D8541.PDF

Rev. sec. tech. Off. int. Epiz., 1986, 5 (4), 897-918.
Malignant catarrhal fever
W. PLOWRIGHT*
Summary:
Whilst malignant catarrhal fever (MCF) is generally a sporadic
disease, its incidence is probably
increasing in farmed
deer; the sheepassociated infection (SA-MCF)
of cattle has, possibly, diminished
recently.
Wildebeest-derived
disease (WD-MCF) is a problem in Africa where cattle and
wildlife share pasturelands;
it is also now reported more often in zoological
collections and ranches with exotic
ruminants.
A discussion of the clinical signs and pathogenesis
of MCF is followed
by
an account of the epidemiology
of both forms. An increasing number
of
species in the family Bovidae, especially in the subfamilies Caprinae, Alcelaphinae and Hippotraginae, exhibit widespread inapparent
infection
with
herpesviruses, related to the Alcelaphinae prototypes AHV-1 and AHV-2.
The
circumstances in which these viruses spread from "reservoir"
to
"indicator"
hosts are discussed. The range of the latter is still
widening.
The alcelaphine
viruses are gammaherpesviruses
with resemblances
to
H. saimiri and H . ateles. Lymphoblastoid
cell lines with NK cell characteris­
tics, sometimes
capable of reproducing
MCF, have been established
from
tissues of SA-MCF infected animals; virions or viral antigens have not yet
been unequivocally
identified in them.
Methods for laboratory confirmation
of a diagnosis of MCF are outlined.
Control still depends on separation of reservoir and indicator
hosts.
K E Y W O R D S : Antelope - Bovine herpesvirus - Cattle diseases - Diagnosis Disease control - Epidemiology - Lesions - Malignant catarrhal fever virus Pathogenesis - Symptoms - Wild animal diseases.
INTRODUCTION
Of the herpesvirus infections of animals which are covered by this issue,
malignant catarrhal fever (MCF) is undoubtedly the least important economically.
It is sufficiently infrequent that some observers publish papers which record large
clusters of cases on a property as an "epizootic". The incidence of MCF has pro­
bably declined in some European countries, as traditional practices of housing
sheep and cattle together in winter have become less common, but has probably
increased in importance in zoological collections and on ranches which include
exotic ruminants or farmed deer. New Zealand, in particular, has seen dramatic
growth of its farmed red deer population, to about 250,000 in 1983 and estimated
to reach 750,000 by 1990 (86); there are now estimated to be about 300,000 exotic
ruminants on ranches in Texas alone (27). In Africa the threat of wildlife reservoirs
of MCF to the cattle of nomadic pastoralists or ranchers can still disrupt grazing
patterns and increase pressure on "game" animals which are major tourist or
sporting attractions.
Scientifically, on the other hand, MCF offers a serious challenge to the new
technologies — particularly to identify the agent of the sheep-associated disease and
* Whitehill Lodge, Goring-on-Tharnes, Reading, RG8 0LL, United Kingdom.
— 898 —
to explain its epidemiology, pathogenesis and immunology. Furthermore, the
evolution of a distinctive group of herpesviruses in African antelopes and wild or
domesticated caprines should provide a fascinating research topic for years to
come.
There have been several reviews of various aspects of MCF in recent years and it
is not proposed to repeat here many details found in these papers (24, 43, 60, 61,
66, 69, 75).
GENERAL REMARKS
Malignant catarrhal fever is a clinicopathological entity which has been reported
from virtually every country in the world capable of a reliable diagnosis; it should
be emphasized that it is not yet proved to have a single aetiological agent, although
papers are still published which imply that this is the case (30, 39). Outside Africa it
can usually be associated with more or less close contact between presumed carrier
sheep and susceptible indicator species. This "sheep-associated" (SA) disease has
also been reported by many workers in Africa (12, 53, 54, 56), where the majority
of cases are, however, known to be derived from contact with two species of
alcelaphine antelopes, the blue or "white-bearded" and the black or "white-tailed"
wildebeest (Connochaetes taurinus and C. gnu, respectively). The use of the term
"African MCF" could, therefore, be misleading, although it has the virtue of
brevity; since the isolation of the causal herpesvirus from wildebeest (62), the
description "wildebeest-derived" (WD) is accurate and more informative;
"wildebeest-associated" seems unnecessarily cautious.
CLINICAL SIGNS OF M C F
The classical signs of MCF have been recognised in Central Europe for well over
a century, often under the name "Kopfkrankheit" which was a sporadic, non­
contagious disease to be differentiated from rinderpest or "bovine typhus"
(10, 87). The use of the term "head-and-eye form" for the majority of cases in
cattle seems to date from a paper by Götze (15) who also described peracute, intes­
tinal and mild forms, the occurrence of which has been frequently substantiated,
especially in recent observations on the disease in deer, as well as in cattle and exo­
tic ruminants.
The "mild" category is the one about which the greatest doubt exists, as a
natural phenomenon; a few such cases have been proved to follow experimental
infection with African (wildebeest) virus (see 58, 63, for example). Incidentally, the
first ox in the transmission series described by Mettarn (40) developed fever on one
day only, following inoculation of wildebeest blood, but its blood was virulent for
another ox at that time and, surprisingly, it succumbed to challenge less than four
months later. There was no serological evidence, in a limited survey, that subclini­
cal or mild infection occurred in cattle in Kenya Masailand, an area of heavy
wildebeest exposure (76).
It is difficult to obtain significant figures for the mortality in naturallyoccurring outbreaks of the disease, since some cases are often slaughtered, but
Pierson et al. (50) described a remarkable incident in which 87/231 cattle were
affected and died in Colorado, USA, whilst Maré (37) reported a 16.6% mortality
— 899 —
in a 1,000 cow herd over a 3 month period in California. James et al. (31) reported
that all 28 cattle clinically affected on one property died in New Zealand; it is advis­
able to assume that any appreciable rate of recovery is an indication of concurrent
infection or mistaken diagnosis. During serial transmission of MCF in cattle inocu­
lated with wildebeest herpesvirus the mortality rate has varied from 94-100 per cent,
the lower figure (292/311) being associated with concurrent anaplasmosis in some
cases, which can reduce fatalities (56, 58). Essentially similar though incomplete
figures were provided for N. American cattle (32).
