a Virology 08 Respiratory
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- upper respiratory tract infections
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- common cold viruses (adenoviruses, non-SARS coronaviruses and rhinoviruses)
- replicate in epi surface of nasal mucosa
- primarily in columnar and ciliated epi cells - lower respiratory tract infections
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- paramyxoviruses (parainfluenza virus, respiratory syncytial virus, and human metapneumovirus
- myxoviruses (influenza)
- SARS(severe acute resp synd)- coronavirus
- primarily cuase bronchitis, acute laryngotracheobronchitis (croup), bronchiolitis and pneumonia - The Common Cold
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- acute resp illness
- mild and self-limited
- inflam of the Mucous Membranes of the nasopharynx (catarrh)
- watery nasal discharge (which may contain sloughed columnar epithelial cells)
- no fever
- from rhinoviruses (100+ antigenic types) or coronaviruses (2) - Pharyngitis
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- acute inflammatory of pharynx
- sore and scratchy throat
- edema and hyperemia of tonsils and pharyngeal Mucous Mems
- from rhinoviruses usually(may involve variety of viruses) - Laryngitis
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- inflam of larynx MMs
- w/ common cold and influenza
- lowering of the normal pitch, hoarseness, aphonia
- from influenza, sometimes rhinoviruses, adenoviruses and parainfluenza viruses - Laryngotracheobronchitis
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- croup
- acute, involving the larynx, trachea and bronchi
- kids under four
- high fever and blockage of the larynx and perhaps bronchi
- dyspnea and creaking notes
- typically due to one of the parainfluenza viruses(maybe others) - bronchitis
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- inflam of tracheobronchial tree
- ass. w/ generalized resp infection
- hyperemic and edematous MM ⇒ increased bronchial secretions
- cough to clear them
- destruction of epi(minimal->severe)
- accompanys a variety - Bronchiolitis
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- acute inflam and necrosis of the bronchiole epi
- before the age 2
- acute onset of wheezing and hyperaeration, tachypnea and resp distress
- from resp syncitial virus - Pneumonia
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- inflammation of the lungs
- 6th death cause in US
- destruction of ciliated epi
- diffuse congestion of alveoli w/ erythrocytes
- fluid may be seen
- from RSV and parainfluenza viruses in children
- influenza viruses in adults - Adenoviruses Structure and Replication
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- naked icosahedral particles
- linear dsDNA
- several dozen serotypes, divided into subgroups (A-F) based on antigenicity/RBC agglutinatation ability - Adenoviruses pathogenesis
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- genes E1A and E1B mediate transformation by deregulating cell cycle control by interacting w/ pRB gene
- not linked to human cancers
- can maintain a long-term ass. w/ host by persisting in lymphocytes for years
- discovered accidentally in cultured uninfected adenoidal tissue, from absence of immune surveillanc - Adenoviruses clinical features
-
- can infect and replicate in:
1)RT
2)eye
3)GI
4)bladder
5)liver
- 5-10% of acute RI in kids
- also causes acute resp disease(ARD), a syndrome from fatigue and crowding among young military recruits - Adenoviruses Epi
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- worldwide
- sporadic to epidemic
- mostly fecal/oral in kids, but can occur via the resp route - Adenoviruses vaccine
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- vaccines to prevent disease by certain adenovirus types
- vaccination -> asymptomatic virus replication in GI
- not for civilians - concerns for spread of non-attenuated virus and oncogenic potential - Rhinovirus Structure and replication
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- (+) polarity ssRNA
- naked icosahedral capsid
- capsid from copies of 4 proteins, like picornavirus
- 30-40% of winter colds
- replication T sensitive at 37° -> limits to URT(T<37) - Coronavirus Structure
-
- (+) polarity ssRNA
- helical nucleocapsid
- w/ envelope containing 3 or 4 glycoproteins in spikes
- pleomorphic shape
- 20-30% of winter colds - Rhinovirus and Coronavirus pathogenesis
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- confined to URT
- minimal and self-limiting
- may set stage for more serious bacterial infections (sinusitis, Otitis Media)
- only coronavirus can cause more serious disease in kids like bronchiolitis, bronchitis and pneumonia - Rhinovirus and Coronavirus Immunity
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- strain specific immunity after infection
- lots of serotypes (over 100 r)
- c immunity limited - can be re-infected w/in 2 years w/ same strain
-Long-Term immun to either is unusual - Rhinovirus and Coronavirus Epi
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- nose->hand->nose b/t people
- r can survive for hours on environmental surfaces(fomites-cups, doorknobs, etc.)
