Herpes simplex 1 and 2 (To “The sound of silence” Simon and Garfunkle) Hello, herpes, our old friend Will be with us to the end. ‘ Cause the virus softly creeping Left its genes while we were sleeping Not integrated into our genome, It will roam that episome. The DNA of herpes.
Herpesviruses Ubiquitous, all vertebrate species ds DNA, approximately 100 genes Co-evolved with their hosts, well adjusted Enveloped Latent infections The case of the elephant herpesviruses T.rex at exam time
The case of the elephant herpesviruses (Richman et al. 1999. Science 283:1171) Asian elephant herpesvirus (“cold sores”) Fatal hemorrhagic Disease in African elephants African elephant herpesvirus (“cold sores”) Fatal hemorrhagic Disease in Asian elephants
The elephant herpesvirus Richman et al. 1999. Science 283:1171
REPLICATION The genome structure of herpesviruses: (A) Alphaherpesvirus genomes comprise two regions designated long (L) and short (S). Terminal repeat (TR) and internal repeat (IR) sequences may bracket unique sequences (U L , U S ) of both L and S or only S. Repeat sequences are shown as boxes and are encoded as indicated by the direction of the arrows. Repeat sequences allow the DNA they bracket to invert relative to the rest of the genome such that where both U L and U S are bracketed by repeat sequences, four isomers are made and packaged in equimolar amounts into virions. Where only S is bracketed by repeat sequences, two equimolar isomers are made. (B) The genome of equine herpesvirus 2, a betaherpesvirus, contains terminal direct repeat structures. (C) The genome of bovine herpesvirus 4, a gammaherpesvirus, contains multiple direct terminal repeat sequences (small boxes) in a nonequal, variable number of copies.
Replicative cycle inclusion body cell-cell spread
REPLICATION Diagram representing transcription, translation, and DNA replication of a typical herpesvirus. Transcription and posttranscriptional processing occur in the nucleus, translation in the cytoplasm, and some of the and proteins are involved in further transcription and some proteins in DNA replication.
Infection in the animal reactivation from latency replication in epithelial cells (rhinotracheitis) Infection of susceptible animal systemic cell-associated spread infection of the fetus -> abortion encephalitis replication in epithelial cells establishment of latency (infection for the first time)
Complications of BHV-1 infection abortions encephalitis fatal disease in newborn calves Shipping fever (P. hemolytica, P. multocida) Bronchopneumonia -> fibrinous pleuropneumonia
Factors contributing to shipping fever Environmental Crowding animals from different sources Stress Host-virus Paralysis of mucociliary escalator Release of iron and nutrients Increased colonization immunosuppression
Vaccination against BHV-1 Modified-live (attenuated) Intra nasal Intra muscular Inactivated Intra muscular
Intranasal vs intramuscular vaccines Route of Inoculation Advantages Disadvantages Intra nasal Stimulates mucosal and systemic immunity. Stimulates interferon. Less affected by maternal antibody. Immunity not as long-lasting as IM. Serum antibody titres lower. Difficult to administer. Intra muscular Longer lasting, higher levels of immunity. Susceptible to maternal antibody.
Considerations for vaccination Economics New born calves
Vaccines for eradication gB gB gB gB gene for gE deleted gE gB infected vaccinated ELISA for antibodies infected vaccinated gD subunits gE gD gD gD
Respiratory epithelium Lamina propria Drainage lymph nodes Circulation Dissemination of infection Key stages in pathogenesis (Allen et al., 1998)
efferent lymphatic EHV-1 epithelial invasion and generation of viremia Infected endothelial cells in epithelial lamina propria Infected T lymphocytes in drainage lymph nodes Viremia Infection of epithelium and lamina propria (Kydd et al., 1994)
Viremia central to pathogenesis strictly cell associated EHV-1 infects mainly CD5+/CD8+ T lymphocytes (Scott et al., 1983; Slater et al., 1994; Meulen et al., 2000) associated with neutropaenia and lymphopaenia termination of viraemia requires generation of class I restricted, CD8+ cytotoxic T lymphocytes (CTL) (Allen et al., 1995; O’Neill et al., 1999) viremic lymphocytes express virus antigens briefly and are only transient targets for CTL after this virus persists in lymphocytes in a latent form
Circulatory immune responses: summary Strong humoral response to infection with transient CF and longer lived VN antibody responses (Thompson et al. 1976) Protection from reinfection is short lived (Allen and Bryans 1986) No correlation between circulating antibody levels and protection from re-infection (Hannant et al. 1993; Mumford et al. 1994) MHC I restricted CD8+ CTL responses are generated in response to infection (Allen et al. 1995)
EHV-1 abortions Late in gestation (7th to 11th month) Few weeks to several months after respiratory outbreak Abortion storms
Pathogenesis of abortion viremia endometrial endothelial cell infection endometrial vasculitis and thrombosis
Pathogenesis of abortion viremia endometrial endothelial cell infection endometrial vasculitis and thrombosis extensive infarction: virus negative fetus
Myeloencephalopathy by EHV-1 Often but not always associated with respiratory disease Often several horses Sudden onset rapid progression, early stabilization Ataxia, paresis, urinary incontinence, cystitis Little evidence of viral replication in neural tissues (immune mediated?) Vasculitis, thrombosis, hemorrhages (See Wilson, Vet Clin N. Am - equine pract. 1997 13:53)
Prevention of EHV-1 disease Management Vaccines Short-lived immunity (mares - 5,7,9 months of gestation Reduce severity but do not prevent Exacerbate myeloencephalitis??
Marek’s disease lymphoproliferative, neurological disease of young chickens unilateral paralysis, ataxia due to infiltration of spinal nerves involvement of iris, skin stable in feather follicle dander
malignant catarrhal fever (gamma herpesvirus) other ruminants ? other species malignant catarrhal fever
clinical signs in susceptible species peracute high fever, diarrhoea, death in 1-3 days acute fever, depression, enlarged lymph nodes, serous nasal discharge, erosive lesions, corneal opacity, high mortality chronic form