The most important clinical manifestations of MCF are listed in Table I and
additional comments follow. Good colour plates of the visible lesions are to be
found in several publications (29, 80, 81).
TABLE I
The clinical signs of malignant catarrhal fever
(a)
(b)
(c)
(d)
Sudden, persistent pyrexia
Severe congestion, necrosis and erosion of nasal and oral mucosae
Serous, later mucopurulent, discharges
Scleral and conjunctival congestion; centripetal corneal opacity;
hypopyon
(e) Generalized enlargement of lymph nodes, etc.
(f) Muscular tremors (meningo-encephalomyelitis)
(g) Diarrhoea or dysentery (especially deer)
(h) Dermatitis and laminitis
(a) (e) The fever and lymphadenopathy in MCF
In typical "head-and-eye" cases caused by WD virus the pyrexia is of sudden
onset, reaching a peak of about 105° to 106°F (mean 105.5°) by the 3rd or 4th days
of the disease (56). Its onset is frequently used as an indicator of the end of the
incubation period, but a few observers also use local or general enlargement of
lymph or haemolymph nodes, which occasionally may be palpated 1-4 days prior to
fever in the WD form (11, 53, 56). However, lymph node enlargement was regularly
noted by others (52) as much as 5-10 days before pyrexia and the prefebrile clinical
signs, including lymphadenopathy, could last 2-7 days in N. American cattle (32).
A minority of experimental cattle infected with WD virus showed a biphasic res­
ponse, not attributable apparently to intercurrent infection; the first reaction was
usually at 4-7 days, lasted 2-3 days and reached a lower peak, not exceeding 104°F
(Plowright, unpublished). Such reactions were possibly related to an as yet undescribed generalization phase in the pathogenesis of the disease and are reminiscent of
the bimodal distribution of reaction times (peaks at 3 and 11 days, respectively)
noted in rabbits used for an SA transmission series (71).
In the experimental SA form a frequent delay of 2-3 days in the onset of
lymphadenopathy was recorded (51), whereas Selman et al. (81) noted enlargement
of nodes in 6/10 calves at 7 days post-infection, although the "incubation period"
was at least 20 days.
— 900 —
(b) (c) Congestion, necrosis and erosion of superficial mucosae and muzzle
These signs were recorded in the oral and nasal mucosae in the majority of cases
caused by WD virus (32, 52, 56), the time of first detection of oral necrosis being
given in Table II which shows a peak prevalence (100%) delayed to the 6th day of
pyrexia. In the naturally-occurring SA form, mucosal necrosis is noted less
frequently or is less severe in some outbreaks in cattle (31) or deer (13, 67), though
constant in others (80). In the experimental SA form the speed of development of
mouth lesions varies considerably in cattle, except for the early diffuse congestion
(81). Generally speaking, the development of marked lesions of the muzzle or oral
and nasal cavities is dependent on longer survival times, which are more character­
istic of WD cases and less prominent in the hyperacute or acute disease. Similarly,
whilst mucopurulent nasal and ocular discharges, together with excessive salivation,
are almost invariable in "head-and-eye" cases, they tend to develop less frequently
in those which run a shorter course.
TABLE II
The frequency and time of appearance of clinical signs
of WD-MCF in experimental cattle*
N o . of
animals
1
Cumulative % with lesion on given day of disease
2
3
4
5
6
>7
234
4
25
55
80
90
94
97
116
58
76
91
97
99
100
—
Corneal
opacity
Oral necrosis
and erosion
* From Plowright, 1964.
(d) The eye lesions in MCF
Conjunctival and scleral congestion are recorded in the great majority of SA
and WD cases, accompanied by a progressive centripetal opacity of the cornea, the
keratitis being accompanied by cellular and fibrinous exudates into the anterior
chamber — an iridocyclitis with hypopyon. Table II shows the time of appearance
of corneal opacity in over 200 cases of the WD form which were observed daily; the
frequency did not exceed 50% until the 3rd day of pyrexia.
(f) The nervous signs of MCF
Signs of CNS involvement, such as muscular tremors, incoordination, head
pressing, nystagmus, twitching of the ears, torticollis and even aggressive behaviour
have been reported at various times in the majority of species infected by the WD
or SA agents. The underlying meningo-encephalomyelitis is one of the most consis­
tent histopathological changes. During serial transmission of the WD viruses, ner­
vous signs apparently became less frequent (56).
(g) Diarrhoea or dysentery.
These manifestations have more recently come to the fore in cattle, deer and
rabbits infected with the SA agent and exhibiting a rapid course to death (13, 37,
38, 46, 67). Thus, for example, 8/16 experimental cases in a Colorado (USA) expe-
— 901 —
rimental series were classed as predominantly "intestinal" with a further 3 develop­
ing diarrhoea (52). However, in experimentally-infected red deer, diarrhoea did not
develop until the second or third days of fever, and dysentery about 24 hours later
(46). In the experimental WD disease the frequency is very low, less than 1% in
uncomplicated cases (56).
(h) Dermatitis and laminitis in MCF
The relative frequency of skin, hoof and horn lesions in MCF in Europe was
one of the early reasons for regarding it as different from S. African "snotsiekte"
(40). Severe congestion, with exudation and sloughing of the skin of the udder, was
observed in the USA in an SA outbreak (37). Dermatitis is certainly infrequent in
the WD form, only 2 cases being observed among several hundred experimental
cases in E. Africa; both were young calves, and only one case of laminitis was
detected (56). Exudation into the horn cores with loss of these appendages as well
as laminitis was recorded not infrequently in the older European literature. Arthri­
tis and synovitis have been recognized histopathologically in a majority of cases of
experimental and natural SA-MCF (36) but associated clinical signs are not usually
reported.
T H E P A T H O G E N E S I S OF M C F
The three essential components in the pathogenesis of MCF (55, 61) are:
1. A destruction of smaller lymphocytes, particularly those in the germinal folli­
cles of lymph and haemolymph nodes and in the thymus (14). Diffuse areas of
necrosis appear in some cases and karyorrhexis is marked, together with macro­
phage activation. It may be that the necrosis is a late event, coincident with the
onset of fever, as in rabbits infected with SA-MCF (65, 66).
