流感病毒-INFLUENZAVIRUS

1、1INFLUENZA VIRUS20022FLU 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 3South Carolina 1996-1997 DHEC bulletinhttp:/www.state.sc.us/dhec/

2、LAB/labbu017.htmno virusinfluenza Ainfluenza BCULTURE RESULTSmalathia influenzae per le stelle41918-19 Spanish flu 500,000 US20,000,000 world1957-58 Asian flu70,000 US1968-69 Hong Kongflu34,000 USTHE IMPACT OF INFLUENZAPANDEMICSDeaths:5THE IMPACT OF INFLUENZA 1972-1994 (19 influenza seasons) 20,000

3、US deaths in 11 seasons 40,000 US deaths in 6 of these many more hospitalizations (110,000 per year)6THE IMPACT OF INFLUENZA recently some increase in morbidity and mortality - possible factors? more elderly people CF patients live longer more high risk neonates more immunosuppressed patients7ORTHOM

4、YXOVIRUSEShttp:/www.uct.ac.za/depts/mmi/stannard/fluvirus.html pleomorphic influenza types A,B,C febrile, respiratory illness with systemic symptoms8ORTHOMYXOVIRUSESM1 proteinhelical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complexlipid bilayer membrane NA - neuraminidasetype

5、 A, B, C : NP, M1 protein sub-types: HA or NA protein9TRANSMISSION AEROSOL 100,000 TO 1,000,000 VIRIONS PER DROPLET 18-72 HR INCUBATION SHEDDING10NORMAL TRACHEAL MUCOSA3 DAYS POST-INFECTION7 DAYS POST-INFECTIONLycke and Norrby Textbook of Medical Virology 198311 DECREASED CLEARANCE RISK BACTERIAL IN

6、FECTION VIREMIA RARELycke and Norrby Textbook of Medical Virology 198312RECOVERY INTERFERON - SIDE EFFECTS INCLUDE: FEVER, MYALGIA, FATIGUE, MALAISE CELL-MEDIATED IMMUNE RESPONSE TISSUE REPAIR CAN TAKE SOME TIME13An immunological diversionINTERFERON14INTERFERONtimecourse of virus production will var

7、y from virus to virus15INTERFERON16INTERFERONantiviral stateantiviral stateantiviral stateantiviral state17INTERFERONantiviral stateantiviral stateantiviral stateantiviral state18INTERFERONantiviral stateantiviral stateantiviral stateantiviral state19INTERFERONTHE VIRUSES ARE COMING!http:/www.paulre

8、/midnight.htmlPAUL REVERE/collections/one_hour/6.htm20TYPES OF INTERFERON TYPE IInterferon-alpha (leukocyte interferon, about 20 related proteins)- leukocytes, etcInterferon-beta (fibroblast interferon)- fibroblasts, epithelial cells, etcTYPE IIInterferon-gamma (immune

9、interferon)- certain activated T-cells, NK cells 21INDUCTION OF INTERFERONinterferon-alpha and interferon-beta- viral infection (especially RNA viruses), double stranded RNA, certain bacterial components- strong anti-viral propertiesinterferon-gamma - antigens, mitogenic stimulation lymphocytes22INT

10、ERFERON induce various proteins in target cells many consequences, not all fully understood23INTERFERON-ALPHA AND INTERFERON-BETA24interferon-alpha, interferon-betainterferon receptor induction of 25oligo A synthaseinduction of aprotein kinase 25oligo Ainduction of ribonuclease L activated ribonucle

11、ase L ATPds RNAds RNAactivatedprotein kinase activated25oligo A synthaseATP25oligo AmRNA degraded phosphorylated initiation factor (eIF-2)inhibition of protein synthesis 25interferons only made when needed26OTHER EFFECTS OF INTERFERONS ALL TYPES INCREASE MHC I EXPRESSION CYTOTOXIC T-CELLS ACTIVATE N

12、K CELLS CAN KILL VIRALLY INFECTED CELLS27OTHER EFFECTS OF INTERFERONS INTERFERON-GAMMA INCREASES MHC II EXPRESSION ON APC HELPER T-CELLS INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES INTRINSIC EXTRINSIC28THERAPEUTIC USES OF INTERFERONS ANTI-VIRAL e.g. interferon-alpha is currently approved for certai

13、n cases of acute and chronic HCV and chronic HBV MACROPHAGE ACTIVATION interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis ANTI-TUMOR have been used in e.g. melanoma, Kaposis sarcoma, CML MULTIPLE SCLEROSIS interferon-beta29Viral response to host immune systemV

