1 chapter 24 viruses associated with respiratory infections Department of pathogenic biology xie-shuixiang

2 ORTHOMYXOVIRUSES pleomorphic pleomorphic influenza types A,B,C influenza types A,B,C febrile, respiratory illness with systemic symptoms febrile, respiratory illness with systemic symptoms

3 ‘ FLU ’ True influenza True influenza –influenza virus A or influenza virus B (or influenza virus C infections - much milder) Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often called ‘ flu ’ Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often called ‘ flu ’

4 THE IMPACT OF INFLUENZA PANDEMICS Deaths:

5 INFLUENZA VIRUS

6 Composition of Influenza Virus 1.Core RNA ： -ssRNA, 8 fragments RNA ： -ssRNA, 8 fragments NP (nucleoprotein) NP (nucleoprotein) RNA dependent RNA polymerase RNA dependent RNA polymerase 2. envelope M protein M protein lipid envelope lipid envelope sipke hemagglutinin(HA) 5 sipke hemagglutinin(HA) 5 neuraminidase(NA) 1 neuraminidase(NA) 1

7 M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase type A, B, C : NP, M1 protein HANA sub-types: HA or NA protein

8 Nomenclature Host of origin geographical origin geographical origin strain number strain number parentheses parentheses antigenic description antigenic description of HA and NA of HA and NA e.g. A/swine /Iowa/3/70(H 1 N 1 ) e.g. A/swine /Iowa/3/70(H 1 N 1 ) A/Hong Kong/1/68(H 3 N 2 ) A/Hong Kong/1/68(H 3 N 2 )

9 Functions of Hemagglutinin HA causes agglutination of red blood cells. HA causes agglutination of red blood cells. Viruses bind to the mucous membrane cells by HA1 interacting with membrane receptor. Viruses bind to the mucous membrane cells by HA1 interacting with membrane receptor. Virus ’ envelope fuse with cell membrane by HA2 forming a fusion pore. Virus ’ envelope fuse with cell membrane by HA2 forming a fusion pore.

10 SS SS SS cell enzymes acid pH HA protein - attachment, fusion HA protein - attachment, fusion

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12 Functions of Neuraminidase NA help the virus to permeate mucin and escape from “ non-specific ” inhibitor. NA help the virus to permeate mucin and escape from “ non-specific ” inhibitor. NA can increase the number of free virus particles, hence more virus spread from the original site of infection. NA can increase the number of free virus particles, hence more virus spread from the original site of infection. NA is important in the final stages of release of the new virus particle from infected cells. NA is important in the final stages of release of the new virus particle from infected cells.

13 NA protein - neuraminidase NA protein - neuraminidase

14 ANTIGENIC DRIFT Minor changes in antigens due to gene mutation in influenza virus. Minor changes in antigens due to gene mutation in influenza virus. HA and NA accumulate mutations HA and NA accumulate mutations –RNA virus immune response no longer protects fully immune response no longer protects fully sporadic outbreaks, limited epidemics sporadic outbreaks, limited epidemics

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16 ANTIGENIC SHIFT Major changes in antigens due to gene reassortment in influenza virus. Major changes in antigens due to gene reassortment in influenza virus. “ new ” HA or NA proteins “ new ” HA or NA proteins pre-existing antibodies do not protect pre-existing antibodies do not protect may get pandemics may get pandemics

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18 INFLUENZA A PANDEMICS Ryan et al., in Sherris Medical Microbiology

19 where do “ new ” HA and NA come from? 15 types HA 15 types HA 9 types NA 9 types NA –all circulate in birds pigs pigs –avian and human

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

21 why do we not have influenza B pandemics? so far no shifts have been recorded so far no shifts have been recorded no animal reservoir known no animal reservoir known

22 TRANSMISSION AEROSOL AEROSOL –100,000 TO 1,000,000 VIRIONS PER DROPLET HR INCUBATION HR INCUBATION SHEDDING SHEDDING

23 DECREASED CLEARANCE DECREASED CLEARANCE RISK BACTERIAL INFECTION RISK BACTERIAL INFECTION VIREMIA RARE VIREMIA RARE Lycke and Norrby Textbook of Medical Virology 1983

