BLUETONGUE: PATHOGENESIS AND DURATION OF VIREMIA N James MacLachlan

Transcription

1 BLUETONGUE: PATHOGENESIS AND DURATION OF VIREMIA N James MacLachlan

2 LIFE CYCLE OF BLUETONGUE VIRUS INFECTION Described by Spreull in the late 19th century in South Africa with C. imicola Cattle implicated as asymptomatic reservoir hosts of the virus

3 BLUETONGUE: A DISEASE OF SHEEP AND SOME WILD RUMINANTS BUT NOT CATTLE Courtesy M. Domingo

4 BLUETONGUE; CARDIAC LESIONS

5 BLUETONGUE; ENDOTHELIAL INJURY Endothelial injury is central to expression of bluetongue in susceptible ruminants Courtesy E. Howerth

6 ROLE OF ENDOTHELIUM IN THE PATHOGENESIS OF BTV INFECTION OF SHEEP AND CATTLE Plasma TX: PC, indicative of enhanced coagulation, greater in BTV-infected sheep than cattle Reviewed: DeMaula et al., Virology 2002 Cattle as virus reservoirs virus production, EC activation Sheep as a target species sensitivity to cell death, minimal EC activation, enhanced coagulation

7 THE PATHOGENESIS OF BTV INFECTION OF CATTLE Comparable in sheep. Pini, Onderstepoort J Vet Res, 1976 Reviewed: Barratt-Boyes and MacLachlan, JAVMA, 1995

8 VIREMIA IN BTV-INFECTED RUMINANTS IS PROLONGED BUT NOT PERSISTENT Data from infection with recent strains of BTV and C. sonorensis from California BTV RNA detected by RT- PCR for days in the absence of infectious virus PCR+, VI- bloods NOT infectious to either insect or ruminant hosts of BTV Bonneau et al., Vet Microbiol, 2002

9 CELLULAR ASSOCATION OF BTV DURING VIREMIA Initially associated with all blood cell types - later associated only with erythrocytes Virus co-circulates with neutralizing antibodies for weeks _ antibody; virus in whole blood ( ), red cells ( _. _ ), platelets (. ), leukocytes (.. )

10 INTERACTION OF BTV WITH ERYTHROCYTES FACILITATES PROLONGED INFECTION OF RUMINANTS Titers of BTV in erythrocyte fraction reflect those in whole blood Duration of PCR+ status of blood reflects erythrocyte lifespan No replication of BTV in erythrocytes Brewer and MacLachlan, Vet Pathol, 1992; Archives of Virol, 1994 Barratt-Boyes and MacLachlan, Vet Micro, 1994

11 BLUETONGUE VIRUS INFECTION OF MONONUCLEAR CELLS In vitro infection of monocytes and replicating T cells (IL- 2/mitogen), not resting T cells Whetter et al., J Gen Virol, 1989; Stott et al., J Gen Virol, 1990; Barratt-Boyes and MacLachlan, J Gen Virol, 1992; Brewer and MacLachlan, Archives of Virol, 1994; Takamatsu et al., J Gen Virol, 2003 Transient isolation of BTV from IL-2 stimulated mononuclear cells from blood and tissues Barratt-Boyes & MacLachlan, Vet Microbiol, 1994; Maclachlan et al., Proc USAHA, 1989

12 MAXIMAL DURATION OF VIREMIA IN BTV-INFECTED RUMINANTS VIREMIA IS PROLONGED BUT NOT PERSISTENT DURATION CAN CORRECTLY BE DETERMINED ONLY BY INFECTION OF VECTOR INSECTS ( <60 DAYS) BTV NUCLEIC ACID DETECTED UP TO 8 MONTHS PCR +/ VIRUS ISOLATION BLOODS NOT INFECTIOUS TO VECTOR INSECTS OR RUMINANTS Intrathoracic inoculation and oral feeding of insects Inoculation of sheep with animal tissues and blood DURATION OF PCR+ STATUS CORRELATES WITH LIFESPAN OF ERYTHROCYTES IN SHEEP AND CATTLE Reviewed: Tabachnick et al., Am J Trop Med Hyg, 1996; Bonneau et al., Vet Micro, 2002

13 WHAT IS THE ROLE OF RUMINANTS IN THE DISSEMINATION AND OVERWINTERING OF BTV?

14 EMERGING BLUETONGUE DISEASE IN THE 20 TH CENTURY DOGMA OF THE TIME - A SILENTLY SPREADING EPIDEMIC

15 PERSISTENT INFECTION OF CATTLE: A FAILED SCENARIO TO EXPLAIN THE GLOBAL DISTRIBUTION OF BLUETONGUE VIRUS

16 BTV INFECTION OF FETAL RUMINANTS BTV infection in early gestation leads only to fetal death and/or cerebral malformation (teratogenesis) - NOT PERSISTENT POST- NATAL INFECTION Cell culture adapted strains of BTV can cross the placenta to cause teratogenic defects only described where MLV vaccines are used Reviewed: MacLachlan et al., Anim Reprod Sci, 2000

17 Geographic distribution of bluetongue virus and clinical disease Modified from Gibbs and Greiner (1994) Endemic zone-infection common and disease uncommon Epidemic zone-disease at regular intervals Incursive zone-disease unusual

18 GEOGRAPHIC DISTRIBUTION OF BTV SEROTYPES 2, 10, 11, 13, 17 C. sonorensis 1-3, 9, 12, 14-21, 23 C. brevitarsis and others? C. insignis 1, 3,6, 8, 12, 14, , 22, 24 C. imicola 1, 3, 9, 15, 16, 20, 21,23 C. brevitarsis Florida Medical Entomology Laboratory

19 I II III IV III GLOBAL STRAINS OF BLUETONGUE VIRUS SEGREGATE INTO REGION- SPECIFIC TOPOTYPES BASED ON PHYLOGENETIC ANALYSIS OF THEIR NS3 GENES 88 I I II III IV II III Balasuriya et al., 2003

20 BLUETONGUE VIRUS INFECTION OF RUMINANTS IS HIGHLY SEASONAL IN THE WESTERN UNITED STATES Stott et al., Proc USAHA, 1981

21 BTV INFECTION OF RUMINANTS IN THE WESTERN UNITED STATES: VIRUS ISOLATIONS SHEEP CATTLE GOATS JAN-JUNE 2 / / / 2457 JULY - DEC 222 / / / 2328 No isolations in January, February, March, or May; 1 in April, 3 in June, low #s in December Peak transmission August November (>95% isolates); Overwintering period at least 6 months! Osburn et al., Am J Vet Res, 1981; Stott et al., 1 st BT Symposium, 1984

22 OVERWINTERING OF BTV BY A LOW LEVEL INFECTION CYCLE IN THE RUMINANT AND INSECT HOSTS Mechanism outlined by Neville, Onderstepoort J Vet Res, 1971 Consistent with the sporadic isolation of BTV from naïve sentinel ruminants during the overwintering months in California reflects the periodic emergence of insects that already harbor BTV No evidence of recrudescence of viremia in previously infected ruminants; feeding vectors are present long before the end of the overwintering period THE SIGNFICANCE AND RELEVANCE OF LABORATORY OBSERVATIONS CAN ONLY BE DETERMINED BY APPROPRIATE STUDIES IN THE FIELD

23 New theories don t make progress by their eloquence or through their greater explanatory power, but simply because their opponents eventually die Attributed to Lister