14、iruses may :block interferon bindinginhibit function of interferon-induced proteinsinhibit NK functioninterfere with MHC I or MHC II expressionblock complement activationinhibit apoptosisetc!30SIDE EFFECTS OF INTERFERONS FEVER MALAISE FATIGUE MUSCLE PAINS31BACK TO INFLUENZA32PROTECTION AGAINST RE-IN

15、FECTION IgG and IgA IgG less efficient but lasts longer antibodies to both HA and NA important antibody to HA more important (can neutralize)33SYMPTOMS FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS34CLINICAL FINDINGS SEVERITY VERY YOUNG ELDERLY IMMUNO-COMPROMISED HEART OR LUNG DISEASE35PULMO

16、NARY COMPLICATIONS CROUP (YOUNG CHILDREN) PRIMARY INFLUENZA VIRUS PNEUMONIA SECONDARY BACTERIAL INFECTION Streptococcus pneumoniae Staphlyococcus aureus Hemophilus influenzae36NON-PULMONARY COMPLICATIONS myositis (rare, in children, with type B) cardiac complications recent studies report encephalop

17、athy studies of patients in children, in type B) cardiac complications encephalopathy liver and CNS Reyes syndrome peripheral nervous system Guillian-Barr syndrome39Guillian-Barr syndrome 1976/77 swine flu vaccine 35,000,000 doses 354 cases of GBS 28 GBS-associated deaths recent vaccines much lower

18、risk40MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH BACTERIAL PNEUMONIA CARDIAC FAILURE 90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE41DIAGNOSIS ISOLATION NOSE, THROAT SWAB TISSUE CULTURE OR EGGS SEROLOGY RAPID TESTS provisional - clinical picture + outbreak42SSSSSScell enzymesacid pH HA

19、 protein - attachment, fusion 43 NA protein - neuraminidase 44ANTIGENIC DRIFT HA and NA accumulate mutations RNA virus immune response no longer protects fully sporadic outbreaks, limited epidemics45ANTIGENIC SHIFT “new” HA or NA proteins pre-existing antibodies do not protect may get pandemics46INF

20、LUENZA A PANDEMICSRyan et al., in Sherris Medical Microbiology 47where do “new” HA and NA come from? 13 types HA 9 types NA all circulate in birds pigs avian and human48where do “new” HA and NA come from?49why do we not have influenza B pandemics? so far no shifts have been recorded no animal reserv

21、oir known50SURVEILLANCECDC/Katherine Lord51actual percentage of deaths(CDC MMWR 2003 / Vol. 52 / No. RR-8)52010203040506070809010099/0000/01 01/02 02/03H1N1H3N2B53VACCINE BEST GUESS OF MAIN ANTIGENIC TYPES CURRENTLY type A - H1N1 type A - H3N2 type B each year choose which variant of each subtype is

22、 the best to use for optimal protection54VACCINE inactivated egg grown sub-unit vaccine for children reassortant live vaccine approved 2003 for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years55CDC56RECOMMENDATIONSPersons at High Risk for Influenza-Relat

23、ed Complications $ 65 years residents of nursing homes and other chronic-care facilities adults/children who have chronic pulmonary or cardiovascular disorders, including asthma adults/children who have required regular medical follow-up or hospitalization during the last year because of chronic met

24、abolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications) 57RECOMMENDATIONSPersons at High Risk for Influenza-Related Complications children and teenagers (6 mths to 18 yrs) receiving long-term aspir

25、in therapy - might be at risk for developing Reye syndrome after influenza women who will be in the 2nd or 3rd trimester of pregnancy during the influenza season.58RECOMMENDATIONSPersons aged 50-64 years increased prevalence of high-risk conditionsfrom public health point of view, easier to target b

26、y age than by high-risk condition (which may not have been discovered)59RECOMMENDATIONSPersons Who Can Transmit Influenza to Those at High RiskPersons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. 60RECOMMENDATIONS

27、 physicians, nurses, and other personnel in both hospital and outpatient-care settings employees of nursing homes and chronic-care facilities who have contact with patients or residents employees of assisted living and other residences for persons in high-risk groups persons who provide home care to

28、 persons in high-risk groups household members (including children) of persons in high-risk groups.61RECOMMENDATIONSChildren from 0-23 mths are at increased risk for hospitalization from influenza, vaccination is encouraged for their household contacts and out-of-home caretakers, particularly for contacts of children aged 05 months because influenza vaccines have not been approved for use among children aged 6 months.62RECOMMENDATIONS others, including travelle