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Virology > Influenza Viruses > Flashcards

Influenza Viruses Flashcards

1
Q

What is the history of Influena?

A
  • Influenza has been described as early as 400 bc.
  • Major epidemics and pandemics of influenza have occurred throughout history.
  • Many virologists think another influenza pandemic that could kill millions of humans is inevitable.
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2
Q

What is the epidemiology of influenza?

A

Epidemics become unmanageable at alarming speeds because:

  • Short incubation period (1-4 days)
  • One droplet can contain 100,000 to 1,000,000 virus particles
  • Symptomatic people do not stay home =spread
  • Lack of herd immunity

Absenteeism from schools is the best indicator of the scale of an epidemic.

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3
Q

What are the statistics of Influenza?

A
  • 1957–1987: 20 influenza epidemics were recorded in the United States
  • > 200,000 people in the US are hospitalized each year for respiratory and heart conditions illnesses associated with seasonal influenza virus infections
  • 36,000–50,000 people have died as a direct or indirect consequence of an influenza infection annually
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4
Q

What is involved in the 1918 Influenza Pandemic?

A
  • Also called the Spanish flu
  • Killed 675,000 Americans; 50-100million people worldwide
  • National average death rate was 4.39 out of every 1000 people
  • Unique epidemic: healthy adults ages 20-40 died of the flu, in addition to children and elderly ( who are usually high-risk)
  • It decreased the life expectancy in the US by 11 years
  • Close troop quarters and massive troop movements hastened the pandemic
  • John Barry’s “The Great Influenza”
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5
Q

What are the clinical features of Influenza?

A

Uncomplicated Infection

Onset of symptoms:

  • Heachache
  • Aching in the limbs and back
  • Fever (100-103)
  • Malaise
  • Dry cough
  • Tickling throat
  • Sore throat
  • Myalgia
  • Chest x-ray is normal

Usually resolves itself after 7 days.

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6
Q

What are the clinical features involved in complicated infection?

A
  • Age-dependent
  • Young children: croup, secondary bacterial pneumonia, middle ear infections
  • Elderly: life-threatening secondary bacterial pneumonia, pre-existing conditions like congestive heart disease exacerbated
  • Immune compromised individuals at risk of death during an influenza epidemic
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7
Q

What is Reye’s Syndrome?

A
  • Rare condition
  • Risk of developing Reys’s syndrome increases with aspirin use
  • R.S. affects all organs of the body

Most harmful to the brain and liver

Casues pressure in the brain and massive accumulation of fat in the liver and other organs

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8
Q

What is the classification of Influenxa viruses?

A
  • Orthomyxoviridae family
  • 3 types of influenza: A, B and C
  • All 3 can infect and cause similar symptoms in humans.
  • Infection with one type does not confer immunity to another type of influenza.
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9
Q

What is the laboratory Diagnosis of Influenza?

A

Office-based rapid tests: ELISA assays

  • Some can distinguish between influenza A and B
  • Fast results: 1 to 20 minutes
  • Some false-positive or negative results

Other tests

  • Cell culture: inoculate MDCK cells, most accurate test

Serology

  • Analyze convalescent serum and analyze for an increase in antibody titer

“Flu chips” or microarrays

  • Microarray detection panel used during 2009 H1N1 pandemic
  • Glycan microarray analysis
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10
Q

What is the cellular pathogenesis of the virus?

A
  • Droplet transmission
  • Virus enters repiratory tract
  • Attaches to ciliated columnar epithelial cells lining the sinuses and airways
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11
Q

What is the Influenza Pathogensis?

A
  • Primary site of infection: tracheobronchial tree, involving nasopharynx
  • As virus replicates, cilia are destroyed.

Cleaning system in the lungs does not work as well.

More mucus stays in the airway, clogging them and causing coughing.

  • Destruction of cilia contribute to secondary bacterial pneumonia infections, sinusitis, otitis
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12
Q

What is the Humoral Immunity?

A
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13
Q

What are Mucosal Antibodies?

