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20 chapter20 chapter viruses associated with viruses associated with respiratory infections respiratory infections

Department of pathogenic biology

xie-shuixiang

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ORTHOMYXOVIRUSESORTHOMYXOVIRUSES

• pleomorphicpleomorphic

• influenza types influenza types A,B,CA,B,C

• febrile, respiratory febrile, respiratory illness with illness with systemic symptomssystemic symptoms

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‘‘ FLU’FLU’

• True influenzaTrue influenza– influenza virus A or influenza virus B (or influenza virus A or influenza virus B (or

influenza virus C infections - much milder)influenza virus C infections - much milder)

• Febrile respiratory disease with Febrile respiratory disease with systemic symptoms caused by a systemic symptoms caused by a variety of other organisms often called variety of other organisms often called ‘flu’ ‘flu’

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1918-19 Spanish flu 500,000 US20,000,000 world

1957-58 Asian flu 70,000 US

1968-69 Hong Kongflu

34,000 US

THE IMPACT OF INFLUENZATHE IMPACT OF INFLUENZAPANDEMICSPANDEMICS

Deaths:

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INFLUENZA VIRUSINFLUENZA VIRUS

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Composition of Influenza Composition of Influenza VirusVirus

1.1.CoreCore RNARNA ： ： -ssRNA-ssRNA, 8 fragments, 8 fragments NP (nucleoprotein)NP (nucleoprotein) RNA dependent RNA polymeraseRNA dependent RNA polymerase2. envelope2. envelope M proteinM protein lipid envelopelipid envelope sipke hemagglutinin(HA) 5sipke hemagglutinin(HA) 5 neuraminidase(NA) 1neuraminidase(NA) 1

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M1 protein

helical nucleocapsid (RNA plus NP protein)

HA - hemagglutinin

polymerase complex

lipid bilayer membrane

NA - neuraminidase

type A, B, C : NP, M1 protein sub-types: HAHA or NANA protein

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NomenclatureNomenclature

Host of originHost of origin

geographical origingeographical origin

strain numberstrain number

parenthesesparentheses

antigenic descriptionantigenic description

of HA and NAof HA and NA

e.g. A/swinee.g. A/swine/Iowa/3/70(H/Iowa/3/70(H11NN11))

A/Hong Kong/1/68(HA/Hong Kong/1/68(H33NN22))

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Functions of HemagglutininFunctions of Hemagglutinin

• HA causes agglutination of red blood HA causes agglutination of red blood cells.cells.

• Viruses bind to the mucous membrane Viruses bind to the mucous membrane cells by HA1 interacting with cells by HA1 interacting with membrane receptor.membrane receptor.

• Virus’ envelope fuse with cell Virus’ envelope fuse with cell membrane by HA2 forming a fusion membrane by HA2 forming a fusion pore.pore.

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S S

S S

S S

cell enzymes

acid pH

HA protein - attachment, HA protein - attachment, fusion fusion

1111

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Functions of NeuraminidaseFunctions of Neuraminidase

• NA help the virus to permeate mucin NA help the virus to permeate mucin and escape from “non-specific”inhibitor.and escape from “non-specific”inhibitor.

• NA can increase the number of free NA can increase the number of free virus particles, hence more virus spread virus particles, hence more virus spread from the original site of infection. from the original site of infection.

• NA is important in the final stages of NA is important in the final stages of release of the new virus particle from release of the new virus particle from infected cells.infected cells.

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NA protein - neuraminidase NA protein - neuraminidase

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ANTIGENIC DRIFTANTIGENIC DRIFT

• Minor changes in antigens due to Minor changes in antigens due to gene mutation in influenza virus.gene mutation in influenza virus.

• HA and NA accumulate mutationsHA and NA accumulate mutations– RNA virusRNA virus

• immune response no longer protects immune response no longer protects fullyfully

• sporadic outbreaks, limited epidemicssporadic outbreaks, limited epidemics

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ANTIGENIC SHIFTANTIGENIC SHIFT

• Major changes in antigens due to Major changes in antigens due to gene reassortment in influenza virus.gene reassortment in influenza virus.

