MCB 2610 Lecture Notes - Lecture 14: Influenza Vaccine, 1918 Flu Pandemic, 2009 Flu Pandemic
25 May 2018
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Steps of infection :
Viral binding absorption -> virus associates with its host to start the infection
1)
-> association is specific and vital or essential for infection
-> Antibodies drugs or host mutations that alter this step prevent infection
Ex: P lambda- infects E. Coli through maltose transport
-HIV infects white blood cells called T4 lymphocytes: HIV binds to CD4 (surface molecules of T4 lymphocytes).
IF there is no CD4, HIV can’t infect the white blood cells. There is another co-receptor called CCR5 and it’s also on
the surface of T4 lymphocytes. The CCR5 32 misses 32 bp and inactivated the infection process of HIV. -> bubonic
plague and small pox. Europeans don’t have CCR5 32 (receptor for chemokines)
Virus has host binding proteins. Host has “virus receptors” on its surface. For example, influenza vaccine prevents
virus from host cell.
2)
After binding: Virus goes into the host (eukaryotic virus) , or virus genome gets injected into the host (bacterial
virus)
Once it’s inside the host, genome comes out of the capsid and released out to cytoplasm from the capsid.
Take over of host function:
Disable host defense systems :
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+Eukaryotes dsRNA/ dsDNA in the cytoplasm: virus will mount its immune response or force the cells into
apoptosis (host cell death) or cut the dsRNA -> misinterpreted as inflammation -> obesity/ Alzheimer/ diabetes ->
this explains that dsDNA should be in the nuclei to prevent it from viral infection
+Prokaryotes:
-Restriction enzymes cut dsDNA at specific sites. For example, EcoRI: 5 GAATTC 3. There’s also a protective
enzyme that methylated same site of host genome. Restriction enzyme cuts DNA at their methylated site.
-CRISPR targets and cuts double strand DNA and contains the whole host genome of the virus. If the virus comes
into attack, CRISPER army virus comes in and cuts the virus. CRSPR-CAS9: CCR into CAS9 -> mouse embryo ->
CAS 9-> CCR5 -> cut the DNA at CCR 5 gene and the cell will repair that. 10% the repair will be bad -> mutations.
Inactivate defense
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Acquire the ability to target host polymerase DNAP RNAP to make viral genomes
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—-> next step: synthesize viral components -> genomes and proteins.
—-> viral assembly
—-> viral release
Viral replication
2 things:
Making proteins -> need mRNA -> ssRNA -> ssRNA (+) means that this type of ssRNA can be directly translated.
1)
For example, 5’ AUG GGG 3’ -> protein MET-gly -> ssRNA (+) and ssRNA (-) is the complementary
The virus will take the ssRNA(-) to make complementary RNA (+)
Making new viral genomes. Problem: RNA -> dsRNA , ssRNA (+), ssRNA (-). DNA -> ds DNA, ssDNA(+), ssDNA(-). -> make Virus interesting and weird.
2)
Ex: phage t2 can infect E. Coli strain K12 but not 0157: H7. Phage PP01 can infect 0157: H7 but not K12. ->
BALB/c mice : cMHV can interact with its Bgp1a -> infection
Poliovirus attaches to cell surfaces and injects its phases into the host cell and release its RNA into the host cell
Budding in virus: the nucleocapsid become su
Influenza: new particles of virus with envelopes released into the spaces. The endoplasmic reticulum is taken over by the virus and synthesize viral proteins and
buds off and fuses with the membrane. Viral genome come up against the membrane and capture genome fragments more and more and bud out of the cell and
attack adjacent cells.
For example, virus has a single strand RNA (-): How does this happen without DNA
Makes ssRNA (+)
1)
Makes new ssRNA (-)
2)
Paths to mRNA :
DsDNA
Bacteriophages MS2
SsRNA (+) :
•
-infects E. Coli and does this by attaching to mating pilus
-this pilus is made only when E. Coli contain “F-element
Plasmid”
Icosohedral virus - 180 copies of coat protein capsid and has 4 genes only
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Make protein: single strand ssRNA
1)
Make more viral genome
2)
How to make RNA from the dsDNA (-)
Human virus
Herpes viruses -> related to each other dsDNA -> generally speaking this family causes a number of different diseases
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Hepatitis virus -> similar disease but very different virus
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Herpesvirus : 160,000 bp per gene .
