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20

PATHOGENESIS OF
INTRAUTERINE INFECTIONS
WITH BOVINE VIRAL
DIARRHEA VIRUS
Volker Moennig, Prof. Dr. med. vet.,
and Bernd Liess, Prof. Dr. med. vet., Dr. h.c.

INTRODUCTION

Infection of nonimmune pregnant animals with pestiviruses usually

results in transplacental infection of the fetus. Although the majority of
acute postnatal infections lack dramatic clinical signs, sometimes infec-
tions may be associated with symptoms, e.g., a short febrile period,
salivation, nasal discharge, coughing, and/or diarrhea. 38, 47 A recently
described hemorrhagic syndrome with severe thrombocytopenia or bo-
vine viral diarrhea virus (BVDV)-associated diabetes mellitus add to the
facets of acute BVDV infection.42, 12,32,5,49 However, the major economical
damage caused by BVDV in susceptible herds is still caused by intrauter-
ine infections. 21, 43, 23 Modern herd management practices and reproduc-
tive techniques, e.g., embryo transfer (ET) have increased the impact of
BVDV infections. 33, 35, 4
The outcome of intrauterine infections with BVDV primarily is
determined by time of fetal infection and properties of the virus, e.g.,
pathogenie potential, biotype, and target cell range, respectively. The
latter factors, however, have not yet been clearly defined. In this review,
the effects of BVDV infections before and during gestation are discussed
in chronologie order.

From the Federal Research Centre for Virus Diseases of Animals, Ttibingen (VM); and the
Institute of Virology, Hannover Veterinary School (BL), Hannover, Germany

VETERINARY CLINICS OF NORTH AMERICA: FOOD ANIMAL PRACTICE

VOLUME 11 • NUMBER 3 • NOVEMBER 1995 477

478 MOENNIG & LIESS

THE EFFECT OF BVDV ON FERTILITY

The interaction of BVDV with reproduction begins before concep-

tion. Acute or persistent infection of bulls may affect breeding results
considerably.28 It was shown that the virus could influence semen quality
markedly. Four susceptible bulls were infected intranasally with BVDV.
On days 10 to 14 post infection virus was isolated from the semen of
two animals. Although clinically healthy, semen quality of one bull
deteriorated, i.e., density and motility were reduced and abnormalities
were increased. Recovery was observed only after 76 days after infec-
tion. 4D Bulls persistently infected with BVDV regularly yielded BVDV-
contaminated semen of significantly reduced quality. 3D As in other or-
gans, the virus is also found in testical tissue (Fig. 1).
Experimental infection of susceptible heifers may produce pro-
longed ovaritis (61 days).48 Whether this can cause transient infertility is
not clear. BVDV infections, e.g., by contaminated semen, were often
suspected to be a major cause for repeat breedings. Experimental infec-
tions of cows at estrus supported that suspicion. Although conception
rates were not reduced when seronegative heifers were infected with
BVDV oronasally at the time of insemination and inoculation of BVDV-
contaminated semen in seropositive animals did not produce any detect-
able damage, the insemination of seronegative heifers with contaminated
semen reduced conception rates considerably.51 The studies were ex-
tended and confirmed by Grahn et aP7 using superovulated seronegative
cows for artificial insemination with normal and alternatively with
BVDV-contaminated semen. Fertilization rates and early development

Figure 1. Immunofluorescence staining of BVDV antigen in sections of testicular tissue of

a persistently infected bull.
 PATHOGENESIS OF INTRAUTERINE INFECTIONS WITH BVDV 479

