Paramyxoviruses; Rubella

1. Paramyxoviruses; Rubella • Chapter 40

2. Paramyxoviruses • Features • ssRNA viruses • Nonsegmented, ~15 kb • Enveloped • Hemagglutinin glycoprotein • Fusion glycoprotein • Labile, but highly infections • Major classification (Paramyxovirinae) • Respirovirus (parainfluenza viruses) • Rubulavirus (mumps, parainfluenza viruses) • Morbillivirus (measles) • Henipavirus (Hendra and Nipah viruses) • Pnuemovirus (respiratory syncytial virus) • Metapneumovirus (metapneumovirus)

3. Measles • Symptoms • Begins with fever, runny nose, cough, red weepy eyes • Fine rash appears within a few days • Appears first on forehead, then spreads to rest of body • Symptoms generally disappear within 1 week • Many cases complicated by secondary infections • Pneumonia and earaches are most common secondary conditions • Less common complications include encephalitis and subacute sclerosing panencephalitis (SSPE) • Measles does not kill; instead, it leads to secondary infections that do kill

4. Measles • Pathogenesis • Infection via respiratory route • Virus replicates in epithelium of upper respiratory tract • Spreads to lymph nodes • Further replication occurs here • Spreads to all parts of the body • Infected mucous membranes important diagnostic sign • Membranes covered with Koplik spots • White spots seen in back of throat opposite molars • Infected membranes may explain increased susceptability to secondary infection • Especially to middle ear and lungs • Skin rash is due to effects of virus replication within skin cells • Rash also due to cellular immune response to viral antigens in the skin

5. Measles • Epidemiology • Humans are only natural host • Virus spread by respiratory droplets • Before routine immunization, over 99% of population infected • Vaccine resulted in decline of annual cases • Measles is no longer endemic in United States • Outbreaks still occur and are due to susceptible populations • Populations include • Children too young to be vaccinated • Preschool children never vaccinated • Children and adults inadequately vaccinated • Persons not vaccinated for religious or medical reasons • Prevention and Treatment • Prevention by vaccination • Vaccine is usually given in conjunction with mumps and rubella vaccine • MMR

6. Measles • Measles virulence factors • P protein • Transcription factor for cellular enzyme A20 • A20 negatively regulates NF-κB • NF-κB activates antiviral responses in infected cells • V protein • Blocks JAK phosphorylation of STAT1 • Blocks STAT1/STAT2 dimerization • C protein interferes with PKR

7. Measles as a Global Health Problem • Measles occurs predominantly in Africa and Asia • In 2000, there were more than 700,000 deaths per year from measles • The great majority of these deaths were children • In 2001 the Measles Initiative was started by the WHO • Deaths in 2005 were 454,000 • Deaths in 2010 were 164,000 • A 90% reduction is targeted by 2010 (from 2000 levels) • Vigorously supported by Rotary International

8. Rubella • Aka - German Measles • Typically mild • Often unrecognized • Difficult to diagnose • Significant infection in pregnant women • Symptoms • Slight fever with mild cold symptoms • Enlarged lymph nodes behind ears and back of neck • Faint rash on face • Rash consists of light pink spots • Adults commonly complain of joint pain • Symptoms last only a few days • Joint pain may last up to 3 weeks • Congenital rubella syndrome • First trimester susceptibility highest • Can lead to fetal death, or neurological disease in survivors (deafness, mental retardation)

9. Rubella • Causative Agent • Rubella virus • Member of Togaviridae family • Small, enveloped • Single-stranded RNA genome • Pathogenesis • Enters body via respiratory route • Virus multiplies in nasopharynx, then enters bloodstream • Causes sustainedviremia • Blood transports virus to body tissues • Immunity develops against viral antigens resulting antigen-antibody complexes most likely responsible for rash and joint pain

10. Rubella • Epidemiology • Humans are only natural host • Disease is highly contagious • Less so than measles • 40% of infected people fail to develop symptoms • These individuals can spread virus • Infectious 7 days before appearance of rash to 7 days after • Prevention and Treatment • Vaccination with attenuated rubella virus vaccine • Administered at 12 months and boosted at 4 to 6 years of age • Produces long-lasting immunity in 95% of recipients • Vaccine not given to pregnant women due to potential complications • Women are advised not to become pregnant for 28 days post vaccination • Vaccine has significantly reduced incidence in United States

11. Mumps • Causative Agent • Mumps virus • Member of the Paramyxoviridae family • Enveloped • Single stranded RNA genome • Symptoms • Early symptoms • Fever with loss of appetite and headache • Later symptoms • Painful swelling of one or both parotid glands and spasms • Usually makes it difficult to chew and swallow • Symptoms disappear in about a week • Symptoms much more severe in individuals past puberty • Post-pubertal males can suffer painful swelling of testicles • Ovarian involvement occurs in about 20% of cases • Pregnant women often miscarry

12. Mumps • Pathogenesis • Transmitted by inhalation of infected droplets • Long incubation period • 15 to 20 days • Virus replicates in the upper respiratory tract • Virus spreads throughout body via bloodstream • Produces symptoms after infecting tissues • In salivary glands • Virus multiplies in epithelium of salivary ducts • Destroys epithelium and releases virus into saliva • Inflammation produced • Inflammation responsible for symptoms and pain

13. Mumps • Epidemiology • Humans only natural host • Natural infection confers lifelong immunity • Virus is spread by asymptomatic individuals in high numbers • Virus can be present in saliva of symptomatic persons • Prevention and Treatment • Prevention directed at immunization • Usually given in same injection as measles and rubella • MMR • Immunization prevents latent recurrent infections • Due to only one viral serotype • No effective antiviral treatment

14. Henipaviruses • Members • Hendra virus (HeV; Australia) • Nipah virus (NiV; Asia) • Paramyxoviruses • Subfamily Paramyxovirinae • Bat viruses • Genus Pteropus (flying foxes) • Genome organization • Negative strand RNA • HeV - 18.2 nt • NiP - 27 nt • Six genes • N - nucleocapsid • P - phosphoproteins • M - matrix protein • F - fusion protein • G - glycoprotein (mediates attachment) • L - Large polymerase

15. Henipaviruses

16. Henipaviruses

17. Henipaviruses • Features • Only zoonotic paramyxoviruses • Infections • Bats • Humans • Horses • Pigs • Dogs • Ferrets • Raccoons • Lions • Hamsters • 2004 Bangladesh outbreak: 75% fatality rate • BSL-4 pathogens and select agents

18. Henipaviruses

19. Henipaviruses • Infections • Bats - no apparent pathology • Horses (HeV) and pigs (NiV) • Respiratory transmission (communicable) • Neurological manifestations • Facial swelling • Nasal discharge • Humans • Respiratory transmission (communicable) • Severe acute encephalitis • NiV manifestations can occur up to 4 years post infection • Relapse encephalitis

20. Henipaviruses • Molecular biology of infection • G protein • Provides broad species tropism • Along with F protein can induce fusion of cells from different species • Cellular receptor is ephrin B2 protein • Neurons • Smooth muscle • Capillary endothelial cells • F protein • Single polypeptide (F0) is cleaved into F1 and F2 by cellular furin protease in the Golgi • F1 and F2 are disulfide-linked on virus membrane to form F protein • P gene • Single polypeptide cleaved into P, V and W proteins • P and V interact with and disable STAT1 transcription factor • W interacts with and disables IRF-3 transcription factor • These events disable the type I IFN pathway of infected cells