2. A proliferation and infiltration in many tissues by large lymphoblastoid cells,
particularly around blood vessels and in T-cell dominated areas such as the interfollicular and paracortical areas of lymph nodes or periarterial sheaths in the spleen.
This lymphoproliferation is progressive through the incubation period but may not
be an essential component, as its prevention in rabbits by cyclosporin-A treatment
did not change the fatal course of infection (65).
3. An angiitis, affecting all components of the walls of arteries and veins. This is
irregularly segmental in distribution, most readily seen in medium-sized arteries,
such as those which abound in the capsule of the adrenal gland, in the carotid rete
and arcuate arteries of the kidney cortex. There is often a fibrinoid degeneration of
the medial elements with hypertrophy and lymphoid infiltration of the intima. Par­
tial occlusion of the vascular lumina is common, complete thrombosis leading to
infarction relatively rare. Particularly good descriptions of the vascular lesions are
given by Liggitt and others (33, 34).
Similar infiltrative and degenerative changes to those in blood vessels occur in
the capsule and trabeculae of lymph nodes and spleen, in perinodal connective or
adipose tissues and in the smooth muscle layer of hollow viscera. Changes of types
2 and 3 occur in the lamina propria and deeper layers of many mucosal surfaces
and the skin where they are associated with degeneration and necrosis of the surface
epithelia (35). They are often predominant in the supporting tissues of parenchyma­
tous organs such as liver, kidney and lungs, whose specialized cells may show dege­
neration and necrosis.
— 902 —
There is increasing evidence that these changes are primarily cell-mediated,
immunopathological events and this would be consistent with an extended but vari­
able incubation period, long prapatent viraemia associated with lymphocytes and
the virtual absence of viral cytopathology, antigens or virions in any of the lesions.
Suggestions that hypersensitivity to viral antigens, autoimmune (graft-v-host)
reactions or immune complexes are involved (61, 75) have not yet been substantia­
ted but the work of Reid and his collaborators in establishing the association of
MCF infectivity (SA and WD) with large, granular T lymphocytes possessing
cytolytic (NK) activity does offer a novel and credible hypothesis (65, 66).
EPIDEMIOLOGY
The epidemiology of both the SA and WD forms of MCF is essentially the same
world-wide. The great majority of outbreaks can be related to close contacts bet­
ween the reservoir species, sheep or wildebeest and the indicator hosts; the reservoir
animals show no clinicopathological evidence of infection although suspected MCF
in sheep has been reported recently (79). The reservoir hosts are not capable of
transmitting infection at all times, otherwise MCF would be a much more serious
problem. With very few reservations it can also be said that transmission by contact
between indicator hosts does not occur.
(a) Sheep-associated disease (SA-MCF)
After prolonged, sometimes acrimonious, exchanges during the 1930's about
the origin of MCF it was generally accepted that direct sheep contacts, during the
previous 6 months or so, could be established on the overwhelming majority of pro­
perties where multiple cases of MCF occurred, albeit spread over long periods. In
these cases removal of the sheep normally resulted in cessation of MCF within 3-4
months (Götze (16a) with whom was associated the dictum "ohne Schafe kein
Katarrhalfieber"). It was also shown convincingly, as on many later occasions, that
mixing known "carrier" sheep with cattle could lead to numerous cases of MCF
(12, 15, 17, 54, 83, 84). Others, such as Wyssmann (87, 88), were unsuccessful in
demonstrating sheep: cattle transmission. Wyssmann found that only single cases
were reported from 83% of affected farms, on 20-25% of which there could not
possibly have been any contact with sheep. In New Zealand, 95% of cases from
1974 to 1976 were single animals and sheep association was reported for 77%, with
no information on 12% (22). The basic questions about alternative hosts to sheep
have still not yet been answered and, furthermore, it has not yet been possible to
produce typical MCF in cattle by inoculating them with material from suspected
carrier sheep or other potential caprine reservoirs.
Several more recent publications have reiterated that infection of cattle or deer
is most likely during the sheep lambing season (21, 65, 66, 69) and the seasons of
highest incidence for cattle, often reported as late winter and spring to early sum­
mer in temperate zones, would be consistent with this hypothesis (e.g. 50). Others
have reported more cases in autumn and winter, as for example in Yugoslavia (80)
whilst, in Finland, the highest incidence amongst 335 cases, over 5 years to 1949,
was in summer (84). In South Africa SA-MCF was not related to season (1), where­
as in New Zealand the disease in deer is most frequent in mid-winter, i.e. June/July
(38, 65) and in cattle in September/October (22).
— 903 —
Numerous old references to cases of MCF which could not be related to direct
or indirect contacts with sheep (84, 87, 88) certainly necessitated an open mind on
the possible existence of other reservoirs, an increased need since the accession of
serological evidence for MCF infection in other species of the subfamily Caprinae
(64, 27). The most frequently positive species (>20%) appear to be in the ibex
varieties (Capra ibex spp.), moufflon sheep (Ovis orientalis), Barbary sheep
(Ammotragus lervia), markhor (Capra falconeri heptneri) and Himalayan tahr
(Hemitragus jemlahicus), all in the subfamily Caprinae, and the chamois (Rupica­
pra rupicapra) in the subfamily Rupicaprinae. Until the herpesviruses present in
these species have been characterized, it is too early to judge their significance.
Equally well, it is necessary to accept that intermediate contagion could play a
role in transmission from sheep to cattle or deer (67) and there is also some evi­
dence that the infection may, unusually, spread amongst highly susceptible deer by
contact (38, 71), but the evidence for this in cattle is absent or unconvincing (37).
(b) Wildebeest-derived (WD) MCF
WD-MCF has long been known as a menace to cattle owners in Africa (60, 61).
The strains of agent studied by important earlier workers (11, 40, 53) were all pro­
bably derived from wildebeest and had the advantage over SA "viruses" that they
were easily transmissible, both to cattle and rabbits. Except in one case (40), how­
ever, proof of the species of origin was lacking. The recovery of a herpesvirus from
5/35 blue wildebeest in Kenya in 1959/60 proved the role of this species as a reser­
voir, confirmed the ready transmissibility of the agent and showed its limited cytopathogenicity and strictly cell-associated infectivity in cell cultures and intact hosts
(62).
