שפעת Influenza

1. שפעת Influenza מחלת השפעת ונגיפי השפעת

2. מחלת השפעת Flu • Flu sometimes is confused with the common cold. However, the flu is caused by influenza virus, and is a much more severe disease than the common cold, which is caused by a different type of virus. Influenza is a more severe viral infection of the respiratory tract that shows the additional symptoms to those of the common cold (rapidly rising fever, chills, and body and muscle aches). • Respiratory Syncytial Virus אשר תוקף בעיקר ילדים גורם למחלה דמוית שפעת. • עוד מחלה של מערכת הנשימה נגרמת ע"י נגיף אדנווירוס (Adenovirus 3) מתאפיינת באותם סימפטומים ועל כן נקראת “flu" בארה"ב גם על ידי חולים וגם רופאים. אחד הסיבוכים בעקבות ההדבקה יכולה להיות דלקת ריאות וכדומה.

3. מגיפות השפעת • ב-400 השנים האחרונות, תועדו שלושים מגפות השפעת בעולם המערבי. • המגפה הספרדית Spanish Flu היא המפורסמת מכולן. • 1918 - מגפת השפעת (influenza) גרמה למותם של 20 מיליון בני אדם, ולהפסקת מלחמת העולם ה -I . • במלחמת העולם I נפלו פחות קורבנות מ-"היספנקה".

4. מגיפות השפעת • זני הנגיפים החדשים של השפעת שהופיע והתפשטו בעולם ב-50 השנים האחרונות לא היו אלימים כל כך. • הייתה מגפה של השפעת האסיאתית (1957-1958), היו מגפות גדולות כל 10 שנים, אבל פחות מסוכנות. • תסמונת ריי - Reye Syndrome - זהו סיבוך אשר מתבטא בחדירת נוזלים לתוך המוח. פוגעת בילדים.

5. INFLUENZA - the name • Influenza is Italian for "influence", Latin: influentia. It used to be thought that the disease was caused by a bad influence from the heavens.

6. מחלת השפעת

7. Fluשפעת • אנחנו יודעים שהשפעת היא מחלת מערכת כלי הנשימה. אבל כל אחד זוכר גם • כאבי שרירים • עייפות • "עצלנות"

8. CLINICAL FEATURES • לא קל להיות החבר הכי טוב... • Influenza is characterized by fever, myalgia, headache and pharyngitis. In addition there may be cough and in severe cases, prostration. There is usually not coryza (runny nose), which characterizes common cold infections. • Infection may be very mild, even asymptomatic, moderate or very severe.

9. Source • The reservoir is acute infection in other human beings. Spread • Is rapid via aerial droplets and fomites with inhalation into the pharynx or lower respiratory tract.

10. Incubation • Is short: 1-3 days. Rapid spread leads to epidemics

11. Complications • Tend to occur in the young, elderly, and persons with chronic cardio-pulmonary diseases. • Consist of: • 1. Pneumonia caused by influenza itself; • 2. Pneumonia caused by bacteria (not influenza virus itself): • - Haemophilus influenzae , • - Staphylococcus aureus , • - Streptococcus pneumoniae . • 3. Other viral superinfection, eg. Adenovirus. • Overall death rates increase in times of influenza epidemics.

12. Types of influenza virus • There are three types of influenza: • Influenza C - Common but seldom causes disease symptoms • Influenza B - Often causes sporadic outbreaks of illness, especially in residential communities like nursing homes. • Influenza A - Responsible for regular outbreaks, including the one of 1918. Influenza A viruses also infect domestic animals (pigs, horses, chickens, ducks) and some wild birds.

13. Structure of influenza A virus • סלילי • קופסית חלבונית • מעטפת • חודים (Spikes) • 8 מקטעים של רנ"א חד-גדילי – (שלילי) • גורם מחלת השפעת In the lipid bilayer there are two integral membrane proteins: Hemagglutinin –”H”andneuraminidase - ”N”

14. Influenza Viruses. Morphology • Influenza virus particles are highly pleomorphic, mostly spherical/ovoid, many forms occur. • The outer surface of the particle consists of a lipid envelope from which project prominent glycoprotein spikes. • The inner side of the envelope is lined by the matrix protein. • The genome segments are packaged into the core.

15. Genomic organization of influenza A virus • The (-) strand RNA genome comprises 8 segments, each encodes at least one protein: • 1) 3 distinct hemagglutinins: H1, H2, and H3 • 2) 2 different neuraminidases N1 and N2 • 3) nucleoprotein • 4) matrix proteins • 5) NS (nonstructural proteins, that are not incorporated into viral particles) gene encodes two different non-structural proteins • 6)-8) subunits of RNA polymerase

16. Subtypes of influenza A • The hemagglutinin of the 1918 flu virus was H1, its neuraminidase was N1, so it is designated as an H1N1 "subtype". • Flu pandemics occur when the virus acquires a new hemagglutinin and/or neuraminidase.