A
  • Secretory antibodies are the first line of defense
  • IgA in the upper respirator tract
  • Accumulates in mucosal secretions
  • Stimulated by nasal vaccine
  • IgG involved in systemic protection
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14
Q

What is Cellular Immunity against influenza?

A

T cell response directed against “conserved” viral proteins

  • CD4 T cells stimulate antibody responses
  • CD8 T cell kill virally infected cells

Immunity generated against one strain may provide protection against another stratin (heterosubtypic immunity)

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15
Q

What is a cytokine storm?

A
  • Also referred to tas systemic inflammatory response syndrom (SIRS)
  • SIRS may explain the devastating nature of the 1918 strain of influenxa.
  • The immune system overreacts towards teh pathogen
  • Cytokines signal macrophages to travel to the site of infection, causing damage to the body and organ failure.
  • H5N1 avian influenza virus also causes SIRS and is at least 50% lethal in humans
  • See Virus File 12-2
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16
Q

Describe the properties of the Influenza A Viral Particles?

A

Properties of the Influenza A Particle

  • Immediately after isolation, particles are filamentous
  • After several passages in cell cultures, the particles become spherical
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17
Q

What is the Influenza Nomenclature?

A
  • Influenza type (A or B)
  • Species isolated form/(unless human)
  • Place of isolation (geographic)
  • Strain designation/Isolate number
  • Year isolation
  • HA and NA subtypes
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18
Q

What is HA and NA subtypes of Influenza A Viruses?

A
  • 16 different HA subtypes
  • 9 different NA subtypes
  • Only H 1, 2 and 3, and N 1 and 2 are comomonly found in human
  • H5, H7, and H9 occur rarely (bird transmitted viruses)
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19
Q

What is the Influenza Virus Genome?

A

Eight influenza virus genome segments (-ssRNA) code for a total of 11 different viral proteins

  • Nine of the proteins are packaged into viral particles.
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20
Q

What are important parts of Influenza A Life cycle?

A

The low pH causes HA to undergo a conformational change

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21
Q

What is Viral Hemagglutinin?

A

Hemagglutinin (HA) protein binds to cell receptors and mediates fusion of the envelope with the endosomal membrane

  • Heemagglutinin protein binds to sialic acid resdiues on muco-proteins
  • HA can agglutinate red blood cells which is the basis for the hemagglutination assay
  • HA is a type I transmembrane protein
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22
Q

What is involved in the uncoating step in Influenza A?

A
  • M2 ion channel in the viral envelope allows H+ ions to penetrate the virion
  • Weakens the viral M1 matrix protein from the viral RNA, NP and transcriptase complex (RNP)
  • RNPs released into the cytoplasm
  • Amantidine (sold as Symmetrel) and rimantidine (sold as Flumadine) block the M2 ion channel function, interfering with uncoating
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23
Q

What are viral Nucleocapsids?

A

Nucleocapsid protein (NP) binds to viral genome RNA

  • NP protein wraps the RNA into an unususal twin helical conformation with a central loop

Trimer consisting of RNA polymerase proteins PA, PB1, and PB2 bound to 5’ and 3’ ends of RNA

  • Contain nuclear localization signals that interact with importin-a to protmote entry into the nucleus
  • Nucleocapsids enter the nucleus where mRNA synthesis and RNA replication occur.
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24
Q

What is involved in the Transport of Viral mRNAs and Proteins during replication?

A

Unlik other RNA viruses, orthomyxoviruses replicate in the nucleus.

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25
Q

Wha tis the mRNA synthesis and replication of virion RNA?

A

After the viral RNPs enter the nucleus, mRNA synthesis begins.

Cap-snatching process

  • Viral PB2 protein binds to the cap structure on the cellular mRNA
  • Viral PB1 cleaves the RNA 10-13 nt from its 5’ end
  • PB1 uses cap as a primer from copying genome RNA into viral mRNA
    *
26
Q

What is involved in Viral mRNA’s terminate in Poly(A) tails?

What is “Stuttering” transcription?