Similar viruses are apparently universal in populations of blue and black wilde­
beest, whether in Africa (1, 19, 60, 61) or in zoological collections (9, 27). Small
groups of animals ( < 10) can probably maintain the viruses indefinitely, since there
is long-term persistence in at least some individuals and transplacental transmission
has been demonstrated (9, 28, 62). Young wildebeest, if not congenitally infected,
acquire the virus by horizontal spread in the annual calf crop, in spite of the pre­
sence of maternal neutralizing antibody. They develop a leucocyte-associated viraemia which is most frequent (40% positive) in the second month of life, declining to
2% by the end of the first year and which is very infrequent thereafter (61). There is
no good evidence for clinical signs or a virus-associated pathology in viraemic wilde­
beest, though it was suggested that a vasculitis found in a yearling or adult animals
was similar to that in MCF (8).
The maximum annual incidence of WD-MCF in cattle is probably of the order
of 7% in Kenya Masailand, concentrated in the months of April to July, following
the wildebeest calving in February to April. The times are earlier but comparable in
Tanzania but in southern Africa it is not clear whether peak cattle transmission
(September to December) is associated with the wildebeest calving (1). In individual
herds the incidence of WD-MCF cases in a single season may reach 13-20% (1, 56).
When viraemic wildebeest calves were housed experimentally with cattle they
developed MCF after maximum incubation periods of 30-47 days in 4/5 cases, 81
days in the fifth case (61): this corresponds closely with delays of 29, 68 and 82 days
in the death from MCF of 3/4 banteng (Bos javanicus) exposed to newborn wilde­
beest in the San Diego Wild Animal Park (18). The cell-free herpesvirus is excreted
— 904 —
as early as one to four days (28, 43), both in the ocular and nasal secretions and was
recovered once from faeces (28) but not in urine or saliva. The titre, particularly in
calves 6-8 weeks old, may be > 10 TCD /ml, probably derived from sites of
replication in the cornea and turbinate mucosa; after 3 months of age the secretions
contain neutralizing antibody, predominantly IgA, which accounts for the rapid
decline in virus shedding and cessation of lateral transmission (43, 61).
3.2
50
Excretion and transmission of MCFV to cattle by adult wildebeest has occurred
under experimental conditions — housing and exposure to heat stress (Plowright,
unpublished), but attempts to reproduce the phenomenon failed. The nasal and
oral secretions of infected cattle do contain MCF infectivity but this is probably in
cell-associated form (32, 44) and contact transmission in this species does not occur
or is very rare (11, 12, 58). Similarly, deer-to-deer transmission of WD-MCF was
not observed (85).
Although "close contact", particularly on common grazing or on housing to­
gether, is generally regarded as necessary for the transmission of the WD virus from
the reservoir host, there are now several accounts of apparent transfer across fences
or even at distances of up to several hundred metres, i.e. direct contact is not essen­
tial (1, 37, 89). The route of entry of virus is probably by the nasopharynx, as intra­
nasal instillation of infectious cell suspensions, or virulent cell-free virus, leads read­
ily to infection in cattle and rabbits (61); aerosols are also successful. Hence, trans­
fer in air currents seems more likely than intermediate contagion and oral uptake of
virus.
(c) Other potential sources of MCF viruses
Work in Africa (61) established that antibodies which neutralize WD-MCFV
(alcelaphine herpesvirus 1 or AHV-1) are by no means limited to wildebeest. Sera
from hartebeest (Alcelaphus buselaphus), topi (Damaliscus korrigum) and fringeeared oryx (Oryx beisa callous) were all found to be frequently positive. In addi­
tion, strains of herpesvirus were isolated from free-living hartebeest and topi (45),
which were serologically related to AHV-1. One of four of the hartebeest isolates
(AHV-2) was shown to be slightly different in that wildebeest sera neutralized it to
lower titre than AHV-1. The hartebeest viruses produced MCF in cattle, in three
cases atypical, whereas the topi isolate, also cell-associated, grew only in topi cells
and was not infectious for cattle or rabbits (see 61). Similar viruses have been isola­
ted recently from the Cape hartebeest (Alcelaphus buselaphus camaa) and Jimela
topi (Damaliscus lunatus jimela) in the USA (27).
The ultimate objective of the African studies was to obtain an MCF-related
virus which would immunize cattle against AHV-1 in the same way that turkey herpes­
virus is used as a vaccine against Marek's disease, but in this they have, so far, failed.
The recent surge of interest in MCF in the USA, especially in zoological collections, has
led inter alia to serological surveys of many species (26, 27, 64). The methods used have
included indirect immunofluorescence, which gives an essentially "group-specific"
reaction for MCF viruses and also cross-reactivity with some bovine herpesviruses (25,
61, 75). The most discriminating antibody is that neutralizing the virus and Tables III
and IV show, predominantly, results obtained by its detection. Details of the test virus,
conditions of exposure of virus-serum mixtures, and the culture system used for assay,
vary considerably and may account for some anomalies. The methodology should
surely now be standardized as soon as possible.
— 905 —
TABLE III
Antibody to alcelaphine herpesvirus 1 in the subfamily Alcelaphinae
Sera positive for antibody (titre range)
Common name
(1)
(2)
(3)
(4)
—
Connochaetes
taurinus
Blue wildebeest
(white-bearded)
23/23*
111/120
(4-256)
33/54
(2-256)
Connochaetes
(gnu)
Black wildebeest
(white-tailed)
—
—
4/11
(12-256)
Alcelaphus
buselaphus
Hartebeest
124/206
0/1
9/20
(4-256)
14/22
Damaliscus
korrigum
Topi
25/62
0/20
—
-
Damaliscus
lunatus
Tsessebe or Tiang
—
26/72
(4-16)
7/14
(2-128)
—
Damaliscus
dorcas
Blesbok
-
0/3
4/16
(2-6)
—
30/46
* No. positive/No. tested. Neutralizing antibody except for (4).
(1) Reid et al. (1975), Res.
et al. (77) - 131/133.
vet.
Sci.,
18, 269-273. See also Plowright (57) - 172/181 and Rossiter
(2) Hamblin and Hedger (19).