of embryos were evaluated on days 3 and 13 after insemination. In

both experiments, the BVDV group's scores were significantly poorer
compared with the controls, yielding fewer fertilized eggs and hatched
embryos, respectively. It was concluded that BVDV infection may some-
how interfere with fertilization. The deleterious effect of the virus on the
results of ET is well documented. 33,45 However, there are no mechanisms
known with respect to the virus' adverse effect. The virus seems not to
penetrate the intact zona pellucida. 26
There is no experimental evidence that either germ line cells or
early embryonic stages are directly susceptible to BVDV infection. In
vitro studies indicated that even a damaged or removed zona pellucida
does not affect survival of bovine embryos in the presence of infectious
BVDV.6 Most likely the fetus becomes susceptible for infection after
transplantation at days 19 to 20 postconception (PC) and/or develop-
ment of fetal cotyledones around day 30 PC. This could happen as a
result of a transient viremia of the susceptible mother. Even BVDV
introduced into the genital tract at the time of insemination or ET will
be a threat to the developing fetus, because it was shown to persist in
the intrauterine environment for up to 53 days.3
The effect of BVDV on ET was observed by Liess et al. 33 Interference
of the virus with ET might occur at different levels and economic
damage might be considerable unless appropriate precautions are taken.

EARLY PREGNANCY

The Role of the Evolving Immune System

Early stages of pregnancy seem to be very sensitive to BVDV infec-

tion. Carlsson et aP7 reported fetal death in four heifers infected between
29 to 41 days' gestation. Two heifers aborted and in two the fetus was
resorbed. The outcome of infection in surviving fetuses is primarily
determined by their developmental stage and in particular their devel-
oping immune system at the time of infection. Bovine fetuses become
immunocompetent to various antigens in a stepwise manner. 24,46 Virus-
specific antibodies are being generated after infections around day 100
of gestation.34 Although lesions caused by infection until approximately
day 150 may vary individually, there is a characteristic pattern for each
stage of gestation.
Immunotolerance can be induced by fetal infection from approxi-
mately day 30 to day 100 to day 120. The induction of immunotolerance
is also described elsewhere in this issue (see the article by Potgieter,
this issue).

Central Nervous Malformations

Because BVDV is capable of crossing both the placenta and the fetal
blood-brain-barrier, severe lesions and malformations are found in the
480 MOENNIG & LIESS

central nervous system (CNS), e.g., the cerebellum. The time-depen-

dency of BVDV infection on cerebellar development was first shown by
Brown et al. 15 Infection of five susceptible heifers between days 79 and
150 yielded four cases of cerebellar degeneration. The fifth fetus (day
107) was aborted. Severity of lesions increased with age of the fetus at
time of infection, i.e., infections after day 100 of conception yielded the
most severe cerebellar lesions. The mean size of the cerebellum in the
four calves that went to term from the affected group was half that in
the normal control group. Additionally, two calves from the heifers
inoculated at 146 and 150 days' gestation had ocular lesions including
cataracts, retinal degeneration, and hypoplasia and neuritis of the optic
nerves. Three of these calves had precolostral serum neutralizing titres
against BVDV, which indicated that intrauterine infection had occurred.
The calf from the dam inoculated at 79 days' gestation was stillborn
and had mandibular brachygnathism, cerebellar degeneration, cataracts,
retinal degeneration, and optic neuritis. The heifer inoculated at 107
days' gestation aborted a mummified fetus 73 days later. The fetus was
estimated to have died 28 days after inoculation of the dam.
In a similar study Done et aP2 inoculated 15 pregnant, seronegative
heifers at gestation day 100. None of the cows showed clinical signs of
illness after exposure, but all had seroconverted within 6 weeks. Five
fetuses were aborted including one set of twins. One mummified fetus
was retained until day 300. The remaining 10 fetuses survived to term,
but all showed evidence of intrauterine growth retardation with or
without gross malformation and/ or dysmyelination of the CNS. Three
were affected clinically with congenital nervous disease. Of the 10 live-
born fetuses, two had specific serum antibodies to BVDV. Noncytopathic
(NCP) BVDV was recovered from the remaining. 8
Brown et aP4 were able to demonstrate that BVDV infection even
affects the CNS at 150 days' gestation. Acute cerebellar lesions consisting
of leptomeningeal inflammation, necrosis of cells in the external germi-
nallayer, focal hemorrhages, and moderate-to-severe folial edema were
seen in the fetuses examined 17 and 21 days after inoculation.
In a study using 50 seronegative pregnant heifers, a live BVDV
vaccine containing both biotypes of the virus was sequentially inoculated
at different stages of gestation. Introduction of the virus before day 90
of gestation resulted in the birth of persistently viremic calves without
precolostral virus-specific antibodies. Calves were either clinically nor-
mal or growth retarded. Some died within the first 24 hours after birth.
Infection between days 90 and approximately 120 yielded some calves
with severe central nervous malformations, e.g., cerebellar hypoplasia,
hydranencephaly and/or internal hydrocephalus. Virus could be de-
tected in some cases; others were virus-negative.
Vaccination after day 120 produced clinically normal calves with
precolostral neutralizing antibodies against BVDV. No virus was demon-
strable. Occasional abortions were observed in this group.39, 34, 50 The
previously mentioned results were attributed to the NCP biotype of the
virus. It is not yet known why cases of severe CNS malformations are
 PATHOGENESIS OF INTRAUTERINE INFECTIONS WITH BVDV 481