17. Taxonomy Family Orthomyxoviridae • 1.Genus Influenzavirus A • Type species influenza A virus • 2.Genus Influenzavirus B • Type species influenza B virus • 3.Genus Influenzavirus C • Type species influenza C virus • 4.Genus Thogotovirus • Type species Thogoto virus

18. OrthomyxovirusesInfluenza A Viruses • Infect a wide variety of mammals, including man, horses, pigs, ferrets and birds. • Pigs and birds are believed to be particularly important reservoirs, generating pools of genetically/antigenically diverse viruses which get transferred back to the human population via reassortment (close contact between pigs and man in the far east; Ducks - migration!). • The main human pathogen, associated with epidemics and pandemics.

19. OrthomyxovirusesInfluenza B Viruses. • Infect much man and birds. • Cause human disease but generally not as severe as A types. • Believed to be epidemiologically important - reassortment with type A leads to epidemics.

20. וירוס השפעתInfluenzavirus A • Virions enveloped • About 500 spikes • Nucleocapsid enclosed within lipoprotein membrane • Virions contain 8 segments of linear negative-sense single stranded RNA • Total genome length is 13588 nt • The largest segment 2341 nt

21. וירוס השפעתInfluenzavirus B • Virions enveloped • About 500 spikes • Nucleocapsid enclosed within lipoprotein membrane • Virions contain 8 segments of linear negative-sense single stranded RNA • Total genome length is 13588 nt • The largest segment 2341 nt

22. וירוס השפעתInfluenzavirus C • Virions enveloped • Many spikes • Nucleocapsid enclosed within lipoprotein membrane • Virions contain 7 segments of linear negative-sense single stranded RNA • Total genome length is 12900 nt • The largest segment 2300-2500 nt

23. OrthomyxovirusesInfluenza C Viruses. • Influenza C viruses infect man alone, but do not cause disease (?). • They are genetically and morphologically distinct from A and B types - little studied.

24. מחזור החיים

25. שכפול הנגיפים - Single-cell reproductive cycle 1. Attachment to the epithalial cells of the host through hemagglutinin. 2. Endocytosis 3. Uncoating -> This exposes the contents of the virus to the cytosol. 4.The RNA enter the nucleus of the cell where fresh copies are made. 5. These copies return to the cytosol where some serve as mRNA molecules to be translated into the proteins of fresh virus particles. 6. Fresh virus buds off from the plasma membrane of the cell (aided by the neuraminidase) thus spreading the infection to new cells.

26. שכפול הנגיפים - Single-cell reproductive cycle • 3) Replication (mRNA) • 5) Transport • 6) Splicing • 7,8,9) Translation • 10) Import • 11,12,13) Catalysis of synthesis

27. Assembly– שלב ההרכבה 1. Packaging 2. Little is known 3. NS2 binding and export of the nucleocapsid to the cytoplasm 4. M1 directs the nucleocapsid to the membrane 5.Viral proteins reach the site 6. Budding 7. Release

28. Life-cycle • New viral proteins are translated from transcribed messenger RNA (mRNA). • New viral RNA is encased in the capsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. • Progeny virions are formed and released by budding. • The cell does not die (at least not initially).

29. Influenza Viruses. Replication

30. Influenza Viruses. Replication • התקשרות חודים לדופן התא מקדמת כניסת הנגיף. • After binding, the particle is engulfed by endocytosis via coated pits (גומות) into endocytotic vesicles and finally endosomes. • Specific nuclear targeting sequences result in translocation of the nucleocapsid (קופסית הגרעין) into the nucleus.

31. שכפול הנגיפים - A

32. שכפול הנגיפים - Single-cell reproductive cycle 1. Endocytosis 2. Release nucleocapsids 3. Transport into the nucleus 4. Copying by RNA polymerase into viral mRNA 5. Transport to the cytoplasm 6. Splicing

33. שכפול הנגיפים - Single-cell reproductive cycle 6. Splicing of NS2 and M2 7. Translation of Ha, Na, M2 8,9. Translation 10. Import into the nucleus of PA, PB1, PB2, and NP proteins 11. Synthesis of full-length (+) RNAs

34. Assembly 1. Packaging 2. Little is known 3. NS2 binding and export of the nucleocapsid to the cytoplasm 4. M1 directs the nucleocapsid to the membrane 5.Viral proteins reach the site 6. Budding 7. Release

35. Life-cycle • New viral proteins are translated from transcribed messenger RNA (mRNA). • New viral RNA is encased in the capsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. • Progeny virions are formed and released by budding. • The cell does not die (at least not initially).

