L3/4 - Influenza Flashcards

1
Q

Where does the variation mostly on influenza?

A

HA segment

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2
Q

What are the 5 criteria for naming influenza?

A
  1. Subtype (A/B/C)
  2. Location
  3. Number
  4. Year of isolation
  5. Information HA/NA
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3
Q

How many HA and NA groups are there?

A

18 HAs

9 NAs

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4
Q

How much % difference can HAs (and NAs) have?

A

30%

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5
Q

What animal species can all types of influenza infect?

A

Birds

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6
Q

How does HA0 make HA1 and HA2?

A

HA0 is cleaved by cellular proteases

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7
Q

What is the determinant of host range?

A

Specificity of receptor binding: HA-SA

a2-3 or a2-6 linkages

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8
Q

Which sialic acid linkages do BIRDS and HUMANS have?

A

Birds: a2-3
Humans: a2-6

PROTECTS HUMANS FROM MANY AVIAN INFLUENZAS

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9
Q

Why is host specificity not so straight forward?

A

HA proteins can attach to both a2-3 and a2-6

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10
Q

What strains tend to be low pathogenicity ‘seasonal’ flu?

A

H1, H2, H3

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11
Q

What strains have decimated chicken populations?

A

H5, H7

240mil chickens culled/died

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12
Q

How do HAs show differenced in their preferred hosts?

A

ability to cleave the host’s sialic acid

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13
Q

How many virus particles can one sneeze contain?

A

1,000,000

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14
Q

What are the 2 ways flu is transmitted?

A

Virus inhalation via respiratory tract

direct contact - fomites

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15
Q

How is direct contact for flu prevented?

A

Personal hygiene

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16
Q

What are symptoms of influenza mostly due to?

A

immune response

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17
Q

What is responsible for the different peak months in north/south hemispheres?

A

Climatic influence of summer and winter

UV exposure

LOW TEMPERATURE
LOW HUMIDITY

Social behaviour - indoor crowding, xmas

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18
Q

What conditions are best for flu transmission?

A

low temp - 5c
Low humidity - 20-35%

viruses are more stable and increased chance of droplet inhalation

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19
Q

What type of flu was the 1918 Spanish flu?

A

H1N1

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20
Q

what are the reasons for the severity of the 1918 Spanish flu?

A

cleavability of the HA protein

The HA protein could be cleaved by OTHER PROTEASES - infect other cells and ORGANS

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21
Q

What is antigenic DRIFT?

A

RdRP makes errors when copying

1/10000

incorporation of SINGLE NUCLEOTIDE CHANGES

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22
Q

Why are most anitgenic drift changes on HA1?

A

HA1 has low functional restrictions

most mutations are OUTSIDE THE RECEPTOR BINDING SITE

changes would affect ability of HA to bind to SA in binding site

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23
Q

What is antigenic SHIFT?

A

2 different flu viruses infect the same cell

RARE EVENT! (PANDEMICS)

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24
Q

How does the pig allow human and avian strains to mix?

A

both a2-3 and a2-6 linkages

25
What 4 viruses make up swine flu?
US pig Eurasian pig US avian Human 3 combined 4th virus eurasian swine then combined
26
What is the barrier between the highly pathogenic H5N1 infecting the human population?
SPECIES BARRIER
27
What are the 3 requirements for human-human spread of H5 strains?
1) enter cells of human URT 2) replicate in HIGH NUMBERS in URT cells 3) exit URT cells
28
Can sialic acid binding easily change through mutation?
yes
29
How many aa changes are required to switch HA specificity?
1 or 2 aa changes
30
Why is the replication rate of avian H5N1 reduced in humans?
different temperature | 37 vs. 41
31
What mutation in PB2 can affect peak replication temeprature?
E627K
32
What were the 3 mutations of H5N1 given to ferrets origianlly?
Q222L G224S E627K
33
Why were the 3 original mutations of the H5N1 virus not enough?
NO aerosol transmission
34
Brief overview of ferret experiment to select an aerosol transmissible virus?
infected with H5N1 (222/224/627) 4 days - sneeze sample infect wait 4 days - repeat x10 (ANTIGENIC DRIFT)
35
What are the 2 additional mutation to the H5N1 (222/224/627)
H103Y | T156A
36
How is the influenza vaccine produced?
GISRS predicts 3/4 dominating strains yearly
37
What is the traditional method of influenza vaccine production?
3 chosen strains - weakened segment exchange (REASSORTMENT) with PR8 256 genotypes INFECT EGGS
38
Which segments are PR8 and which are the circulating strain?
circulating strain - HA, NA rest - PR8
39
What are the 3 drawback of tradition flu vaccine making?
SLOW reassortment - 3 months dependent on eggs (170mil) some H5N1 grow poor in eggs
40
What is the 'new' way to make flu vaccines?
cDNAs - encode the 8 RNA genome sequences wanted make 8 functional RNPs
41
How is the cDNA-based system for vaccines better?
seed in 2 weeks no eggs no issues with egg allergy/growing poorly
42
What are the 3 current targets for anti-influenza therapeutics?
3) Endosome escape 5) RNA synthesis 8) Release
43
(FLU) What anti-virals are used for (step 3) endosome escape?
The Adamantanes AMANTADINE RIMANTADINE
44
What are the pros/cons of the Adamantanes?
PRO - cheap, effective CONS - administered before day 2
45
How is Rimantadine different to amantadine?
added methyl group
46
What influenza does the Adamantanes work against?
ONLY FluA
47
How do Adamantanes work?
prevent M2 ion channel activity blocks/closes pore cannot exit endosome
48
What are issues with Adamantanes?
most human flus now resistant mutations within M2 channel NO LONGER FDA APPROVED
49
(FLU) What anti-virals inhibit the endonuclease active site (step 5 - RNA synthesis)
XOFLUZA
50
How does Xofluza act?
binds the PA endonuclease active site
51
What flus is Xofluza effective against?
fluA, fluB
52
What does step 8 virus release involve?
NA ability of NA to bind to SA and cleave it
53
(FLU) What anti-virals are effective against (step 8) virus release?
Relenza - ZANAMIVIR (aerosol) Tamiflu - OSELTAMIVIR (oral) Repivab - PERAMIVIR (IV) WORK BY MIMICING SIALIC ACID BLOCK NA ACTIVE SITE
54
What is the stockpile of tamiflu and relenza worth?
£500m
55
What is the issue with flu resistance in NA inhibitors?
NA muatates so it no longer binds to tamiflu/influenza
56
What are future flu anti-virals not yet FDA approved?
polymerase inhibitor - FAVIPIRAVIR DAS-181 - HA attachment inhibitor
57
How do NA inhibitors act?
bind with higher affinity to NA than sialic acid exploite weak site 2 in the 5 site NA binding pocket
58
Why do NA inhibitors bind better than SA?
charged guanidino group added - interacts with neg charged Asp and Glu more strongly 100x higher affinity