found virus-negative despite the obvious causative role of BVDV after

experimental infection. 50
The severity of ocular lesions apparently also depends on the time
of infection.13 Susceptible heifers infected at or around day 150 of preg-
nancy gave birth to calves with total retinal atrophy. Sequential studies
showed the lesions to start approximately 20 days after infection.
Lesions were characterized by a mild-to-moderate retinitis that re-
sulted in various degrees of destruction of the different layers, mononu-
clear cuffing of inner retinal vessels, proliferation of pigment epithelium,
and choroiditis. Infections at day 95 resulted in milder ocular damage,
and no lesions were observed in animals infected during earlier stages
of gestation. Field observations suggest that the occurrence of the oculo-
cerebellar syndrome among newborn calves could increase dramatically
in closed dairy herds. l l

Other Teratogenic Disorders

In addition to eNS disorders intrauterine, BVDV infections induce

a number of other fetal abnormalities. Skeletal deformities including
bent front legs, mandibular brachygnathism and other jaw/head ab-
normalities, and general growth retardation are observed. Hypotri-
chosis may be an additional finding. It is suggested that these malfor-
mations are caused by BVDV infection between days 100 and 170 of
pregnancy.22,25

Pathogenic Mechanisms

Little is known about the pathogenic mechanism of fetal malforma-

tions. Direct cell damage by viral infection or destruction of virus-
infected cells by the evolving immune system are possible explanations.
The latter is supported by the observation that cases of severe eNS
malformations are found virus-negative despite the obvious causative
role of BVDV after experimental infection. 5o
Other pathogenic mechanisms, e.g., the role of viral interactions
with distinct target cells emerging in the course of fetal development,
are not understood. They may also contribute to intrauterine pathology
of BVDV infections. 15 In sheep infected with border disease virus (BDV)
the effect of noninflammatory and noncytolytic viral infection of the
thyroid gland was described by Sawyer et al. 44 Intrauterine infection of
the thyroid of bovine fetuses results in decreased T3 and T4 hormone
levels. The hormone deficiency adversely affects the concentration of
2' ,3' -cyclic nucleotide-3' -phosphodiesterase, an enzyme essential for nor-
mal myelination. l This results in hypomyelination, tremors, and other
eNS malfunctions. The hypothesis was supported by the finding that
BDV does not selectively infect oligodendrocytes, indicating that a selec-
tive pattern of infection is not responsible for congenital hypomyelina-
482 MOENNIG & LIESS

tion of sheep with BDV.2 Additionally, the altered thyroid function

affects the development of the skeletal system thus causing a general
growth retardation. Whether an equivalent mechanism contributes to
BVDV-induced fetopathies is not known. BVDV antigen is found in the
functional cells of the thyroid of persistently infected calves (Fig. 2).
Pathologic lesions in relation to time of intrauterine infection are summa-
rized in Figure 3.

THE LAST PHASE OF PREGNANCY

When infected during the last one third of gestation, the result is
comparable to the acute postnatal infection of cattle. By that time, the
bovine fetal immune system is sufficiently developed to mount an effi-
cient response against BVDV. Occasional abortions attributable to BVDV
infection may be observed. 39

UNRESOLVED QUESTIONS

Results of fetal infections at different times of gestation are not

always consistent with the role of the developing immune system as
previously mentioned. Why do fetuses die after infection during the first
trimester of gestation and why are fetuses occasionally aborted after
infection during later stages of pregnancy (>120 days)?

