Paramyxoviruses; Rubella

Chapter 40

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)

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

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

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

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

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

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)

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 sustained viremia

• Blood transports virus to body tissues

• Immunity develops against viral antigens resulting antigen-antibody complexes most likely responsible for rash and joint pain

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

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

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

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

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

Henipaviruses

Henipaviruses

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

Henipaviruses

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

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