(3) Heuschele et al. (27).
(4) Ramsay et al. (64). Results are for IIF tests only on sera diluted 1:20.
Table III summarizes the results to date for species in the subfamily Alcelaphi­
nae. Two viruses, one from blue wildebeest, the other from a hartebeest, have been
provisionally designated alcelaphine herpesviruses 1 and 2 (72). At least three spe­
cies in the genus Damaliscus (topi, tsessebe, blesbok) show evidence of infection
with related viruses; many topi had neutralizing antibody, even when they had not
been exposed to wildebeest.
In the subfamily Hippotraginae (Table IV) there is also widespread evidence of
infection with MCF-related herpesviruses in the Addax and Oryx spp., including
the gemsbok of southern Africa (1) and the Arabian oryx. VN antibodies were
found in all of fifty fringe-eared oryx sera in Kenya, but it was not possible to iso­
late a virus from them (41); more recently, Heuschele et al. (27) reported isolation
of an MCF-related agent from a healthy scimitar-horned oryx (O. gazella dammah)
in San Diego. There is contradictory evidence for the roan and sable antelopes
(Table IV) but recent confirmation of the involvement of the latter is now available
(1). The Waterbuck, reedbuck and kob species, sometimes regarded as a separate
subfamily, the Reduncinae, rather than a tribe, may also be infected, but some work­
ers have encountered difficulties with cytopathogenicity of sera from these species.
The occurrence of neutralizing antibody (low-titre) in free-living members of the
families such as Antelopinae and Hippopotamidae (19) as well as several others in
zoological collections (27) requires further investigation.
— 906 —
TABLE I V
Antibody to alcelaphine herpesvirus 1 in the subfamily Hippotraginae
Sera positive for V N antibody (titre range)
Species
Common name
Oryx gazella
beisa
Fringe-eared or
Beisa oryx
O. gazella
gazella
Scimitar-horned
oryx
O.
O.
leucoryx
Arabian oryx
gazella
Gemsbok
Hippotragus
equinus
Roan antelope
Hippotragus
niger
Sable antelope
Addax
nasomaculatus
Addax
Redunca
redunca
(arundinum)
Reedbuck
Kobus
defassa
(2)
(3)
(4)
3/3*
1/5
(0-2)
—
—
—
55/102
(2-256)
—
—
—
12/19
(2-48)
—
—
—
30/46
(2-256)
13/16
(4-45)
0/18
3/14
(2-6)
0/14
kob
33/211
(4-32)
—
0/14
5/22
(8-16)
0/15
4/23
33/73
(2-160)
Defassa Waterbuck
Kobus
ellipsiprymnus
Adenota
(1)
5/7
7/7
(128-708)
0/18
Ringed Waterbuck
—
—
11/11
(45-1024)
—
Uganda kob
0/12
6/19
—
—
* N o . positive/No. tested. Neutralizing antibody except for (4).
(1) Reid et al. (1975), Res. vet. Sci., 18, 269-273.
(2) Heuscheie et al. (27).
(3) Hamblin and Hedger (19).
(4) Ramsay et al. (64). Results for IIF tests only, on sera diluted 1:20.
It must be emphasized that only wildebeest can yet be incriminated as a source of
MCF for cattle or other susceptible, exotic ungulates. The additional carriers of
MCF-related viruses can apparently be grazed or even housed together with indicator
species with impunity. It should also be borne in mind that any disease induced by
herpesviruses which are harboured by species other than wildebeest, could be atypical
as well as infrequent, and might well have passed unrecognized. The most interesting
epidemiological and virological question is how these viruses have evolved and diverged
in the rich bovid fauna of subtropical Africa.
— 907 —
(d) The range of indicator species of MCFV
All breeds of cattle and domestic buffaloes are susceptible, at all ages, to MCF;
some data suggest a higher incidence in yearling beef cattle in New Zealand (22).
It is evident from the expanding literature that the number and diversity of species which can develop more or less typical MCF, in the clinicopathological sense, is
continually increasing (24, 60, 65). In recording cases, a differentiation should
always be made, where possible, between those probably or certainly derived from
alcelaphine, as opposed to caprine, reservoir species, as the respective indicator
host ranges of the agents may vary. It is now relatively easy to confirm the presence
of several alcelaphine MCF viruses in the laboratory, even if the caprine members
are still virtually impossible to identify. Secondly, if a species is a putative or proven reservoir host it seems unlikely that it would develop MCF in response to infection. For example, it has sometimes been claimed that sheep developed signs of the
disease when infected with presumed SA-MCF and naturally-occurring cases have
been reported (79). The evidence was by no means convincing, except perhaps in
the case of four lambs inoculated in utero (4). Whilst varying accounts of the susceptibility of sheep to AHV-1 have been published, it may be that different breeds
of sheep or different inocula and routes of infection account for the discrepancies
reported and their susceptibility is more plausible (61). It is also surprising that an
Arabian oryx was reported to have died of MCF in San Diego (24).
Judging from the frequency of cases reported in zoological collections, the species most susceptible to AHV-1 disease are probably the Asiatic wild cattle (24), Bos
javanicus (the banteng) and B. gaurus (the Indian gaur), also the N. American and
European bisons (Bison bison and B. bonasus). Some African antelopes, the kudu
(Tragelaphus strepsiceros) and the sitatunga (T. spekei) are certainly susceptible
and the Asian nilgai (Boselaphus tragocamelus). The Cervidae also appear to be
much more susceptible than cattle to SA-MCFV (65, 69), or to AHV-1. Severe outbreaks of SA-MCFV affecting sika, axis, Père David and red deer have been reported whilst Rusa, Barasingha and roe deer have now been added to the list (24, 65,
71). It has even been suggested that there could be ecological advantages for sheep
and some antelopes in carrying viruses so pathogenic to their competitors (65). It is
particularly significant that some of these taxa, Père David deer and European
bison, for example, are "threatened species", which should never be subjected to
the threat of MCF from known reservoirs.