- reducing spread via handwashing, ventilation, disposal of tissues
- Chilling/cold-exposure are NOT responsible - Rhinovirus and Coronavirus Treatment
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1) Capsid-binding antiviral agents (WIN compounds) prevent virus binding and entry for R
- specifically bind a canyon
- not effective against other comm cold(coronav./adenov.)
- hard to administer to nasal mucosa
2) Anti-receptor compounds (ab's) against ICAM-1
- prevent R binding and entry - prevents, doesn't treat
- adding soluble ICAM-1 receptor helps
- resistant mutants rapidly evolve
3)complications
- hard to treat b/c no early clinical recognition, no rapid differentiation, short half-life, poor biodistribution - Preventing Common Cold
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- no vaccine(b/c of lots of serotypes)
- disinfectants
- handwashing(esp. staff of daycare/school/hospitals) - Respiratory Syncytial Virus Structure
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- irregular shape virions
- (-) sense ssRNA
- helical nucleocapsid w/ envelope (3 spiky glycoproteins-virus specific) - Respiratory Syncytial Virus Replication
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- G glycoprotein binding initiated infection
- penetrates via envelope fusion w/ PM By F glycoprot
- F mediates syncytium formation associated w/ infection
- all events for replication in cytoplasm
- transcribed by virion associated polymerase into Several mRNA's
- nucleocapsids bud through PM
- Replicates in wide variety of human/animal cells in culture - Respiratory Syncytial Virus Clinical Features
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- 4 to 5 day incubation
- 6-10 day recovery for kids
- <1% mortality unless immunocompromised(may be fatal)
- bronchiolitis characterized by lymph infiltration & edema
- pneumonia characterized by audible rales or consolidation=infiltrates on x-ray
- no deepter than superficial layers of resp epi - Respiratory Syncytial Virus Immunity
-
- protection/recovery = mediated by secretory Abs, serum Abs and cytotoxic T
- get maternal Abs->low level of protection/infants produce low level of neutralizing Abs
- diminished response of infants from immune immaturity or suppresive effect of maternal Ab or both
- multiple re-infections does immunity in older children
- secretory neutralizing IgA Abs better on nasal mucosa than serum, but not great
- cellular immunity ok, but short-lived
- local immunity most important in URT, serum Ab best in LRT - Respiratory Syncytial Virus Epi
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- severe in infants and kids, mild URT in adults
- infants(2-7 mo/premies)=esp prone to severe LRT-> bronchiolitis and pneumonia
- most important viral thing in infants
- big in immunosuppressed adults and elderly
- all infected by age 2, adult re-infection common
- 1o infection most severe
- subsequent infections are symptomatic but penetrate less deep into RT - Respiratory Syncytial Virus Transmition
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- transmitted by close contact
- aerosolized in large droplets of resp secretions
- infected kids shed for 3 wks
- can stay of surfaces for hrs
- spread in hospitals and daycare is a major problem
- mid-winter to late spring
- handwashing prevents! - Respiratory Syncytial Virus treatment
-
- treat severe kids w/
1) humidified O2
2) bronchodilators
3) assisted ventilation
4) Ribavirin(as aerosol)-not very effective
-RSV Prophylaxis
1) IV IG in high risk cases
2) no vaccines, but live attenuated being tested
3) hard to make infant vaccine b/c of maternal antibody and the immune immaturity - Parainfluenza Virus Structure
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- hPIV1-hPIV4
- (-) sense ssRNA
- virion-associated RNA polymerase - Parainfluenza Virus Replication
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- replicates in cytoplasm
- encode a hemagglutinin / neuraminidase (HN) glycoprotein spike that binds sialic acid to attach and enter
- high [sialic acid] in URT and LRT
- viral genome transcribed(several mRNA's) and nucleocapsids assemble in cytoplasm and bud through PM
- encodes an (F) spike and forms syncytia - Parainfluenza epidemiology
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- throughout world
- often nosocomial
- transmition=person to person contact or spread of contaminated secretions
- Shed for 4-7 days after inf(sometimes longer)
- re-inf w/ same hPIV can occur(illness is less severe)
- 1o inf of hPIV1/2=kids >2(probably maternal Ab protect against sever)
- most kids have hPIV3 Ab w/in 1yr
- hPIV1/2=biannual epidemics(autumn, though strains may be endemic for several years)
- hPIV3 inf tend to be endemic throughout year - Parainfluenza Virus Clinical features
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- 2nd cause of LRT in kids