• ““ new” HA or NA proteinsnew” HA or NA proteins

• pre-existing antibodies do not protectpre-existing antibodies do not protect

• may get pandemicsmay get pandemics

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INFLUENZA A PANDEMICSINFLUENZA A PANDEMICS

Ryan et al., in Sherris Medical Microbiology

1919

where do “new” HA and NA where do “new” HA and NA come from?come from?• 115 types HA5 types HA

• 9 types NA9 types NA– all circulate in birdsall circulate in birds

• pigspigs– avian and humanavian and human

2020

where do “new” HA and NA where do “new” HA and NA come from?come from?

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why do we not have why do we not have influenza B pandemics? influenza B pandemics?

• so far no so far no shifts have shifts have been been recordedrecorded

• no animal no animal reservoir reservoir knownknown

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TRANSMISSIONTRANSMISSION

• AEROSOLAEROSOL– 100,000 TO 100,000 TO

1,000,000 VIRIONS 1,000,000 VIRIONS PER DROPLETPER DROPLET

• 18-72 HR 18-72 HR INCUBATIONINCUBATION

• SHEDDINGSHEDDING

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• DECREASED DECREASED CLEARANCECLEARANCE

• RISK BACTERIAL RISK BACTERIAL INFECTIONINFECTION

• VIREMIA RAREVIREMIA RARE

Lycke and Norrby Textbook of Medical Virology 1983

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RECOVERYRECOVERY

• INTERFERON - SIDE EFFECTS INCLUDE:INTERFERON - SIDE EFFECTS INCLUDE:– FEVER, MYALGIA, FATIGUE, MALAISEFEVER, MYALGIA, FATIGUE, MALAISE

• CELL-MEDIATED IMMUNE RESPONSECELL-MEDIATED IMMUNE RESPONSE

• TISSUE REPAIRTISSUE REPAIR– CAN TAKE SOME TIMECAN TAKE SOME TIME

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INTERFERONINTERFERON

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INTERFERONINTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

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INTERFERONINTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

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INTERFERONINTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

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PROTECTION AGAINST PROTECTION AGAINST RE-INFECTIONRE-INFECTION

• IgG and IgAIgG and IgA– IgG less efficient but lasts longerIgG less efficient but lasts longer

• antibodies to both HA and NA antibodies to both HA and NA importantimportant– antibody toantibody to HA HA more important (can more important (can

neutralizeneutralize))

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SYMPTOMSSYMPTOMS

• FEVERFEVER

• HEADACHEHEADACHE

• MYALGIAMYALGIA

• COUGHCOUGH

• RHINITISRHINITIS

• OCULAR SYMPTOMSOCULAR SYMPTOMS

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CLINICAL FINDINGSCLINICAL FINDINGS

• SEVERITYSEVERITY– VERY YOUNGVERY YOUNG– ELDERLYELDERLY– IMMUNO-IMMUNO-

COMPROMISEDCOMPROMISED– HEART OR LUNG HEART OR LUNG

DISEASEDISEASE

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PULMONARY PULMONARY COMPLICATIONSCOMPLICATIONS• CROUP (YOUNG CHILDREN)CROUP (YOUNG CHILDREN)• PRIMARY INFLUENZA VIRUS PRIMARY INFLUENZA VIRUS

PNEUMONIAPNEUMONIA• SECONDARY BACTERIAL INFECTIONSECONDARY BACTERIAL INFECTION

– Streptococcus pneumoniaeStreptococcus pneumoniae– Staphlyococcus aureusStaphlyococcus aureus– Hemophilus influenzaeHemophilus influenzae

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DIAGNOSISDIAGNOSIS

• ISOLATIONISOLATION– NOSE, THROAT SWABNOSE, THROAT SWAB– TISSUE CULTURE OR EGGSTISSUE CULTURE OR EGGS

• SEROLOGYSEROLOGY

• RAPID TESTSRAPID TESTS

• provisional - clinical picture + provisional - clinical picture + outbreakoutbreak

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VACCINEVACCINE

• ‘‘ BEST GUESS’ OF MAIN ANTIGENIC BEST GUESS’ OF MAIN ANTIGENIC TYPESTYPES– CURRENTLYCURRENTLY

•type A - H1N1type A - H1N1

•type A - H3N2type A - H3N2

•type Btype B

•each year choose which variant of each each year choose which variant of each subtype is the best to use for optimal subtype is the best to use for optimal protectionprotection