C U L T I V A T I O N OF T H E A G E N T OF SA-MCF
Numerous attempts over many years to cultivate the agent of SA-MCF by
methods successful for the alcelaphine herpesviruses, yielded several candidate viruses, none of which would, however, reproduce the disease. The most important
recent discovery in respect to SA-MCF has been the cultivation by Reid and collaborators of lymphoblastoid cell lines from rabbits, deer and cattle infected with the
agent. The sequence of events, as described by Reid and Buxton (66) was briefly as
follows:
The first, MF120, line was propagated by co-cultivation of fetal ovine kidney
cells and rabbit lymph node cells, treated with polyethylene glycol. The kidney cells
degenerated, whilst refractile, rounded cells appeared in the fluid phase and had the
morphological and functional characteristics of large granular lymphocytes (LGL) or
— 908 —
natural killer (NK) cells. They carried " T " cell antigens and Fc receptors, were of
rabbit karyotype, required "feeder" cells for replication, were cytotoxic to cultured
primary cells or established cell lines and, most importantly, were shown to carry
MCF infectivity on inoculation into rabbits in a dose down to 10- .
2
Similar lymphoblastoid cell lines were later cultivated directly from the cere­
brospinal fluid of lymph nodes and cornea of cattle and deer affected by SA-MCF
but these did not reproduce disease on subsequent inoculation into cattle, deer or
rabbits. Similar cells were also cultivated from rats infected with AHV-1, after rab­
bit passage, but again failed to reproduce the disease on return to rabbits or cytopathic effects in permissive cell cultures. These rat cells induce lymphoproliferative
disease in weanling rats and were remarkable in not requiring a feeder layer (70).
Not only do these lines of LGL/NK cells lack infectivity for MCF-susceptible hosts,
they exhibit no electron microscopical evidence of herpes or other viruses and no
viral antigens can be demonstrated in them or on their cell membranes by immuno­
fluorescence using AHV-1 antisera (66, 68). It was suggested that MCF cell lines
were similar to lymphoblastoid strains cultivated from tissues of marmosets infec­
ted with Herpesvirus ateles and H. saimiri, which are also lymphoproliferative
agents in unusual hosts; in these cases only a small proportion of the viral genome
(27%) is essential to maintain transformation. It is proposed that the MCF lines
may have a similarly small proportion of the total viral genome which is inadequate
for expression of viral antigens and, usually, for infectivity in any available system.
Reid and Buxton (65, 66) summarized their hypothesis as proposing that
LGL/NK cells are a prime target for MCF virus replication; NK cells appear in
significant numbers only after the onset of clinical disease in rabbits and lead to the
characteristic lymphoproliferative disease, probably by inducing a benign and poly­
clonal T-lymphocyte hyperplasia, either by production of abundant interleukin 2
and/or by suppression of T-helper-cell function. The necrosis of cells, including
that of lymphoid elements and those in vessel walls would, according to this hypo­
thesis, be due to direct cytotoxic action of the proliferating NK cells.
The proposal is a very attractive one in providing an explanation of an other­
wise puzzling and controversial pathogenesis (61, 75). It appears to fit the facts bet­
ter than a proposal that, as some of the features of MCF viruses are obviously simi­
lar to those of other gamma-herpesviruses, MCF should also be regarded as an
infectious neoplastic disease along with Marek's disease, for example (30). The pre­
sence of a small fraction only of the viral genome in LGL/NK cell lines may also
account for the variable, but always severe, difficulty of transmitting SA-MCF
from cattle or deer to other deer and rabbits (71) and would not conflict with the
suggestion that the viral DNA may be integrated with the cell genome or present in
episomal form (30).
There are no indications at present as to how the "virus of M C F " is maintained
in or excreted by sheep; fully productive infection of superficial cells is presumably
required to make possible transmission to indicator hosts, however infrequent this
may be in contrast with the widespread infection of sheep.
T H E RELATIONSHIP B E T W E E N SA A N D W D FORMS OF MCF
All observers are agreed that it is not possible to differentiate the SA and WD
forms of MCF on clinicopathological criteria and their epidemiology is also essen-
— 909 —
tially similar. There is increasing evidence that SA-MCF will eventually be shown to
be due to a herpesvirus related to but not identical with AHV-1 (27, 66). Significant
data are as follows:
(a) Antibody (IIF) titres against AHV-1 in sheep from many countries were
comparable to those in wildebeest, but there was no significant neutralizing acti­
vity. Congenital infection was suggested by the detection of antibody in gnotobiotic
and colostrum-deprived lambs (73).
(b) Neutralizing antibody was found fairly frequently in species of the subfamily
Caprinae, including domestic sheep and goats in the USA [see Epidemiology, (a)].
Titres were low, except in the Barbary sheep, Ammotragus lervia. It was also repor­
ted that antigens reacting with AHV-1 antisera could be demonstrated by immuno­
fluorescence in the circulating leucocytes of some caprines (27). In the United
Kingdom 86/508 (17%) sheep sera from 13 flocks showed VN antibody for AHV-1,
with titres between 1:2 and 1:32 (20).
(c) Using AHV-1 antigens in Western blot tests, it was shown that all sheep sera
reacted with some of the same bands that were produced by wildebeest sera (66).
Unfortunately, attempts with bovine antisera to demonstrate AHV-1 related anti­
gens, by immunofluorescence, in cultured lymphoid cells or in rabbit tissues
carrying SA-MCF infectivity, have failed. However, it is also very difficult to show
specific fluorescence in animal tissues infected with the homologous agent, except
following their in vitro cultivation and putative derepression of viral protein synthe­
sis (see 61, 66, 75). The results of applying radioactive probes developed from the
DNA of AHV-1 are eagerly awaited.
(d) In the course of SA-MCF, cattle from Europe, the USA and Australia fre­
quently showed rising titres of IIF antibodies specific for AHV-1, but this finding
was not invariable in the United Kingdom and it was suggested that an antigenetically different agent may sometimes be involved (20, 74).
T H E D I A G N O S I S OF MCF
(a) Clinicopathological diagnosis
The majority of cases of MCF, whether of the SA or WD forms in cattle, deer
or exotic ruminants, can be readily recognized from the clinicopathological features
(see previous sections). Hyperacute cases, which are not infrequent in some of the
species of deer, may not arouse suspicion because the characteristic discharges,
necrosis of mucosae, skin and eye lesions, diarrhoea or dysentery, may all be
absent; nevertheless, typical histopathological changes may still be present.