- the most common cause of laryngotracheobronchitis(croup) in kids (esp type 1)
- non-croup infections present as a hoarse cough w/ fever which resolves in 2-3 days - Parainfluenza Virus Immunity
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- nasal secretory IgA Abs better than serum Abs
- only Abs to HN and F have been shown to neutralize virus - Parainfluenza Virus Pathology
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- gets epi of the pharyngeal and nasal mucosa
- spread from cell to cell by fusion then spread to the epi of the larynx and trachea
- resulting inflam -> croup
- restriction to RT b/c host cell proteases cleave the viral fusion protein
- w/out this, virions cant infect other cells - parainfluenza prevention
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- inactivated vaccines fail(b/c of importance of local secretory IgA Ab)
- subunit vaccine(w/ HN and F)=partially effective, but may help live attenuated virus vaccine
- kids vaccinated w/ bovine PIV3 are protected from hPIV3
- lots of attenuated mutants of hPIV3 developed(need to correct problems w/ reversion to wild type) - parainfluenza treatment
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- humidification by ultrasonic nebulizer
- periodic inhalation of racemic epinephrine(somewhat successful)
- inhaled steroids or systemic corticosteroids(somewhat effective at lessening severity of symptoms)
- No anti-viral therapy yet - Influenza Structure
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- pleomorphic virions
- smaller than paramyxoviruses
- 8 segments of (-) polarity ssRNA
- segments individually wrapped into helical nucleocapsids by Nucleoprot(NP) w/ envelope
- viral RNA polymerase is packaged within the virion
- 2 proteins on surface, hemagglutinin (H) and the neuraminidase (N)
- first identifies as H1N1(re-surfaced '77), but H2N2(asian flu '57) and H3N2(hong kong flu '68) also came along (so H1N1 gets people born after '57 b/c older have immunity - Influenza C
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- infects humans and swine
- causes sporadic URT illness, rarely LRT disease
- least severe - Influenza A
-
- in both humans and animals
- most severe - Influenza glycoprotiens
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HA:
-entry into host cell mediated by HA binding to sialic acid
-HA cleaved->2 peptides by extracell proteases(required for uncoating)
- cleavage blocked/altered by mut->virulence=greately reduced
- easier to cleave=more virulent
- Ab to HA blocks virus inf-prevents clinical illness
NA:
-cleaves sialic acid residues->facilitate cell-cell spread(by releasing virus from secretions and infected cells)
- Ab to NA limits spread-lessens clinical disease - Influenza B
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- only human, preferentially kids
- Reye's syndrome is a complication w/ aspirn instead of acetaminophen for fever
- HA and NA relatively stable, genetically - Influenza Replication
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- replication in nucleus
- virus polymerase error prone(lack of proofreading, mutation at freq of 10^-4/-5 per nucleotide per inf cycle)
- individual nucleocapsids encapsidate each segment, then they assemble at random into virions and bud from PM
- as many as 12-15 incorporated to ensure that all 8 required segments are there
- if 2 different strains replicate in same cell -> reassortment and new combos(by RNA reassortment) (esp w/ A, no reassort b/w abc) – bad!!-most rapidly evolving virus in nature - Influenza Clinical Features
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- 3-5 day recovery(fatigue/depression may persist), some may develop pneumonia (will be what kills you)
- asymptomatic to fatal primary influenza(worse in kids/old/already debilitated)
- clinical onset occurs with a sudden rise in temperature within 1- 4 days post-exposure
- correlation b/t level shedding and severity(most self-limiting=several days)
- coughing possibly for months after clearing, as ciliated epi is re-established
- lots of other symptoms, NO such thing as "stomach flu" - Influenza Pathogenesis
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- Spread via inhaled aerosol drops(sneezes/coughs)
-deposited on tracheobronchial tree, replication is initiated in all superficial cells of RT
- replication -> desquamation of ciliated epi(common acute symptoms-sore throat, substernal pain, SOB, nonprod cough) - Influenza Epidemiology
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- great unconquered epidemic
- antigenic drift/shift
- Influenza A evolution->new vaccines need to be made regularly
- new strains spread rapidly in kids and crowded areas
- epidemics cause economically significant absenteeism - Influenza Pandemic
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- excess mortality
- results from novel A virus
- 1918, 1957 and 1968.
