Emerging viruses

1. Emerging viruses Though emerging viruses tend to be at first highly virulent, virus and host co-evolutionary processes tend to converge to less virulent virus and more resistant host populations. Definition: - Viruses that are in the process of adapting to a new host and vice versa. - Viral diseases whose incidence (in humans) has increased in the past two decades or threatens to increase in the near future. Examples of emerging viruses Myxoma virus (Rabbitpox) HIV Influenza and Coronaviruses(SARs) are constantly emerging

2. Emergence of new viral diseases • 1. Evolution of new organisms. • 2. Spread of known viruses to new geographic areas. • 3. Infections in persons living in areas undergoing ecological change resulting in exposure to insects or animals harboring the virus.

3. Re-emergence of known viral diseases • 1. Development of resistance to vaccines or antiviral drugs. • 2. Breakdown of public health measures for previously controlled infections

4. Re-emergence of known viral diseases • 1. Development of resistance to vaccines or antiviral drugs. • 2. Breakdown of public health measures for previously controlled infections

5. The viral paradox: the need to replicate vs. the need to spread Cellular replication vs. inter-host replication

6. Crossing into new hosts

7. Viruses in New Species • Marburg Virus • Ebola Virus

8. Hantavirus pulmonary syndrome

9. Hantavirus pulmonary syndrome • Acute and often fatal pulmonary syndrome in adults • 1. Caused by a newly recognized hantavirus. • 2. First recognized in the southwestern United States in May, 1993. • 3. Laboratory investigation demonstrated antibody to hantavirus antigens. • 4. Hantavirus-specific sequences were found by RT-PCR amplification of viral RNA at autopsy

10. Hantavirus pulmonary syndrome • At the time of the original outbreak. • 1. Four members of the genus hantavirus of the Bunyaviridae family were known human pathogens. • 2. Worldwide distribution of hantaviruses which were primarily associated with hemorrhagic fever along with the renal syndrome. • 3. Rodents were known to be the natural hosts • 4. Before 1993 no hantavirus had been shown to cause acute human disease in North America. • 5. Before this outbreak, no hantavirus had been associated with pulmonary disease anywhere in the world

11. Hantavirus pulmonary syndrome • Deer mouse was shown to be the reservoir for the new hantavirus in the southwest US • 1. Peromuscus maniculatus were trapped around homes of several patients and about half were seropositive for the virus. • 2. The deer mouse is widely distributed in the US, but not in the southeastern states. • 3. Humans were infected by exposure to rodent excreta. • a) Aerosol route from urine. • b) Direct exposure to feces. • c) No person to person spread. • 4. Heavy rainfall in 1993 increased the food supply which resulted in an increase in the rodent population. This increased human exposure to deer mice and the virus.

12. Ebola Virus

13. Ebola Virus • Ebola virus and Marburg virus are in the Filoviridae family. • Single-stranded RNA genome, negative polarity, 19 kb. • Biosafety Level 4 agent: extremely pathogenic virus. • No vaccine or effective antivirals exist. • Natural reservoirs of the virus are unproven (but believed to be fruit bats

14. Emergence of Ebola Virus • History: • 1. 1967 – 31 cases and 7 deaths in Marburg, Germany in a laboratory were workers were preparing cells from monkeys imported from Uganda.

15. Emergence of Ebola Virus • History: • 2. 1976 – Epidemic in Zaire and Sudan with hundreds of deaths. 90% of exposed individualsdead in Zaire outbreak; 50% in Sudan.

16. Emergence of Ebola Virus • History: • 3. 1979 – Another outbreak in Sudan (34 people infected).

17. 1989 – Outbreak in Reston, Virginia • a) A colony of cynomologous Macaques imported from the Philippines was infected with the Ebola virus. • b) Virus was shown to be antigenically and genetically distinct from African ebola virus.

18. Named Reston Ebola Virus • i. Highly virulent for nonhuman primates • ii. Did not appear pathogenic for humans since several handlers were infected but did not get sick. • iii. Appeared to spread from animal to animal via aerosol route. • iv. Subsequent analyses showed that 11.7% of several thousand monkeys imported from the Phillipines and Indonesia were seropositive for Reston ebola virus

19. 1995 – Outbreak in Kitwit, Zaire • a) First case was a charcoal worker who worked in a forest outside of Kitwit. • b) Secondary transmission was by close personal contact with infected blood and body fluids. Lack of modern medical facilities and supplies in local hospital promoted spread of the virus. • c) Kitwit is a large and densely populated center close to other large cities. More potential in this case for spread of virus to larger population. • d) 233 deaths from 293 cases

20. The rapid response of the CDC helped to control the outbreak • . • i. Antigen or antibody was identified 9 h after samples were received in Atlanta. • ii. Ebola sequences were identified by RT-PCR 4 hours later. • iii. the RT-PCR data showed that the virus was a Zaire subtype that differed from the 1976 subtype by 4 bases in a 528 bp sequence (<1%). The polymerase sequences of the two viruses were identical. Only a 1.6% variation was observed in the sequences of the glycoprotein genes.

