathogenesis of fetal infection and the mechanism responsible for
Ž
abortion are not adequately understood Coignoul and Cheville, 1984; Cole et al., 1986;
.
Abortion can occur during either the acute or early convalescent stage of infection, and abortions have been described at anywhere between 3 months of gestation to nearly term. Aborting mares usually exhibit no obvious signs of viral arteritis, and aborted
Ž .
fetuses are delivered in either an autolyzed or non-autolyzed fresh state.
5.2. EAV-induced abortion
The major concern and adverse impact of equine viral arteritis is abortion of pregnant
Ž .
mares Huntington et al., 1990; Timoney and McCollum, 1993 . Transplacental viral infection of the fetus does occur during EAV infection of pregnant mares, however,
Ž
histologic lesions are seldom present in fetal tissues including placenta Jones et al.,
.
1957; Coignoul and Cheville, 1984; Cole et al., 1986; Johnson et al., 1991 . Myometrial necrosis can be a feature of EAV infection, and some workers have attributed EAV-in-duced fetal death to decreased blood supply to the fetus as a consequence of virus-in-duced injury to the myometrium, rather than to any direct effect of the virus on the fetus
Ž .
itself Coignoul and Cheville, 1984; Wada et al., 1994 . It was also proposed that virus in the fetus reflected only contamination attributable to increased permeability of the
Ž .
placenta Coignoul and Cheville, 1984 . More recent data clearly indicates that EAV does infect the fetus, although histologic changes in fetal tissues can be subtle or
Ž .
etiologically non-specific MacLachlan et al., 1996 . The fact that titers of EAV in fetal blood can be considerably higher than those in maternal blood would suggest that virus in the fetus does not reflect mere ‘‘contamination’’ from the dam. Similarly, the relative abundance of viral antigen in fetal tissues, as compared to those of the dam, confirms that the presence of EAV in fetal tissues does not reflect simple contamination.
6. Conclusions
Viruses occasionally are transmitted across the placenta to the fetus. The production of teratogenic defects provides a graphic illustration of the enhanced susceptibility of the fetus to some viral infections. In addition to teratogenic defects, the outcome of fetal viral infections can range from no lesions to severe fetal disease andror death. Fetal disease and stress unquestionably appear to be able to activate the normal process of parturition in large farm animal species, however, fetal death itself can also release the inhibitory effects of pregnancy on the myometrium and result in expulsion of the fetus and its associated membranes. An appreciation of the normal mechanisms that maintain pregnancy and induce parturition in animals is critical to the characterization of virus-induced fetal disease and abortion.
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