- confined mainly to elderly and ill - Influenza Treatment
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1)Supportive treatment for relief of symptoms, does NOT shorten duration or lessen complications
- acetaminophen instead of aspirin reduces risk of Reye’s syndrome from B
2)Anti-Viral Drugs (amantadine or rimantadine)
- inhibits viral uncoating
– gets A if given w/in 48 hrs, NO effect on B or H5N1
– shortens: course by 1-4days, period of reduced pulmonry function
- reduces: sympt severity, titer and duration of viral excretion
3)Neuraminidase Inhibitors (A and B)
- binds sialic acid binding site on NA->blocks replication and symptoms
- non-toxic, available soon
4)Prevention
- prophylactic amantadine (for A only)
- effective against all H1,H2,H3 virus isolates
- side effect, must be taken throughout period of risk - Influenza Vaccines
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1)Currently: formaldehyde-inactivated virions from embryonated eggs(allergic to eggs=no vaccine)
- 2 doses (1month interval) for non-immunized kids, 1 dose for adults
- induces anti-HA Ab(from most recent A and B) in 85%
- immunity short lived(6-12mo)
- WHO network monitors and detects new viruses
- vaccinate old, infants, chronic disorders, and pregnant
2)Others:
- Trivalent vaccine for 2004 - 2005
- FluMistâ„¢ - cold-adapted, live-attenuated, trivalent(inhalation)
- Molecular vaccines
a)appropriate HA Ags in genetically engineered bacteria and live attenuated A and B chimeric viruses - influenza complications
-
1)2o bacterial infections
- lose normal mech for clearance of bact-> increases 2o bact pneumonia
- esp in old, smokers, chronic bronchitis, other pulm func deficits
- common orgs=strep pneumo, staph sp., Haemophilus infl
2)1o viral pneumonia is less common
- usually old or CP disease
- hypoxema and death w/in 1-4 days
3)Reye’s syndrome
- cerebral edema / fatty degen of liver
- in kids w/ B
- high fatality
- 3-way connection w/ ingestion of salicylates(aspirin)
- 300+ cases of Reye's in US during 73-74 infl B epidemic
4)2 other specific CNS syndromes - Influenza Antigenic drift
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1)Antigenic Drift
- high mutation rate (since RNA pol error, lack proofread enzymes)
- HA Ab correlated with protection against disease
- antigenic changes in HA protein -> new strains that can escape neutralizing Ab(unrecognized by Ab)
- antigenically new strains every 2-3 years->people can be re-infected, endemic/epidemic outbreaks - Influenza Antigenic Shift
-
2)Antigenic Shift-3 factors:
– (1) in A zoonotic allows reservoirs(birds,horses,swine) for propagation of viruses, more H and N possibilities(3H's/2N's in humans, but: 15H's, 8N's in birds->H5N1 in hong kong killed 5)
– (2) individual cells may be infected w/ different virus strains
– (3) segmented nature of genome
- Result: random recombination of RNA from diff strains/species(places where people/birds/swine are close(asia) have new pandemics)