The gross and histological features have been described in detail many times
(for the WD form, see 11, 32, 40, 52, 55, 56; for the SA form, see 34, 35, 36, 52,
80, 81). In the case of SA-MCF, diagnosis primarily on clinicopathological grounds
is still essential, as no methods for isolation or demonstration of the causal virus(es)
have yet been developed. The demonstration of rising antibody (IIF or IIP) titres to
AHV-1 can be helpful but this does not occur regularly (see above).
(b) Laboratory confirmation of diagnosis
As there are extremely few cells in infected animals which exhibit immunofluorescing antigens with AHV-1 antisera and SA-MCF antisera have not been developed,
— 910 —
such methods have not generally been found to be of diagnostic value (61, 75). The
claim (26) to have demonstrated MCFV antigens by direct immunofluorescence in
smears of peripheral blood leucocytes from diseased or "carrier" (caprine) ani­
mals, using serum from a chronic AHV-1 infection in a sika deer, is interesting but
not yet corroborated.
The development of antibodies to AHV-1 has, however, proved useful in follow­
ing experimental infections and is potentially useful in diagnosis of clinical cases.
Antibodies usually appear during the incubation period or the early clinical phases
and prior to the almost invariable death; the most useful techniques are indirect
immunoperoxidase (IIP) or indirect immunofluorescence (IIF) using appropriate
anti-IgG reagents (61, 75). Nevertheless, Heuschele (25) did not find IIF was often
of value. Complement-fixation methods were also useful but immunoprecipitation
and immunoelectrophoresis were not found successful in cattle (61, 75). The speci­
ficity of immunohistochemical techniques for antibody has been questioned and
investigated (24, 25, 27, 78); there are undoubtedly cross-reactions with other bovid
herpesviruses, especially BHV-1 (IBRV) and BHV-3 (BCMV) but titres are usually
much lower with heterologous sera. As would be expected, there are similar indica­
tions of broad specificity using ELISA tests, as for IIP or IIF.
The main application of serological techniques in MCF research has been in epi­
demiology and VN tests, which were the first to be developed (42, 67) and which
remain the most specific and economical for investigating the distribution of MCF
viruses in reservoir species, whether in zoos (26) or free-living populations (19).
However, increasing evidence for antigenic (VN) relationships between SA
(caprine)-MCF herpesviruses and the alcelaphine agents has now blurred the divi­
sions between the two groups and much more work is necessary on the relevant epi­
topes using monoclonal antibodies and molecular virological techniques.
Earlier recommendations for the diagnosis of MCF by virus recovery (58, 59,
60) stressed those characteristics of WD-MCF viruses which are important in the
collection and handling of materials from suspected cases. Firstly, virtually all
infectivity in blood or tissues is associated with intact, living cells and is lost imme­
diately on cell death. Secondly, virus infectivity is associated predominantly with
lymphoid cells. Washed blood leucocytes (buffy coat fractions) can be readily pre­
pared from live animals, for inoculation into susceptible cell cultures, especially
monolayers of primary and secondary bovine thyroid (BTh) cells, which exhibit
foci of a characteristic cytopathology within 18-21 days. Lymphoid tissues collected
at death, or within 2-3 hours of this, should be lymph nodes, possibly thymus or
spleen; these and also leucocyte suspensions should be treated to retain cell viabi­
lity, i.e. dispersed in a manner to avoid cell damage, stored at about - 4 ° C (not
frozen) in a nutritive, serum-containing medium and inoculated as soon as possible,
certainly within 3-4 days, into animals or cell cultures. Alternatively, suspensions
may be stored at or below - 7 0 ° C , provided that 10% DMSO or other cryoprotectant is used but some loss of infectivity occurs in the freezing process. Oliver et al.
(46) reported retention of infectivity in 10% suspensions of deer (SA-MCF) lymph
node stored for 8 months at - 7 0 ° C without cryopreservatives, but this was very
exceptional. The stage of disease for collection of bovine, WD-MCF materials is
immaterial as the titre of blood or lymph nodes is nearly always in excess of 10
TCD /ml or 10 TCD /g, respectively (56, 61).
2
3
50
50
The difficulty in producing adequate quantities of BTh cells led to attempts to
use serially-passaged strains of calf (BK) or bovine embryonic kidney (BEK) cells,
— 911 —
especially for in vitro passage of virus isolates, for immunofluorescence tests and
for production of cell-free virus for virus characterization and neutralization (42,
60, 61, 78). It was difficult, however, to maintain a passage series in BK cells using
released virus as an inoculum. Strains of calf testis (BT) cells were later found to be
highly sensitive for the detection and assay of infectivity in animal tissues and pro­
duced high titre cell-free, infectious virus (up to 10 TCD /ml), even in early passa­
ges (48, 49, 60). Infected bovine (calf) blood and lymphoid tissues assayed in tube
culture of BT cells gave infectious centre counts up to about 10 /ml and 10 /g, res­
pectively, figures which are comparable to or greater than those obtained by simul­
taneous titration of similar materials in cattle and in calf thyroid monolayers (56).
In addition, cytopathic foci are more easily detected in BT cells, as the syncytia
exhibit long refractile processes and generalize rather than regress or even disap­
pear, as happens in BTh, BK or BEK cells; the differences are presumably due to
the early production of cell-free virus in BT cells (Plowright and Watt, unpub­
lished; 48).
5
50
3
6
The ease with which BTh and BT cells, in particular, can be used for direct
quantitative recovery of MCFV infectivity from animal tissues or from wildebeest
secretions (43) contrasts with the experiences of N. American workers (6, 7, 25)
who used BTh and BEK cells and concentrated inocula but reported syncytia with
intranuclear inclusions usually after the second, or even up to six subcultures. Two
procedures were advocated to overcome the difficulties. Firstly, inoculation at 3234°C was employed, a procedure first shown in E. Africa to increase the speed of
appearance and amount of cell-free virus in culture fluids and change the predomi­
nant cytopathic effects from syncytium formation to rounding and refractility of
affected elements (21). Secondly, fusion of suspect cell suspensions with permissive
cells by polyethylene glycol (PEG; MW 1000-4000) has been recommended (8, 9).