Figure 2. Immunofluorescence staining of BVDV antigen sections thyroid tissue of a

persistently infected calf.
 PATHOGENESIS OF INTRAUTERINE INFECTIONS WITH BVDV 483

40
I ..•
~
Implantation (days 19-20)
Fetal cotyledones (day 30)

Possible virus persistence in

intrauterine environment (53 days)

80 • Persistent viremia of fetus, no clinical sign-

perinatal death, no precolostral antibodies

120
••
•~ . . .---
.. eNS lesions,
e.g., cerebellar hypoplasia

160 •
1 Ocular damage, day 150:
total retinal atrophy

........
__- Abortions
••
200 .
•

Developing immune system,

240 precolostral antibodies,
clinically normal calves

280
Figure 3. Time line of pathologic events after intrauterine infection.

It seems evident that the outcome of intrauterine infection is not

only determined by time and host reactions but also by differences in
viral pathogenic potential. Because most acute infections go unnoticed,
we assume that BVDV generally seems to be well adapted to cattle with
little virulence. There seem to be differences in viral pathogenicity,
however, and, occasionally, clinical signs may be observed. 19 In extreme
cases, BVDV infection results in a hemorrhagic syndrome. 2o, 32, 41 In the
latter case, pathology seems to be directly attributable to viral virulence
rather than host factors. The question is whether differences in virulence
observed in acute postnatal infection affect the outcome of fetal infec-
tions as well. Abortions and mummifications occasionally occurring
during the first 100 days' gestation or abortions during the last stages
of pregnancy18,29 indeed suggest that viral "virulence" factors might
contribute to the complex picture of intrauterine infections with BVDV.
Whether cytopathogenic (CP) BVDV plays a role in intrauterine patho-
genesis is not fully clear. There is some evidence that the CP biotype of
484 MOENNIG & LIESS

the virus is not able to cross the placenta to establish fetal infection. 16
The target cell spectrum of BVDV is also not clear. In most tissues,
epithelial and immune cells of persistently infected calves NCP BVDV
is found. 7, 8, 9,10 There is little information, however, on whether viral
isolates display differences in their in vivo target cell spectrum. Cellular
receptors are prime determinants of viral cell tropism. For BVDV it was
shown that a single receptor mediates entry of both BVDV biotypes into
cultured bovine cells. 36 Whether the in vitro findings properly reflect the
in vivo situation is questionable. In experimentally induced mucosal
disease, it was shown that at least both biotypes seem to infect different
target cells. 37,31 Whether NCP BVDV isolates vary with respect to their
in vivo target cell spectrum is not yet clear. Further research on cellular
receptors of BVDV is needed to understand viral cell tropism and its
impact on intrauterine pathogenesis.

SUMMARY

BVDV shares with other Pestiviruses the ability to cross the placenta
of pregnant host animals. The effects of fetal infections are complex and
depend on a number of factors, e.g., age of the fetus and properties of
the virus. In early stages of gestation, i.e., the zygote/embryo stage, no
infection seems to occur. During the last one third of gestation the
infection is terminated by the ontogeny of the fetal immune system. This
leaves a window of susceptibility during early stages of fetal develop-
ment allowing establishment of viral persistence and/or the develop-
ment of a number of fetopathologic effects. Additionally, fertility prob-
lems and abortions are observed.
Calves that are born immunotolerant to BVDV and persistently
viremic display a wide variety of abnormalities. However, there is an
unknown proportion of calves born without any clinical signs indicative
of persistent infection. The time of fetal infection during the first stages
of pregnancy seems to playa crucial role with respect to the lesions
induced. Generally, early infections seem to induce less damage com-
pared with late infections, suggesting an indirect, possibly immune-
mediated pathogenesis. Additionally, direct virus-cell interactions may
playa role. Few data exist about the influence of differences in viral
virulence on fetal pathology. Likewise the role of the viral target cell
range is not clear.

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Volker Moennig, Prof. Dr. Vet. Med.
Federal Research Centre for Virus
Diseases of Animals
Paul-Ehrlich-Str. 28
D-72076
TUbingen, Germany