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Themes: Immune evasion by viruses Zoonoses: transmission to humans Viruses as prophylactics.

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Presentation on theme: "Themes: Immune evasion by viruses Zoonoses: transmission to humans Viruses as prophylactics."— Presentation transcript:

1 Themes: Immune evasion by viruses Zoonoses: transmission to humans Viruses as prophylactics

2 Themes 1. Cell, tissue and host tropism of viruses 2. Arthropod transmitted viruses 3. Cancer-causing (oncogenic) viruses 4. Antigenic variation 5. Persistent infections 6. Pathogenic variants generated in situ 7. Zoonotic infections 8. Emerging and re-emerging viral diseases 9. Immune evasion by viruses 10. Viruses as prophylactics/therapeutics

3 Poxviridae Key features 1. Poxviruses are the largest animal viruses and have a complex structure and mode of assembly. Unlike most other DNA viruses, poxviruses assemble in the cytoplasm. 2. Poxviruses affect many species of animals. Although generally species-specific, some poxviruses of domestic animals are zoonotic. 3. All poxviruses cause skin lesions and some additionally cause serious systemic disease. 4. Poxvirus infections are readily diagnosed by clinical signs and electron microscopy. 5. Poxviruses are very resistant to the environment and can persist for many months on dried lesion material. 6. Used as vectors for the delivery of new vaccines.

4 Poxviruses The poxviruses are very large, about 200-300 nm in length. The genome is double stranded DNA of 130-280 kbp, depending on the genus, which encodes around 200 genes. The parapoxviruses can be readily distinguished morphologically from the other genera since they are narrower and have a more oval shape. The viral core contains an RNA polymerase which, immediately following infection, transcribes several viral genes necessary for viral DNA replication and protein synthesis. Different viral proteins are translated before DNA replication (early proteins, mainly enzymes), or after DNA replication (late proteins, mainly structural). Viral particles are constructed in the cytoplasm within viral factories. These factories can be visualised in stained cells as inclusion bodies.

5 Mechanisms of immune evasion All poxviruses produce lesions on the skin Viruses replicate in the face of a host immune response Poxviruses produce many gene products that impair host immune responses Genes may be direct homologues of host genes Novel genes are also encoded Theme : immune evasion by viruses

6 Mechanisms of immune evasion Target many primary host immune mediators complement proteins cytokines e.g. Interferon-gamma binding protein Enhance the viral environment Epidermal growth factor homologue Vascular endothelial growth factor homologue

7 Pathogenesis and immunity All poxviruses cause lesions on the skin. In most cases initial replication at the site of infection (skin, respiratory tract) results in virus being taken to local lymph nodes and via the thoracic duct to the blood. This viraemia spreads the virus throughout the body and particularly to the skin where lesions develop. Immunity to many poxviruses is very strong and lifelong. The exception is the parapoxviruses. Following recovery from natural infection with orf virus, immunity is short lived and sheep become susceptible to re-infection within a few months. Clearly this feature is advantageous to the virus, permitting its survival in flocks.

8 Diseases caused by poxviruses Orthopoxviruses Cowpox (cats), ectromelia (mice), camel pox, (variola, vaccinia) Parapoxviruses Orf (sheep), bovine papular stomatitis, paravaccinia (pseudocowpox) (cattle) Capripoxviruses Sheep pox, goat pox, lumpyskin disease (cattle) Camelpoxviruses Camel pox Leporipoxviruses Myxomatosis, Shope fibroma Avipoxviruses Fowl pox, pigeon pox, canarypox, wild birds

9 Orthopoxviruses Smallpox: The beginnings of vaccination

10 Smallpox (variola): 1000 BC - 1977 AD "The smallpox was always present, filling the churchyards with corpses, tormenting with constant fears all whom it had stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover.”

11 Smallpox and vaccination In the 18th century Edward Jenner, an English country doctor, combined two observations to produce a theory that changed the world. Dairy workers had a very much reduced incidence of smallpox compared to other people who were exposed Often dairy workers were afflicted with the lesions of cowpox, the common disease of dairy cattle Therefore, infection with cowpox prevents smallpox Then Jenner carried out the appropriate experiment

12 Smallpox vaccination Edward Jenner used cowpox from a lesion on the hand of the milkmaid Sarah Nemes to inoculate 8 year old James Phipps. Jenner later challenged James with live smallpox virus and showed that he was protected. Sarah Jenner

13 Smallpox: nomenclature The classical name for smallpox is variola The old name for cowpox was vaccinia Therefore the process of immunisation against smallpox was called vaccination The agent that was continually passaged in people (then cattle) for the purposes of vaccination continued to be called vaccinia

14 Smallpox vaccination Smallpox was eradicated in 1977 due to surveillance and vaccination: last case occurred in eastern Africa Now stocks only held in two secure laboratories in Russia and the USA (Centers for Disease Control, Atlanta) Potential for bioterrorism!!