36. Influenza Viruses. Replication • The virus attaches to the outside of the host cell and its RNA enters into the cell. • The viral genes are transcribed and translated by the cell's enzymes and ribosomes. • In this way, the virus takes over the cell's productivity.

37. Influenza Viruses. Replication • Now, instead of producing only new cellular material, the cell produces hundreds of new virus particles. • The new virus particles are eventually released from the cell and drift off, and some may land on a host cell of their own to pirate.

38. Influenza Viruses. Replication • Virus particles are gradually released from the surface of the cell over a period of several hours. • The cell does not lyse, but eventually dies (due to disturbance of normal cellular macromolecular synthesis?).

39. Influenza. Pathogenesis • Spread is by aerosols. • The influenza virus invades cells of the respiratory passages. Primary infection involves the ciliated epithelial cells in the nose, throat and intestines of birds. • Necrosis of these cells results in the usual symptoms of the acute respiratory infection (fever, chills, muscular aching, headache, prostration, anorexia).

40. Influenza. Pathogenesis • Normally self-limited infection usually lasts 3-7 days (כולל החלמה). • It usually does not kill the patient (the 1918 pandemic was an exception; some victims died within hours) but does expose the lungs to infection by various bacterial invaders that can be lethal. Damage to respiratory epithelial cells predisposes to secondary bacterial infections which accounts for most deaths.

41. Virus reassortment • H and N are encoded by separate RNA molecules. • If an animal is simultaneously infected by two different subtypes, these genes can be reassorted. • For example: pigs simultaneously infected with swine flu virus (H1N1) and the Hong Kong virus (H3N2): H3 and N1 are reassorted in a pig and a new H3N1 virus appears. • Reassortment can also occur in humans with dual infections.

42. Virus reassortment

43. Antigenic shifts

44. חיסונים ותרופות • A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time and different strains become dominant.

45. חיסונים ותרופות • Some vaccines incorporate inactivated virus particles; others use the purified hemagglutinin. Both types incorporate antigens from the three major strains in circulation, (the trivalent flu vaccine) currently: • an A strain of the H1N1 subtype • an A strain of the H3N2 subtype and • a B strain. • Antiviral drugs can be used to treat influenza

46. What is avian influenza? • Avian influenza, or “bird flu”, is a contagious disease of animals caused by viruses that normally infect only birds and, less commonly, pigs. Avian influenza viruses are highly species-specific, but have, on rare occasions, crossed the species barrier to infect humans. • In domestic poultry, infection with avian influenza viruses causes two main forms of disease, distinguished by low and high extremes of virulence. The so-called “low pathogenic” form commonly causes only mild symptoms (ruffled feathers, a drop in egg production) and may easily go undetected. The highly pathogenic form is far more dramatic. It spreads very rapidly through poultry flocks, causes disease affecting multiple internal organs, and has a mortality that can approach 100%, often within 48 hours.

47. Which viruses cause highly pathogenic disease? • Influenza A viruses have 16 H-subtypes and 9 N-subtypes. Only viruses of the H5 and H7 subtypes are known to cause the highly pathogenic form of the disease. However, not all viruses of the H5 and H7 subtypes are highly pathogenic and not all will cause severe disease in poultry. • On present understanding, H5 and H7 viruses are introduced to poultry flocks in their low pathogenic form. When allowed to circulate in poultry populations, the viruses can mutate, usually within a few months, into the highly pathogenic form. This is why the presence of an H5 or H7 virus in poultry is always cause for concern, even when the initial signs of infection are mild.

48. What is special about the current outbreaks in poultry? • The current outbreaks of highly pathogenic avian influenza, which began in South-east Asia in mid-2003, are the largest and most severe on record. • Never before in the history of this disease have so many countries been simultaneously affected, resulting in the loss of so many birds.

49. What is special about the current outbreaks in poultry? • The causative agent, the H5N1 virus, has proved to be especially tenacious. • Despite the death or destruction of an estimated 150 million birds, the virus is now considered endemic in many parts of Indonesia and Vietnam and in some parts of Cambodia, China, Thailand, and possibly also the Lao People’s Democratic Republic. • Control of the disease in poultry is expected to take several years.

50. What are the implications for human health? • The widespread persistence of H5N1 in poultry populations poses two main risks for human health. • The first is the risk of direct infection when the virus passes from poultry to humans, resulting in very severe disease. • Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of cases of severe disease and death in humans.