21. Therefore, in the 19 year period between the outbreaks in Zaire, the Zaire virus appeared to be very stable

22. Future outbreaks of Ebola Virus? • a) Ability to rapidly diagnose virus is critical in control of outbreaks. • b) Fruit bats are considered the most likely natural host, but transmissions to humans from rat dropping are believed to be rare. • c) Most outbreaks can be traced to a single event of a human handling the carcass of a chimpanzee or gorilla.

23. So, what is the picture of Ebola? • A virus that is not adapted to replication in humans -- not in equilibrium • Short prodromal period (short time to spread) • Too lethal for its own good • Not an effective pathogen in humans

24. Viruses in New Areas • West Nile Virus

25. Myxomatosis: a classic tale of an emerging virus

26. Background • In 1759, the European wild rabbit O. cuniculus was introduced into Australia by Thomas Austin for sport hunting. Almost all of the rabbits in Australia are descendants of the 24 original rabbits. • The rabbit spread rapidly, at a rate of advance of about 110 kilometres each year. It now occurs over half of Australia. • The lack of any herbivores capable of competing with the rabbit resulted in the decline of many species of native wildlife by competing with them for food or burrows. This applies particularly to the small ground-dwelling mammals of the arid lands. This situation was made worse by the lack of a large population of predators able to deal with this new prey. • By the mid-20th century, rabbits had denuded the landscape • They couldn’t be eradicated by hunting or poisoning • Something else had to be done

27. Myxomavirus • Myxoma virus, a member of the large Poxvirus group about 280nm in length. • Myxomtosis: The disease was uncovered in South America in 1896 where it had devastating effect on the rabbit population there. • It was found that it was mainly the European rabbit (Oryctolagus cuniculus), imported early that century, that contracted the disease. • Myxoma virus is endemic to the local wild rabbit population (Sylvilagus brasiliensis) which was mostly resistant to the disease and acted at the natural reservoir. • The disease is highly lethal to European rabbits with observed mortality rates of greater than 99%. • Myxoma virus is transmitted by • Contact infection – Discharge from skin and ocular lesions. • Arthropod vectors – Mosquitos, fleas, mites, ticks. Myxoma virus particles

28. The Plan • 1919: first suggestion to use Myxoma virus to control rabbits in Australia. • 1950: Myxomatosis successfully released among Australian rabbits. • Initial mortality rates >90%. • Best spread by mosquitoes in summer. • Epidemic continued for 4 or so years with high mortality rates

29. The outcome – a paradigm of host/virus co-evolution • The virus: • highly virulent forms killed hosts too quickly to be effectively spread • Less virulent forms didn’t kill hosts, more virus produced over longer time • Selection for attenuated virus. • The host: • Susceptible hosts were quickly culled from the population • More resistant hosts lived to reproduce •  Selection for resistant rabbits. • Today: myxomatosis in Australia kills only about 40% of infected rabbits, but rabbit numbers are much lower than they would be in the absence of this disease.

30. Myxomatosis in Europe • Similar to Australia, rabbits were a major cause of damage, particularly to the national forests of France. • 1952: Dr P.F. Armand Delille inoculated two wild rabbits at Maillebois in northern France. • From these two rabbits myxomatosis spread all round Europe, including Britain and Ireland, and as far a field as North Africa. • The main means of transmission of the virus was the mosquito as well as the rabbit flea. • The disease had the same result as in Australia: the majority of the wild rabbit population of Europe was wiped out, including an estimated 90% of French and British rabbits.

31. Myxomatosis in Europe • Attenuation and genetic resistance has occurred in Europe • Unlike in Australia where the highly attenuated strains have replaced the virulent original, in Europe the two coexist. • This is due to a different vector situation where the rabbit flea is believed to be the main vector, especially in Britain where the variation in number of cases of myxomatosis does not vary greatly throughout the year. • Myxomatosis is now an enzootic disease in the wild rabbits of Europe, with occasional summer epizootics, particularly in France.