A

“Stuttering” Transcription

  • Short stretch of poly(U) at end of genomic RNA
  • Viral RNA polymerase pauses and “stutters” at poly(U) sequence
  • Multiple read-throughs and addition of complementary A residues
  • Allows for export out of the nucleus into the cytoplasm for translation
27
Q

What is involved in the suppression of Cellular mRNA production?

A

NS1 is most abundant protein in infected cells

  • Interferes with polyadenylation of cellular mRNAs
  • Prevents nuclear export of cellular mRNAs

PB1 and PB2 degrade cellular pre-mRNAs

28
Q

What is alternative splicing?

A
  • Transcription generates complete set of 8 viral mRNAs
  • Six mRNAs are exported directly to the cytoplasm
  • Two influenza A mRNAs contain splicing sequences recognizable by cellular splicing machinery and undergo alternative splicing

Unspliced RNAs create M1 and NS1
Spliced RNAs create M2 and NS2 (less abundant)

29
Q

What is involved in replication of the viral genome?

A

Genome replication begins when newly synthesized NP protein enters the nucleus

  • Replication of genome requires no primer
  • PB1 copies genomic RNA into complementary (+) strand that is then coated with NP
  • Antigenome RNA copied into genomic RNA by same mechanism
30
Q

What is involved in the immune evasion?

A

The NS1 protein also suppresses a variety of host cell antiviral response pathways

  • Inhibits RIG-I (triggers release of type I IFN)
  • Inhibits double stranded RNA-dependent protein kinase (PKR)
  • Inhibits 2’,5’-oligo(A) synthetase/Ribonuclease L

PB1-F2 may contribute in suppression of the host immune response

  • Localizes to mitochondria and induces apoptosis in host immune cells
31
Q

What is involved in the virion maturation and assembly?

A
  • Capped mRNAs exported from nucleus are translated by ribosomes in the cytoplasm
  • H, N, and M2 are folded and glycoylated and transported to the trans-Golgi network and cell surface where assembly takes place
  • One copy of each genome segment is packaged into the virion.
32
Q

Wha tis the release of the influenza Virions?

A

Virions are released by budding

  • The viral neuraminidase (NA) proteins cleaves the sialic acid on host cells to prevent clumping of viral particles at the host surface.
  • Zamanivir (sold as Relenza) and oseltamivir phosphate (sold as Tamiflu) inhibit the function of NA.
33
Q

What is involved in the genetic varitation?

A
  • Mutations are common during viral replication.
  • Viral RNA dependent RNA polymerase lacks proofreading and correction ability.
  • Two processes, antigenic drift and antigenic shift, mediate genetic variation that causes new strains of influenza to appear.
34
Q

What antigenic drift for influenza involves?

A
  • Small change in HA and/or NA genes
  • Selective pressure from immune system
  • Cause of yearly epidemics
  • Reason for yearly reformulation of flu vaccine
35
Q

What is involved in antigenic shift?

A

Reassortments between human and bird flu viruses resulting in novel strain

  • Only occurs with influenza A viruses

Responsible for pandemic strains

  • No antibodies against new strain
  • Unusally high number of cases and deaths
36
Q

Is china the incubator for flu viruses?

A
  • Close association of humans with animals and birds
  • Influenza A is constantly circulatin gin birds, pigs, and horses
37
Q

Why is influenza more prevalent during the winter?

A
  • Aerosol spread of influenza virus is dependent upon humidity and temperature
  • The virus was best transmitted at low humidity and colder temperatures
  • Supoorting evidence shows that weather conditions play a role in influenza virus transmission
38
Q

Describe teh 1918 Spanish Flu stats..

A

Killed more people in 25 weeks than AIDS killed in 25 years
Killed more people in a year than the plagues of the Middle Ages killed in a century
Estimated deaths: 20 to 50 million, including 675,000 Americans
In NYC, 21,000 children were orphaned by influenza.
7 times as many people died of the 1918 Spanish Flu than in WWI.
True estimates will never be known.

39
Q

What is the effects and why are they unique?