Again, the use of a cell strain (FAK) derived from fetal aoudad (barbary sheep) kid­
ney has been advocated (25, 26), but no data have been provided on the relative
sensitivity of this cell as opposed to those previously employed for detection and
assay of AHV-1 infectivity in animal tissues. BTh or BT cells give rapid results,
positives being seen in unstained cultures within 3-4 days of inoculation of blood
leucocytes from sick cattle.
One reason for the reported differences between N. American and other work­
ers, in the recovery of alcelaphine herpesviruses, could be a preoccupation of the
former with supposedly low titre materials and the real difficulty of detecting cyto­
pathic foci before they regress in BTh or BK cells. This has led to the use of large
inocula whether of buffy-coat or lymphoid tissue suspensions. Both of these latter
in high concentration were found to suppress cytopathic effects, in addition to
lymph node producing cytotoxic effects (56). The suppression may be partial or
complete and has been investigated again recently by assays of infected bovine
lymphoid tissues in a sensitive line of calf testis cells (BT11) (Plowright, unpub­
lished). Typical results are shown in Table V, which indicates that washing the cells
3 times (in serum saline) did not remove the inhibitory factor, which was detectable
down to a w/v dilution of 1:500 (10- ); secondly, subculture of apparently nega­
tive tubes at the lower end of the titrations gave positive results in a proportion only
and added very few positives at the upper end of the titration. The inhibitory factor
was not reduced by the removal'of plastic-adherent cells from the infected suspen­
sions and was not demonstrable in high-speed supernatants of crude, infected
lymph node suspensions. Normal calf lymph node suspensions did not show the
effect, which thus appeared to be mediated by non-adherent cells in infected nodes
and not by antibody or other soluble factor.
2.7
— 912 —
TABLE V
Titrations of calf lymphoid tissue for MCFV (C.500 isolate) in tube cultures
of the BT11 strain of bovine testis cells*
Crude Ten Broeck suspension.
Cytopathic effects at day 19
Dilution w / v of
lymph node
101 0
1.2
-2.0
1010
10
2.7
- 3 . 4
-4.1
10-4.8
5.5
10Titre (log TCD )
10
50
Washed ( X 3) cell suspension.
Cytopathic effects at day 19
(a) Primary
inoculation
(b) First
subculture
(a) Primary
inoculation
(b) First
subculture
0/5
0/5
0/5
5/5
5/5
4/5
0/5
10 /g
ND
4/5
3/5
ND
ND
5/5
0/5
10 /g
0/5
0/5
2/5
5/5
3/5
1/5
0/5
1/5
2/5
4/5
ND
4/5
2/5
0/5
5.08
5.15
10
4 . 3 8
/g
10
4 . 5 9
/g
* The cells were in their 16th in vitro passage. Cultures received 1 ml of inoculum, which was removed
after 2 hours at 37°C by washing twice with serum saline. Subculture of negative tubes was carried out
on the 19th day by mixing versenised cells with clean cell suspensions and dispensing into 5 tubes.
The identification of cytopathogenic isolates as WD-MCF herpesviruses is read­
ily made by IIF or IIP using specific antisera prepared in cattle or rabbits. There is
a need for standard antisera from animals not previously exposed to other bovid
herpesviruses, a need certainly not met by one proposed "international reference"
(2). Neutralization tests can be performed as soon as cell-free virus is available — a
process accelerated by incubation at 32° - 34°C and the use of bovine testis (BT) or
fetal caprine (FAK) cells (21, 25, 60). Virus neutralization may well distinguish
some members if reciprocal quantitative tests are performed, but crossneutralization of AHV-1 by some caprine sera argues for very broad antigenic rela­
tionships. Electron-microscopical examination of cultured cells can be used to sup­
plement observations on the cytopathology in unstained or in fixed and stained pre­
parations (5). In addition, parenteral inoculation of infected cultured cells into rab­
bits, cattle or deer may produce the disease, but not all alcelaphine viruses are
pathogenic (61).
The differentiation of alcelaphine, hippotragine or caprine MCF viruses by
serological or biochemical methods is in its infancy. Gradient centrifugation of
DNA from AHV-1 gave two peaks similar to those (M and H) of Herpesvirus sai­
m i r i and H. ateles (25). Restriction endonuclease patterns of AHV-1 viral DNA
show a clear separation from the homogeneous BHV-4 isolates (bovine cytomegalo­
viruses) and minor differences between the high-passage, low-virulence, WC11
strain and the virulent C500 isolate or a black wildebeest isolate (23, 47). The clon­
ing of restriction fragments of AHV-1 into four vectors opens up the prospect of
probes to investigate its relationship to SA-MCF (3).
THE CONTROL
OF MCF
All forms of the disease can, of course, be prevented by avoiding contacts bet­
ween reservoir and indicator species, especially at times when the former are producing
— 913 —
offspring. In practice, this can be difficult in some parts of Africa where there are
no stock-proof fences and thousands of wildebeest competing with cattle for graz­
ing and water. The occasionally catastrophic results of allowing cattle and other
susceptible species to have close contacts with sheep and possibly other caprine
reservoirs, emphasize the desirability of separating the two classes of host.
In the case of zoos and ranches with mixed exotic species, especially those threat­
ened with extinction in the wild, it has been advocated recently that routine serolo­
gical testing should be employed to avoid introduction or movement of potential
carriers of virus and that notification of cases of MCF should be mandatory. It is
also advocated that hand-rearing of calves of reservoir species, such as wildebeest,
should not be undertaken to avoid the particular risks from these high-level excretors (24, 26, 64).
In those parts of Africa where cattle share the grazing with large herds of wilde­
beest, particularly in the Masailands of E. Africa and in Botswana, MCF vaccina­
tion could be an attractive alternative to restriction or elimination of the game.
Attempts to develop attenuated vaccines (58, 61, and Harkness J.W., personal
communication) or killed virus vaccines (75) by empirical methods have, so far,
been a failure or of limited success, although they were antigenic.
Much further work on the molecular immunology and virology of MCF will be
necessary before a suitable product is likely to emerge and the economics are not
attractive; furthermore, the possibility of superinfection with wild virulent viruses
and congenital infection of the offspring has to be borne in mind (63).
*
**
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