32. New Viruses? • Coronaviruses– SARS • HIV • Influenza new strains

33. Phylogenetic tree showing relationships between primate lentiviruses based on pol sequences.

34. Influenza • All aspects of Influenza A conspire for it to be a constantly emerging virus • Genome: 9 segments of (+) strand RNA. • Segments: Allows for large scale recombinationv – genetic shift. • RNA genome: RDRPs have high error rates…high rates of mutation – genetic drift. • Ecology: reservoir is migrating waterfowl. Alternate hosts are almost all mammals. Impossible to eradicate. • Anthropology: Crowded, agrarian culture in Southeast China provides the ideal environment for exchange of virus variants between hosts. • Technology: high mobility of post 18th century humans ensures efficient and rapid dissemination of new virus variants.

35. The result • Yearly epidemics due to genetic drift. • Virus and host populations evolve toward benign relationship • Periodic pandemics due to genetic shift • Highly virulent virus released on an immunologically naïve population • Both host and virus co-selected • And the cycle continues

36. Control • The WHO monitors Influenza subtypes in Southeast Asia • They have to “guess” which ones will become the most prevalent • Use these to design the vaccine for 2 years later. • It is a hit or miss process.

37. Coronaviruses. • For more information, see http://www-micro.msb.le.ac.uk/3035/Coronaviruses.html • Human CoV cause ≈ 30% of common colds. • Other animal coronaviruses can cause more pathogenic disease, e.g. • Porcine Epidemic Diarrhea Virus • Mouse Heptitis Virus • Avian Infectious Bronchitis virus • SARS-CoV: a scary emerging virus.

38. SARS-CoV • SARS is a type of viral pneumonia • Symptoms include fever, dry cough, dyspnea (shortness of breath), headache, and hypoxaemia (low blood oxygen concentration). • Typical laboratory findings include lymphopaenia (reduced lymphocyte numbers) and mildly elevated aminotransferase levels (indicating liver damage). • Death may result from progressive respiratory failure due to alveolar damage. • The typical clinical course of SARS involves an improvement in symptoms during the first week of infection, followed by a worsening during the second week. • Studies indicate that this worsening may be related to patient's immune responses rather than uncontrolled viral replication. • The SARS virus is believed to be spread by droplets produced by coughing and sneezing, but other routes of infection may also be involved, such as faecal contamination, so wash your hands!

39. History • Severe Acute Respiratory Syndrome (SARS) first appeared in Guangdong Province, China late in 2002. • Its rapid transmission and high rates of mortality and morbidity resulted in a significant threat to global health by the spring of 2003, and the epidemic had significant impacts on the public health and economies of locales affected by SARS outbreaks. • The rapid response of the World Health Organization is credited with containing this contagion by late June of 2003, and only a few cases were reported during the winter cold season of 2003-2004.

40. History The severity of this crisis mobilized the scientific community as well: by March 24, 2003, scientists at the CDC and in Hong Kong had announced that a new coronavirus had been isolated from patients with SARS. • The sequences from two isolates of SARS CoV were published simultaneously on May 1, 2003.

41. Organization of the SARS-CoV genome SARS-CoV Viral Particle Evolutionarily, SARS-CoV is in a class by itself

42. Origins (Good eatin’) • Coronaviruses with 99% sequence similarity to the surface spike protein of human SARS isolates have been isolated in Guangdong, China, from apparently healthy masked palm civets (Paguma larvata), a cat-like mammal closely related to the mongoose. • The palm civet is regarded as a delicacy in Guangdong • It is believed that humans became infected as they raised and slaughtered the animals rather than by consumption of infected meat.

43. Outlook • Could SARS coronavirus recombine with other human coronaviruses to produce an even more deadly virus? • Fortunately, the coronaviruses of which we are aware indicate that recombination has not occurred between viruses of different groups, only within a group, so recombination does not seem likely given the distance between the SARS virus and HCoV. • There is considerable experience of development of coronavirus vaccines for veterinary purposes – though not all of it is encouraging. • On the whole, inactivated coronavirus vaccines induce poor protection.

44. Outlook • The spike protein alone can induce immunity, but the internal nucleoprotein has also been reported to induce protective immunity. • The WHO has recommended that SARS vaccines be developed. • The quickest and probably safest to develop would be an inactivated or subunit vaccine. • Even if such a vaccine were not fully protective against SARS infection, it might still provide some protection against life-threatening SARS pneumonia.

45. Management and Control • Surveillance • Outbreak control • epidemiology • quarantine patients • remove animal reservoir