24 RECOVERY INTERFERON - SIDE EFFECTS INCLUDE: INTERFERON - SIDE EFFECTS INCLUDE: –FEVER, MYALGIA, FATIGUE, MALAISE CELL-MEDIATED IMMUNE RESPONSE CELL-MEDIATED IMMUNE RESPONSE TISSUE REPAIR TISSUE REPAIR –CAN TAKE SOME TIME

25 INTERFERON

26 INTERFERON antiviral state

27 INTERFERON antiviral state

28 INTERFERON antiviral state

29 PROTECTION AGAINST RE-INFECTION IgG and IgA IgG and IgA –IgG less efficient but lasts longer antibodies to both HA and NA important antibodies to both HA and NA important –antibody to HA more important (can neutralize)

30 SYMPTOMS FEVER FEVER HEADACHE HEADACHE MYALGIA MYALGIA COUGH COUGH RHINITIS RHINITIS OCULAR SYMPTOMS OCULAR SYMPTOMS

31 CLINICAL FINDINGS SEVERITY SEVERITY –VERY YOUNG –ELDERLY –IMMUNO- COMPROMISED –HEART OR LUNG DISEASE

32 PULMONARY COMPLICATIONS CROUP (YOUNG CHILDREN) CROUP (YOUNG CHILDREN) PRIMARY INFLUENZA VIRUS PNEUMONIA PRIMARY INFLUENZA VIRUS PNEUMONIA SECONDARY BACTERIAL INFECTION SECONDARY BACTERIAL INFECTION –Streptococcus pneumoniae –Staphlyococcus aureus –Hemophilus influenzae

33 DIAGNOSIS ISOLATION ISOLATION –NOSE, THROAT SWAB –TISSUE CULTURE OR EGGS SEROLOGY SEROLOGY RAPID TESTS RAPID TESTS provisional - clinical picture + outbreak provisional - clinical picture + outbreak

34 VACCINE ‘ BEST GUESS ’ OF MAIN ANTIGENIC TYPES ‘ BEST GUESS ’ OF MAIN ANTIGENIC TYPES –CURRENTLY type A - H1N1 type A - H1N1 type A - H3N2 type A - H3N2 type B type B each year choose which variant of each subtype is the best to use for optimal protection each year choose which variant of each subtype is the best to use for optimal protection

35 VACCINE inactivated inactivated egg grown egg grown sub-unit vaccine for children sub-unit vaccine for children reassortant live vaccine approved 2003 reassortant live vaccine approved 2003 –for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years

36 live vaccine development adapted from Treanor JJ Infect. Med. 15:714

37 TREATMENT - DRUGS RIMANTADINE (M2) RIMANTADINE (M2) type A only, needs to be given early type A only, needs to be given early AMANTADINE (M2) AMANTADINE (M2) type A only, needs to be given early type A only, needs to be given early ZANAMIVIR (NA) ZANAMIVIR (NA) types A and B, needs to be given early types A and B, needs to be given early OSELTAMIVIR (NA) OSELTAMIVIR (NA) types A and B, needs to be given early types A and B, needs to be given early

38 NA protein - neuraminidase NA protein - neuraminidase

39 OTHER TREATMENT REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

40 CORONA VIRUSES COLDS AND SARS

41 Severe acute respiratory syndrome (SARS)

42 SARS Coronavirus, SARS CoV Severe Acute Respiratory Syndrome(SARS) Severe Acute Respiratory Syndrome(SARS) 2002/ /11

43 SARS symtom Droplet or osculation Droplet or osculation Latent period ： 2~12d ， usually4~5d Latent period ： 2~12d ， usually4~5d Centralization in family and hospital apparently Centralization in family and hospital apparently

44 Biological properties nm ， envelope with spikes nm ， envelope with spikes +ssRNA ， 29.7KB ， 14 ORF:RNA polymer- ase 、 S 、 E 、 M 、 N +ssRNA ， 29.7KB ， 14 ORF:RNA polymer- ase 、 S 、 E 、 M 、 N Vero cell--CPE Vero cell--CPE Infected quadrumana – typical SARS symptom Infected quadrumana – typical SARS symptom