15 Where is cowpox today? The virus produces lesions on the teats and the contiguous parts of the udder of cows and is spread through herds by the process of milking. However, Cowpox has almost disappeared from domestic cattle. Cowpox is zoonotic and the lesions that it produces in man resemble those of smallpox, but are localised and transient

16 Here it is! Rodents are reservoirs. Also infects zoo animals Infects felids, anteaters, okapi, elephants Particularly severe in cheetahs

17 Cowpox infection in cats Highest risk of infection Free range cats in rural or suburban areas Cat-to-cat transmission Occurs, but disease is uncommon Cat-to-human transmission must be prevented Immunodeficient people are at high risk Theme : zoonotic disease N.B. Lesions in humans usually appear as single maculopapular eruptions on the hands or the face; infection is accompanied by systemic signs such as nausea, fever, and lymphadenopathy

18 Cowpox infection in cats How is the virus maintained? Likely to be transmitted from small wild mammals. Bank vole, field voles and wood mice But 40% of bank voles have anti-cowpox antibodies May be maintained in burrows by insect transmission

19 Skin inoculation Original single skin lesion on head, neck or forelimb Secondary skin lesions Local growth of virus Lymph nodes Viraemia Dermal nodules Ulcerated papules Vesicles (tongue) Scabbing Recovery (6-8 weeks) Cowpox infection in cats Rarely fatal in cats Accurate diagnosis is important Virus isolation - sensitive Electron microscopy – rapid PCR

20 Camel pox Camelpox virus is responsible for a very important systemic disease of camels in Africa and Asia, with extensive skin lesions. Up to 25% of affected animals may die.

21 Parapoxviruses Orf, bovine papular stomatitis, pseudocowpox Viruses very closely related All are potential zoonoses

22 Orf Orf, or contagious pustular dermatitis, is a very common infection of sheep and goats. The name is derived from an old word for ‘rough’, referring to the lesions. The virus is generally spread to lambs from their mothers and causes large proliferative lesions on the lips & nose, particularly at muco-cutaneous junctions. Although often extensive, the lesions usually resolve within a few weeks and the animal recovers completely. However, immunity is short lived and sheep can become re-infected.

23 Orf in sheep and goats Contagious pustular dermatitis Typically affects mouth and nasal planum, eyelids, feet, teats. Crusty lesions which can bleed * May prevent lambs from suckling * Live, virulent vaccine virus. Only use in affected flocks Use in ewes pre-lambing. Short-lived immunity

24 Orf as a zoonosis OedemaPapuleCrust Spontaneous recovery from orf in 3 to 6 weeks

25 Bovine papular stomatitis Little clinical significance Worldwide distribution BPS is endemic in cattle causing vesicular lesions in the mouth and lips. The condition is not usually serious but on occasion, when the lesions are more severe, has to be distinguished from other vesicular diseases such as foot- and-mouth disease or mucosal disease.

26 Pseudocowpox Common in cattle Pseudocowpox (paravaccinia) in cattle Characteristic “horseshoe” scabs Milker’s nodules in humans

27 Capripoxviruses Early lesions of sheep pox Economically the most impt. pox disease of domestic spp. Endemic in Africa, Middle East, India Notifiable Disease Morbidity rate: Endemic areas 70-90% Mortality rate: Endemic areas 5-10%

28 Extensive lung lesions Skin lesions Sheep pox These are by far the most severe poxvirus conditions of domestic animals. In outbreaks in fully susceptible animals the mortality rate may reach 50%. The disease is particularly severe in young lambs or kids. Sheeppox is a systemic disease in which widespread nodules develop in the skin, particularly in areas with little hair. Lesions may extend to lungs

29 Lumpy skin disease Lumpyskin disease is a condition similar to sheepox but affects cattle and buffalo in some parts of Africa. The mortality rate is very much less than in sheeppox infection. A vaccine against sheeppox also protects against lumpyskin disease

30 Lumpy skin disease High morbidity, low mortality Prolonged recovery affects productivity Transmitted by insect vectors

31 Leporipoxviruses Two closely related viruses Myxoma virus - myxomatosis Shope fibroma virus - vaccine

32 Myxomatosis Skin ‘tumours’ result from an initial proliferation of undifferentiated mesenchymal cells in the dermis which become large stellate cells termed ‘myxoma cells’ Only mild disease in cottontail rabbits Spread by fleas/mosquitos

33 Myxomatosis Transmitted by the rabbit flea Mechanical vector The characteristic signs of myxomatosis are: Swollen head, eyelids, genitalia Purulent conjunctivitis Live, attenuated myxoma virus vaccine

34 Shope fibroma Shope fibroma virus causes benign, self-limiting tumours The virus is antigenically related to myxoma virus and can be used as a vaccine against myxomatosis

35 Myxomatosis was the first agent used for the biological control Australia in the 1950s Myxomatosis vaccines are not available in Australia

36 Avipoxvirus :Fowlpox Lesions on non-feathered areas of the skin (nodules develop on the head, comb and wattles). Transmission by biting arthropods. Also diphtheritic form Birds with the other more serious form, which spreads by aerosol, have proliferative lesions in the epithelium of the upper respiratory tract, which frequently leads to asphyxia and death Fowlpox is now uncommon in commercial poultry flocks Virus elimination is difficult

37 Poxviruses are used as vectors for genetically modified vaccines Foreign gene inserted into poxvirus genome Protein expressed when infecting cells i.e. following vaccination Recombinant Poxvirus Theme: viruses As prophylactics

38 Canarypox as a vaccine vector Because of their large content of DNA, poxviruses are good candidates as vectors for the delivery of genes of interest into cells. Several poxvirus genes have been identified which are not essential for viral growth and can be deleted without affecting the growth of the virus. Therefore any gene of interest can be swapped for one of these non-essential genes. The resulting recombinant poxvirus will then deliver that gene into cells by infection and will promote the expression of the gene and the production of the encoded protein, as well as poxvirus proteins. Avipoxviruses, which complete their full replication cycle only in avian cells, go through an abortive replication cycle in mammalian cells, expressing only their early genes.

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