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VACCINEVACCINE

• inactivatedinactivated• egg grownegg grown• sub-unit vaccine for childrensub-unit vaccine for children

• reassortant live vaccine approved 2003reassortant live vaccine approved 2003– for healthy persons (those not at risk for for healthy persons (those not at risk for

complications from influenza infection) complications from influenza infection) ages 5-49 yearsages 5-49 years

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live vaccine developmentlive vaccine development

adapted from

Treanor JJ Infect. Med. 15:714

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TREATMENT - DRUGSTREATMENT - DRUGS

• RIMANTADINE RIMANTADINE (M2)(M2)•type A only, needs to be given earlytype A only, needs to be given early

• AMANTADINEAMANTADINE (M2)(M2)•type A only, needs to be given earlytype A only, needs to be given early

• ZANAMIVIR ZANAMIVIR (NA)(NA)•types A and B, needs to be given earlytypes A and B, needs to be given early

• OSELTAMIVIR OSELTAMIVIR (NA)(NA)•types A and B, needs to be given earlytypes A and B, needs to be given early

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NA protein - neuraminidase NA protein - neuraminidase

.. ..

. . ...

..

....

..

..

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OTHER TREATMENTOTHER TREATMENT

• REST, LIQUIDS, ANTI-FEBRILE REST, LIQUIDS, ANTI-FEBRILE AGENTS AGENTS (NO ASPIRIN FOR AGES (NO ASPIRIN FOR AGES 6MTHS-18YRS)6MTHS-18YRS)

• BE AWARE OF COMPLICATIONS AND BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELYTREAT APPROPRIATELY

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CORONAVIRUSESCORONAVIRUSES

COLDS AND SARSCOLDS AND SARS

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Severe acute respiratory syndrome

(SARS)

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SARS Coronavirus, SARS CoVSARS Coronavirus, SARS CoV

• Severe Acute Respiratory Syndrome(SARS)Severe Acute Respiratory Syndrome(SARS) • 2002/112002/11

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SARS symtomSARS symtom

• Droplet or osculationDroplet or osculation• Latent periodLatent period ：： 2~12d2~12d ，， usually4~5dusually4~5d• Centralization in family and hospital apparentlyCentralization in family and hospital apparently

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Biological Biological propertiesproperties

• 60-130nm60-130nm ，， envelope envelope with spikeswith spikes

• +ssRNA+ssRNA ，， 29.7KB29.7KB ，， 114 ORF:RNA4 ORF:RNA polymer- polymer- asease 、、 SS 、、 EE 、、 MM 、、 NN

• Vero cell--CPE Vero cell--CPE

• Infected quadrumana Infected quadrumana –typical SARS –typical SARS symptomsymptom

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SARS GenomeSARS Genome

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Transmission Transmission and and EpidemiologyEpidemiology

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Chinese SARS Chinese SARS epidemiologyepidemiology

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Diagnosis Diagnosis

• Mainly depend on the clinic and Mainly depend on the clinic and epidemiologic data epidemiologic data

• Pathogen diagnosisPathogen diagnosis– Isolation and identification of virusIsolation and identification of virus– RT-PCRRT-PCR– ImmunofluorescenceImmunofluorescence 、、 ELISAELISA

• P3 laboratoryP3 laboratory• Pathogen diagnosis is immaturePathogen diagnosis is immature

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Prevention Prevention

• SARS CoVSARS CoV 比普通比普通 CoVCoV 抵抗力强，室温下抵抗力强，室温下痰、粪便、尿中可稳定存活痰、粪便、尿中可稳定存活 1~2d1~2d

• 对温度敏感，对温度敏感， 3737ooCC 存活存活 4d4d ，， 5656ooCC 存活存活90m90m ，， 7575ooC30mC30m

• 对含氯消毒剂、过氧乙酸及对含氯消毒剂、过氧乙酸及 UVUV 均敏感，均敏感，• WHOWHO 推荐中效以上的消毒剂，如过氧乙酸推荐中效以上的消毒剂，如过氧乙酸

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5252

5353

5454

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Pathologic cytoarchitectural changes indicative of diffuse Pathologic cytoarchitectural changes indicative of diffuse alveolar damage, as well as a multinucleated giant cell alveolar damage, as well as a multinucleated giant cell with no conspicuous viral inclusions.with no conspicuous viral inclusions.