45 SARS Genome

46 Transmission and Epidemiology

47 Chinese SARS epidemiology

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49 Diagnosis Mainly depend on the clinic and epidemiologic data Mainly depend on the clinic and epidemiologic data Pathogen diagnosis Pathogen diagnosis –Isolation and identification of virus –RT-PCR –Immunofluorescence 、 ELISA P3 laboratory P3 laboratory Pathogen diagnosis is immature Pathogen diagnosis is immature

50 Prevention SARS CoV 比普通 CoV 抵抗力强，室温下痰、 粪便、尿中可稳定存活 1~2d SARS CoV 比普通 CoV 抵抗力强，室温下痰、 粪便、尿中可稳定存活 1~2d 对温度敏感， 37 o C 存活 4d ， 56 o C 存活 90m ， 75 o C30m 对温度敏感， 37 o C 存活 4d ， 56 o C 存活 90m ， 75 o C30m 对含氯消毒剂、过氧乙酸及 UV 均敏感， 对含氯消毒剂、过氧乙酸及 UV 均敏感， WHO 推荐中效以上的消毒剂，如过氧乙酸 WHO 推荐中效以上的消毒剂，如过氧乙酸

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

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57Paramyxoviridae -ssRNA

58 Koplik's spots on mucosal membranes Maculopapular rash (extends from face to extremities) measles (rubeola)

59 Measles virus measles (rubeola)

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

61 Lab Diagnosis Histopathology of measles pneumonia. Giant cells.

62 Prevention MMR MMR ( mumps, measles, rubella ) vaccine contains live, attenuated forms of all three of these viruses. ( mumps, measles, rubella ) vaccine contains live, attenuated forms of all three of these viruses.

63 MUMPS VIRUS Mumps MUMPS VIRUS Mumps British "to mump" - to grimace or grin, from the appearance of the patient as a result of parotid gland swelling. British "to mump" - to grimace or grin, from the appearance of the patient as a result of parotid gland swelling. (Note: Other agents can also cause parotitis). (Note: Other agents can also cause parotitis).

64 very contagious very contagious

65 RESPIRATORY SYNCYTIAL VIRUS spherical or pleomorphic enveloped viruses ( nm) with single-stranded, negative sense linear RNA spherical or pleomorphic enveloped viruses ( nm) with single-stranded, negative sense linear RNA

66 Infection of cells results in syncytium formation Infection of cells results in syncytium formation Upper respiratory infection (‘bad cold’) in older children and adults Upper respiratory infection (‘bad cold’) in older children and adults Lower respiratory infection- Bronchiolitis and/or pneumonia may occur after the upper respiratory infection Lower respiratory infection- Bronchiolitis and/or pneumonia may occur after the upper respiratory infection Severe infections occur in infants ( 2-6m) Severe infections occur in infants ( 2-6m)

67 Others

68 ADENOVIRUS non-enveloped non-enveloped linear double-stranded (ds) DNA linear double-stranded (ds) DNA Icosahedral capsid, Icosahedral capsid, capsomeres capsomeres hexons; hexons; at the vertices are 12 pentons, from which a fiber with a terminal knob projects. This complex is toxic to cells - causing rounding and death of cells through inhibition of protein synthesis. at the vertices are 12 pentons, from which a fiber with a terminal knob projects. This complex is toxic to cells - causing rounding and death of cells through inhibition of protein synthesis.

69 Eye Eye Epidemic Keratoconjunctivitis (EKC), acute follicular conjunctivitis, pharyngoconjunctival fever Epidemic Keratoconjunctivitis (EKC), acute follicular conjunctivitis, pharyngoconjunctival fever Respiratory system Respiratory system Common cold (rhinitis), pharyngitis (with or without fever), tonsillitis, bronchitis, pharyngoconjunctival fever, acute respiratory disease (LRI) Common cold (rhinitis), pharyngitis (with or without fever), tonsillitis, bronchitis, pharyngoconjunctival fever, acute respiratory disease (LRI) Genitourinary Genitourinary Acute hemorrhagic cystitis Acute hemorrhagic cystitis Gastrointestinal Gastrointestinal Gastroenteritis. Gastroenteritis.

70 Rash Congenital rubella cataracts RUBELLA

71 RUBELLA (GERMAN MEASLES) VIRUS Togavirus Togavirus +ssRNA +ssRNA Fetal damage Fetal damage live vaccine (attenuated strain) live vaccine (attenuated strain)