Pathogenesis of Transboundary Animal Diseases
Corrie Brown, DVM, PhD, DACVP
University of Georgia, Athens, GA (corbrown@uga.edu)
Transboundary animal diseases are defined as those diseases capable of causing
significant economic and social upheaval1. In the US, we have long called these “foreign
animal diseases” but more recently we are adopting the more politically acceptable term,
and the one used by the rest of the world, “transboundary animal diseases.” Below is a
brief review of some of these diseases.
Foot-and-mouth Disease (FMD):
From an economic perspective, FMD is the most important animal disease in the world.
The financial impact of an FMD incursion in an exporting country can be monumental.
The disease itself has a low mortality rate but an incredibly high morbidity rate. FMD is
one of the very few infections that is truly aerosol in nature. Animals exhale the virus in
large quantities and infection in neighboring animals is ensured.
The earliest cells infected are in the lymphoid tissues of the nasopharynx2. Replication
here and also to some extent in the lung creates an aerosol and also engenders a viremia.
Once in the bloodstream, the virus is picked up by Langerhans cells travelling to the skin.
Stratum spinosum cells in thick non-haired epithelium are very permissive for FMD so
when the infected Langerhans cells settle in these types of epithelium, virus gets passed
along to every stratum spinosum cell the Langerhans processes contact. The virus is very
cytolic. As a result, a whole raft of cells in the middle of these thick non-haired epithelial
sites falls apart and the result is....a vesicle. So any thick non-haired stratified squamous
epithelium is where vesicles may occur, which would iniclude coronary band, interdigital
cleft, tongue, hard palate, and, for swine, snout.
The vesicles will coalesce, producing bullae that rupture easily, leaving an ulcerated
epithelial surface. In cattle it is not uncommon for the epithelium of the tongue to slough
in a large sheet and in swine for the entire claw to detach as a result of the severe
ulcerations. Lesions on the tongue heal rapidly through re-epithelialization but lesions on
the feet tend to become complicated through secondary infection, delaying the healing
process.
Rift Valley fever (RVF):
Rift Valley fever in ruminants is predominantly a liver disease. The virus has a definite
tropism for hepatocytes. Virulence of the virus stems from the nonstructural protein NSs
which blocks type I interferon production and also shuts off transcription3. The younger
the liver, the more severe is the damage. Adults might not be adversely affected at all,
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the newborns might have some icterus, but in the fetuses, livers can be completely
necrotic. The virus also infects and damages trophoblasts, and between the fetal liver
infection and the placentitis, the fetus dies and is expelled.
Usually RVF presents in outbreak form and this requires some understanding of climate
and vectors. The virus can survive for years in the dried eggs of Aedes mosquitoes. The
female Aedes mosquito lays her eggs in a wet area, then that area dries, and the eggs can
survive for many dry years. Then, if there are some heavy rains, the eggs might hatch,
and the hatched Aedes mosquito, which contains viable Rift Valley fever virus, moves to
find a blood meal nearby, often in a ruminant. Ruminants, even those that do not show
any remarkable illness, develop an extremely high viremia with the Rift Valley fever
virus. The viremia is high enough for any mosquito, not just Aedes, to take it from one
animal to another. Culex spp. mosquitoes, which are quite abundant, will pick up the
infection, and although the virus is not vertically transmitted in this mosquito, it becomes
a very capable vector. Once numerous mosquitoes are infected, sooner or later some will
feed on humans, many of whom will become ill, making RVF a serious public health
problem, in addition to its effect on livestock.
Peste des petits ruminants (PPR):
Peste des petits ruminants virus is to small ruminants what rinderpest is (was) to cattle.
The viruses of the two diseases are very closely related, and pathogenesis is similar.
Currently PPR is spreading extensively throughout Asia, and threatens to become a
global pandemic.
Infection occurs via droplet inhalation/ingestion. The virus, a morbillivirus, is not
particularly hardy in the environment, and so spread requires relatively close contact
among animals.
The virus is able to enter lymphocytes and certain types of epithelial cells4. Initial
replication is at the lymph nodes draining the naso- and oro-pharynx, then there is
viremia, with virus entering epithelial cells of the intestine and lung. The intestinal phase
tends to be severe in younger animals, probably because of the slower turnover rate of the
enteric epithelium. The PPR virus enters and replicates in both crypt and villus cells.
Damage is especially severe in the parts of intestine associated with lymphoid tissue
because there is augmented viral presence here.
At the same time the virus is replicating in and damaging the intestine, it is also infecting
cells at the bronchiolo-alveolar junction, beginning a bronchointerstitial pneumonia. So
animals that survive the intestinal phase of the disease often succumb to a pneumonia.
Morbidity and mortality with PPR are both fairly high. This disease is a major problem
for sheep and goat farmers/herders.
