PATHOGENESIS, PATHOLOGY AND IMMUNITY

The pathogenesis of BTV infection presented below is from domestic ruminant studies unless otherwise stated.

BTV is inoculated intradermally into its ruminant hosts by the vector Culicoides, but the minimum infectious dose is uncertain.

I n its ruminant host, BTV first multiplies in regional lymph nodes before spreading systemically. Virus replica­tion occurs primarily in endothelial cells of capillaries and small blood vessels. In disease- susceptible species, cyto- pathic changes in these cells lead to vascular occlusion, stasis and exudation, which eventually give rise to hypoxia, oedema and haemorrhage, and to secondary lesions in the overlying epithelium. The severity of the lesions is influ­enced by the species of animal, stress and mechanical abrasion, and they develop mainly in tissues exposed to the environment, e.g. oral mucosa and coronary bands. Exposure of animals to strong sunlight exacerbates lesion severity, and the mortality rate can also escalate when infected animals are exposed to cold, wet conditions.

There is no published information on the development of BTV lesions in any wild European ruminant species. No evidence of increased mortality was observed in red deer in Belgium during an outbreak of BTV8⁽⁷⁾, or in Spain during outbreaks of BTV1 and BTV4⁽²¹⁾. Neither were any BTV-induced lesions detected in red deer experi­mentally infected with BTV1 or BTV8 in Spain⁽¹⁷⁾.

Following replication in lymphoid tissues and endothe­lial cells, BTV usually appears in the circulation 3—6 dpi.

In blood most BTV is sequestered within membranes of erythrocytes and cells of the buffy coat, where it is protected from antibody. In consequence, virus and anti­body may coexist in the circulatory system and virus is likely to persist until the ‘infected’ erythrocytes are cleared.

Abortion or malformation, particularly of the central nervous system of lambs and calves (e.g. cerebellar hypo­plasia and hydranencephaly (absence of cerebral hemi­spheres with cerebrospinal filled sacs)) and of other areas (e.g. the leg joints, causing arthrogryposis) may follow infection of pregnant ewes and cows with laboratory- modified strains of BTV or vaccination with live virus vaccines. There is little published information dealing with the infection of wild ruminant species with such strains of BTV.

In 2007, two Eurasian lynx (Lynx lynx) in a Belgian zoo that had eaten ruminant fetuses and stillbirths from areas where many cases of BT were occurring died. The first animal died 2 days after developing clinical signs and the second 5 months later. The animals showed petechial haemorrhages and lung congestion and oedema. Histo­logically, acute vasculitis and enlarged endothelial cells were observed in muscle, myocardium and lung. BTV8 was recovered from the lungs of the first animal, and BTV antibodies were identified in the second⁽²³⁾.

In disease-susceptible species, lesions relate to the sever­ity of damage to the microvascular system. Lesions can include: congestion, hyperaemia, haemorrhage, erosion and ulceration of the mucosa of the upper gastrointestinal tract; oedema and haemorrhage of the lymph nodes; haemorrhages within the subcutis; subintimal haemor­rhages in the pulmonary artery, pulmonary oedema, pleural and pericardial effusions; facial and submandibular oedema; oedema within the fascial planes of the muscles of the abdominal wall; and necrosis of the skeletal and cardiac muscles⁽²⁴⁾. Microscopic lesions in skeletal and cardiac muscle range from acute myonecrosis to more chronic lesions with fibrosis and infiltration of mononu­clear inflammatory cells. Pulmonary oedema is character­istic ofmany fatal BTV infections but is not pathognomonic. Changes within skin capillaries and capillaries adjacent to lesions are variable, but acutely affected vessels may exhibit endothelial hypertrophy with perivascular oedema and haemorrhage, and perivascular accumulation of lym­phocytes and macrophages⁽²⁴⁾.

Cattle rarely exhibit significant pathological changes. However, generalized lymphadenopathy with petechial haemorrhages on the tongue, spleen and kidneys was observed in a bovine infected with BTV8.

White-tailed deer develop consumptive coagulopathy (disseminated intravascular coagulation) leading to haem­orrhagic diathesis as a consequence of BTV-induced endothelial damage⁽²⁵⁾. South American camelids showed severe, acute congestion and oedema of the lungs. The alpaca also had erosions in the oral cavity⁽²⁶’²⁷⁾.

Type-specific neutralizing antibodies to BTV can be detected from 10 to 12 dpi. After field infection they persist for at least 6 months, and possibly for life. Subsequent to vaccination, they usually persist for a shorter period; accord­ingly, annual re-vaccination is recommended. The sequen­tial inoculation of two or more BTV serotypes induces a heterotypic response that extends for several months.

Although cellular immune responses play an important role in protection against BTV⁽²⁸⁾ information on these responses is limited and has been obtained from domestic sheep and cattle. BTV can induce interferon (IFN) in vitro and in vivo. However, its influence on virus clearance and the adaptive immune response is unknown. Indeed, virae­mia continues beyond the detection of IFN, suggesting that BTV may be at least partially resistant to this antiviral mechanism⁽²⁹⁾. Ruminants infected with BTV frequently develop lymphopenia, although the underlying mechanism is unknown. Cytotoxic T cells (CTL) are important for protection against intracellular pathogens, and anti-BTV CTL have been demonstrated in BTV-infected sheep⁽²⁸⁾.