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ParamyxoviridaeParamyxoviridae

-ssRNA

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Koplik's spots on mucosal membranes

Maculopapular rash (extends from face to extremities)

measles (rubeola)

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Measles virusMeasles virusmeasles (rubeola)measles (rubeola)

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SUB-ACUTE SCLEROSING SUB-ACUTE SCLEROSING PANENCEPHALITIS (SSPE)PANENCEPHALITIS (SSPE)• Very rarely (7 in 1,000,000 cases) Very rarely (7 in 1,000,000 cases) • 1-10 years after initial infection. 1-10 years after initial infection. • progressive, fatal disease. progressive, fatal disease. • defective forms of the virus in the braindefective forms of the virus in the brain

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Lab DiagnosisLab Diagnosis

Histopathology of measles pneumonia. Giant cells.

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PreventionPrevention

MMRMMR • ((mumpsmumps, , measlesmeasles, , rubellarubella) vaccine ) vaccine

contains live, attenuated forms of all three contains live, attenuated forms of all three of these viruses.of these viruses.

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MUMPS VIRUSMUMPS VIRUSMumps Mumps • British "to mump" - to British "to mump" - to

grimace or grin, from grimace or grin, from the appearance of the the appearance of the patient as a result of patient as a result of parotid gland swelling. parotid gland swelling.

• (Note: Other agents can (Note: Other agents can also cause parotitis).also cause parotitis).

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• very contagiousvery contagious

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RESPIRATORY SYNCYTIAL VIRUSRESPIRATORY SYNCYTIAL VIRUS

spherical or spherical or pleomorphic pleomorphic enveloped viruses enveloped viruses (100-350 nm) with (100-350 nm) with single-strandedsingle-stranded, , negative sense linear negative sense linear RNA RNA

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• Infection of cells Infection of cells results in syncytiumresults in syncytium formationformation

• Upper respiratory Upper respiratory infection (‘bad cold’) in infection (‘bad cold’) in older children and adultsolder children and adults

• Lower respiratory Lower respiratory infection- Bronchiolitis infection- Bronchiolitis and/or pneumonia may and/or pneumonia may occur after the upper occur after the upper respiratory infectionrespiratory infection

• Severe infections occur Severe infections occur in infantsin infants ( (2-6m)2-6m)

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OthersOthers

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ADENOVIRUSADENOVIRUS• non-envelopednon-enveloped• linear double-stranded (ds) linear double-stranded (ds)

DNADNA• Icosahedral capsid, Icosahedral capsid, • capsomerescapsomeres hexons;hexons; at the vertices are 12 at the vertices are 12 pentonspentons, ,

from which a from which a fiberfiber with a terminal with a terminal knob projects. This complex is knob projects. This complex is toxic to cells - causing rounding toxic to cells - causing rounding and death of cells through and death of cells through inhibition of protein synthesis. inhibition of protein synthesis.

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• EyeEye

Epidemic Keratoconjunctivitis (EKC)Epidemic Keratoconjunctivitis (EKC), , acute follicular acute follicular conjunctivitisconjunctivitis, pharyngoconjunctival fever, pharyngoconjunctival fever

• Respiratory systemRespiratory system

Common cold (rhinitis), pharyngitis (with or without fever), Common cold (rhinitis), pharyngitis (with or without fever), tonsillitis, bronchitis, pharyngoconjunctival fever, acute tonsillitis, bronchitis, pharyngoconjunctival fever, acute respiratory disease (LRI) respiratory disease (LRI)

• GenitourinaryGenitourinary

Acute hemorrhagic cystitisAcute hemorrhagic cystitis• GastrointestinalGastrointestinal

Gastroenteritis. Gastroenteritis.

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Rash

Congenital rubella

cataracts

RUBELLA

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RUBELLA (GERMAN MEASLES) VIRUS RUBELLA (GERMAN MEASLES) VIRUS

• Togavirus Togavirus • +ssRNA+ssRNA• Fetal Fetal

damage damage • live vaccine live vaccine

(attenuated (attenuated strain) strain)