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Newcastle disease (ND):
Newcastle is a widespread and severe disease of poultry, causing threats and problems for
smallholders and commercial farmers alike. It has a global distribution, with notable
exceptions being selected developed countries.
Infection occurs via droplet inhalation/ingeston. The virus, a paramyxovirus, replicates
very well in macrophages. So, from its entry at the oro-nasopharynx, virus replicates
initially in the lymphoid areas of the region – conjunctiva, caudal pharynx, and Harderian
gland. Then there is a viremia with involvement of all lymphoid tissues - Peyer’s
patches, spleen, bursa, thymus, and bone marrow.
Macrophages systemically are permissive for replication, ND virus grows to large
amounts in the cytoplasm of these cells, and the cells become very activated, spewing
abundant quantities of cytokines that promote innate immunity5. The result is necrosis,
with associated hemorrhage, of all the lymphoid tissues, and the birds have pronounced
depression and are acutely ill. The virus also has a tropism for CNS neurons and
astrocytes, but it takes longer to become established in these cells. But if birds survive for
more than 3 or 4 days, there will be pronounced neurologic signs.
Newcastle disease is often divided into velogenic viscerotropic (VV) and velogenic
neurotropic (VN) strains. The difference is that the neurotropic strains cause only
minimal release of pro-inflammatory cytokines, so the early and severe systemic illness is
not apparent6. However, these strains still can get to the brain, so often the first thing
seen, rather than a very severely depressed and dying bird, is a bright and alert chicken
with neurologic signs. Often these birds infected with the VN strains die because they are
unable to get to the water or feed.
Highly pathogenic avian influenza (HPAI):
Highly pathogenic avian influenza is a disease caused by various strains of influenza that
result in severe disease in poultry. It is not nearly as common as Newcastle disease
globally, but it garners far more attention because some strains of HPAI have caused
disease and death in humans. Notably, the strain H5N1, also known as “bird ‘flu”, has
sickened and killed hundreds of people. It should be noted that the two terms, HPAI and
bird ‘flu, are not synonymous. Bird ‘flu is just one strain of HPAI.
The pathogenesis of HPAI has been vigorously investigated7. Although many strains of
HPAI have some differences, the basic template is that the virus is encountered via
inhalation or ingestion. Upper airway epithelium is susceptible, allowing the virus access
to the circulation. Once viremic, if then infects capillary endothelium. It seems to
particularly enjoy capillary endothelium that is at slightly lower than core body
temperature. As a result, capillaries of the comb, wattles, subcutis, and trachea, are
particularly compromised, and this is where edema and hemorrhage may be most
prominent. However, the virus may also get into capillaries elsewhere, and so there can
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be capillary damage in heart, liver, lung, and brain. The virus is very prolific and will
spill out of the capillaries and if in high enough concentration, cells nearby get infected,
and if that happens in the heart or the brain, death quickly ensues. Some strains have a
broader tropism, with direct infection of numerous visceral organs, leading to multisystem organ failure and death, often within 48-72 hours of infection.
References:
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in the third millennium. Veterinary Pathology 47(1):15-27, 2010
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in cattle after aerosol inoculation. Identification of the nasopharynx as the primary
site of infection. Veterinary Pathology Nov;47(6):1048-63, 2010. doi:
10.1177/0300985810372509.
3. Bird BH, Albariño CG, Hartman AL, Erickson BR, Ksiazek TG, Nichol ST, Rift
Valley Fever Virus Lacking the NSs and NSm Genes Is Highly Attenuated, Confers
Protective Immunity from Virulent Virus Challenge, and Allows for Differential
Identification of Infected and Vaccinated Animals. Journal of Virology 82(6):2681,
2008. doi: 10.1128/JVI.02501-07.
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Peste des petits ruminants virus infection of small ruminants: a comprehensive
review. Viruses Jun 6;6(6):2287-327, 2014. doi: 10.3390/v6062287.
5. Cattoli G, Susta L, Terregino C, Brown CC. Newcastle disease: A review of field
recognition and current methods of laboratory control. Journal of Veterinary
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6. Ecco R, Brown CC, Susta L, Cagle C, Cornax I, Pantin-Jackwood M, Miller PJ,
Afonso CL. In vivo transcriptional cytokine responses and association with clinical
and pathological outcomes in chickens infected with different Newcastle disease virus
isolates using formalin-fixed paraffin-embedded samples. Veterinary Immunology
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7. Dybing JK, Schultz-Cherry S, Swayne, DE, Suarez DL, Perdue ML. Distinct
Pathogenesis of Hong Kong-OriginH5N1 Viruses in Mice Compared to That of Other
Highly Pathogenic H5 Avian Influenza Viruses. Journal of Virology 74(3):1443,
2000. DOI: 1450.2000
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