A
  • It killed 20- to 40-year old adults
  • It killed quickly (2-3days)
  • Those infected suffered from hemorrhagic symptoms
40
Q

Why was the 1918 spanish flu so Deadly?

A
  • Johan Hultin exhumed bodies of flu victims buried in frozen ground at Brevig Mission, Alaska.
  • Removed frozen lung tissues and provided them to Jeffrey Taubenberger (Armed Forces Institute of Pathology in Washington, DC), who sequenced the viral genome of the 1918 strain.
  • 1918 was an avian—not swine—strain.
41
Q

What was involved in the recreation in the lab of influenza?

A
  • Terrence Tumpey, CDC researcher
  • Reverse genetics
  • Work done in an enhanced BSL-3 laboratory
42
Q

What was the Yoshihiro Kawaoka in 2007?

A
  • Infected macaques with the reconstructed 1918 influenza virus
  • Carried out experiments in a BSL-4 laboratory
  • Macaques died of SIRS (cytokine storm)
43
Q

What was involved in the 1957 asian flu?

A
  • 70,000 Americans died
  • Asian flu first identified in northern China (February 1957) and spread to the United States by June 1957
  • Vaccine was made and available by August 1957.
44
Q

What was involved in the 1968 Hong Kong flu?

A
  • First detected in Hong Kong during early months of 1968
  • Reached the United States by September 1968
  • Deaths in the United States peaked in December 1968–January 1969 (mostly elderly)
  • Mildest pandemic in the century, killing only 33,800 people in the United States
45
Q

What was a pandemic “scare” in 1976 Swine flu?

A
  • February 1976: Cadets at Fort Dix, NJ came down with the flu; one private died.
  • CDC investigated the outbreak.
  • 4 out of 19 throat washings tested positive for H1N1 influenza A (at the time believed to be a “swine” flu closely related to the 1918 Spanish flu virus).
  • 150 million doses of vaccine were prepared in the United States.
  • 46 million doses were administered within a few months.
  • Vaccine was fast-tracked.
  • Congress passed a liability protection bill to protect manufacturers of the vaccine.
  • Early problems of the vaccine:
  • Guillain-Barré syndrome (532 people within 10 weeks)
  • 32 deaths
  • Vaccine campaign was suspended in the late fall of 1976.
  • U. S. government paid more than $90 million on claims cases.
46
Q

Describe the 1977 Russian Flu Scare: A/USSR/77/H1N1?

A

May 1977: Influenza A H1N1 isolated in northern China

Primarily children and younger adults became ill.

This strain was similar to the 1957 strain.
Individuals born before 1957 would have no cross-reacting/partial immunity toward the virus.

47
Q

Describe the 1997 Avian Flu Scare: H5N1

A

May 1997: 3-year-old boy in Hong Kong died.
Influenza A isolated from the boy but the H subtype could not be identified.
Later confirmed to be H5
H5 not known to infect humans before (subtype isolated from birds only)
The “jump” of an avian strain directly to humans had never happened before.
The same H5N1 strain was killing chickens.

48
Q

What was teh Hong Kong H5N1 scare?

A

Veterinary authorities slaughtered chickens to prevent the spread of H5N1 to chickens and people.

49
Q

What were the lessons learned from the 1997 H5N1 Hong Kong flu?

A

Only 18 human cases in 1997
33% fatality rate
1918 flu was about 4% fatal in the United States.
It is possible that a single insertion (mutation) could enable the virus to spread much more efficiently to the brain and heart.
The most important control measures are:
rapid culling of infected or exposed bird and proper disposal of carcasses
quarantining and rigorous disinfection of farms
Continual surveillance is key
60 individuals infected with H7N9 “bird flu” in China 2013

50
Q

Describe the 2009 H1N1 Swine Flu?

A
  • Contrary to what many experts expected, the first pandemic of the 21st century started in North America and not in Southeast Asia.
  • More than 75% of individuals infected were younger than 30 years of age.
  • U.S. conservative estimates: H1N1 flu deaths ranged from 7,500 to 12,000
  • Seroprevalence studies: Older people had strong antibody reactions toward H1N1 than younger people, suggesting they had some cross-reacting antibodies from exposure to influenza viruses before 1957.
51
Q

Describe the 2009 H1N1 swine influenza genetics?

A

Arose via recombination between viruses of Eurasian and North American swine
HA protein strongly resembles HA protein of 1918 pandemic virus
Little variation over 90 years because viruses circulated in swine

52
Q

What are part of the antivirals for influenza treatment?

A

First drugs: M2 inhibitors (prevent uncoating step)

  • Amantidine (sold as Symmetrel)
  • Rimantidine (sold as Flumadine)

New class of antivirals: N inhibitors (prevents neuraminidase from cleaving sialic acid during budding)

  • Causes viruses to clump at the cell surface, reducing viral spread
  • Oseltamivir (sold as Tamiflu, pill form)
  • Zanamivir (sold as Relenza, must be inhaled)
  • Peramivir received Emergency Use Authorization to treated hospitalized patients with a severe case of H1N1 in 2009.

Treatment must begin within 36 hours of onset of symptoms.
Used prophylactically in chronic care facilities

53
Q

What are the vaccines involved?

A
  • Most effective way to prevent influenza
  • Flu vaccination time in the United States
  • October and November
  • Vaccine grown in eggs
  • Inactivated trivalent vaccine
  • Live attenuated vaccine (LAIV)
  • Licensed in 2003
  • Only approved for healthy people ages 5–49 years
54
Q

What is trivalent vaccine (TIV) composition?

A
  • Recommendations made based on antigenic analyses of recently isolated influenza viruses, epidemiologic data, and post-vaccination serologic studies in humans
  • Vaccine is a cocktail of 3 virus strains
  • 2 strains of influenza A
  • 1 influenza B strain
  • Efficacy depends on age
  • Children: 30-70%
  • Adults: 70-90% (when matched)
  • Elderly (> 65 yrs):
55
Q

What is FluMist Vaccine (LAIV)?

A

Cold-adapted attenuated viruses; replication restricted to upper respiratory tract

  • Viral reassortants of circulating strains (H1N2, H3N2, B)

Individuals 2-49 years of age

  • Not for children < 24 months old or asthmatics
  • Concerns with immunocompromised individuals

Induction of mucosal antibodies and T cell immunity

56
Q

What is the effectiveness of the vaccine?

A

TIV vs. LAIV
Age of the vaccine recipient
Immunocompetence of the recipient
Degree of similarity between the viruses in the vaccine and those in circulation

57
Q

What are the target groups for Vaccination?

A
  • Persons aged 50 or older
  • Individuals in chronic care facilities
  • including nursing homes
  • Individuals with pre-existing chronic problems
  • asthma, other pulmonary or cardiovascular problems, immunosuppression
  • Children on long-term aspirin therapy
  • Pregnant women
  • Healthcare workers
  • Travelers
58
Q

What is the international Influenza Surveillance?

A
  • In 1946, WHO established influenza surveillance program.
  • U.S. sentinel physicians send flu statistics to the CDC.

Patient visits for influenza-like illness
Age groups
Morbidity and mortality statistics
Identify circulating strains for inclusion in annual flu vaccine formulations

59
Q

Will there be another killer flu?

A
  • Virologists say it is inevitable.
  • Many pandemic planning teams are at the international, national, state, and local levels.
  • Mass media played a vital role communicating to public and healthcare professionals during the 2009 H1N1 pandemic.
60
Q

What is reverse genetics to create pandemic avain flu vaccines?

A
  • Avian influenza strains cannot be grown in embryonated eggs.
  • Avian strains kill the eggs.
  • Reverse genetics allows experts to grow avian strains in cell cultures.
  • Developed by Dr. Webster so that rapid avian flu vaccines can be made.
61
Q

How do you prepare for a pandemic influenza vaccine reverse genetics or a universal vaccine?

A

Researchers working on a universal vaccine based on the used of the influenza A, M2 protein.

Virology (23 decks)

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