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HSV1 and HSV2 :
HSV1 cause cold sore (oral herpes) - pneumonia and meningitis *Hutchinson : bone marrow transplant :
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+goes into the host cell makes new genome and leave the tissue cells by budding aggressively and killed host cells.
+the immune system will mount and attack and slow down the HSV1 infection
+HSV1 infection is kinda mean bc it travels down to the nerve and reassigns itself to the spinal cord and live in nerve cell bodies in
spinal cord (latent/ dormant). So infected person is permanently infected -> immune system is weak and HSV1 can be reactivated
anytime -> secondary infection.
HSV2 cause S.T.D (sexually transmitted diseases)- (genital herpes)
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HHV3 -> varicella zoster virus (VZV) -> chicken pox:
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+ shingles : chicken pox deactivation - the older you are when you get shingles, the worse it is.
Epstein Bar Virus (EBV) : cause mononucleosis - lymphocytes (immune infection that infects white blood cells, fever, Fatigue).
When this is reactivated, it can cause certain cancers.
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HHV4
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HHV5 -> Cytomegalovirus (CMV) : cold, fever , greater than 50% of ppl in the U.S have this
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+AIDS: caused by CMV,
+Roseola: common in infants, high fever followed by rash days later.
HHV6 a and HHV6b
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HHV7 : drug induced hypersentivitiy - epilepsy, mono like illness
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HHV8: AIDS -> Kapsis sarcoma -> cancer in blood vessels and causes blood vessels grow normally fast
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Hepatitis : inflammation of liver
Can be caused by virus (A,B,C,D,E), alcoholism.
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Hep A: Picnavirus ssRNA (+)
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-> Infectious hepatitis : transmitted oral-fecal route. Very common in daycare. Commonly found in water supply or shell fish.
40% of U.S.A have antibodies to Hep A: This means that Americans have exposed to the virus and possessed immune response to this.
The symptom is usually mild -> G.I symptoms, fever, self-limiting. This virus is hard to kill -> unaffected by standard sources of
disinfectants, is also heat resistant.
Hep B: Hepdnavirus => DNA virus
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-> transmitted by the same way as HIV transmitted (needles, sex, blood, old day transfusions)
This infects more than 500 million people worldwide. 40% people will die because of the disease. Fortunately, there is a vaccine for Hep
B (virus particles from the human blood) - HeptaVac
Hep B is an eukaryotes virus and it is extracted by the method of recombinant subunit.
Hep C: ssRNA -> same as HepB and HIV
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Was being transmitted via transfusion
4 million people in the U.S infected and expected to kill 40,000
Leading cause for liver transplants.
Treatment available for HepC: was enormously expensive (300,000usd for treatment), which the pharmaceutical company argued that it
is less expensive than liver transplants.
Hep D:
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Hep E: Calicivirus RNA -> Problem in developing countries
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Similar to Hep A in terms of transmission -> oral/fecal route
About 10 times more fatal than Hep A.
Especially it’s bad for pregnant women. Pregnant women infected with Hep E experienced 20% mortality rate.
Influenza Virus A -> Flu:
Respiratory, GI virus
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Influenza A is a single stranded RNA virus (-) orthomyxo virus
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Main feature in human is respiratory -> coughing, sneezing, bronchitis, and pneumonia, fever, bad muscle aches
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Infects human and pigs and waterfall and horses and chicken and turkeys, sea mammals.
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In human: it usually strike in winter months in Northern Hemisphere.
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Genome of influenza virus a is unusual because it is segmented. Every virus has 8 segments of RNA.
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The 8 segments encode 10 proteins.
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Hemagluttin:
There are 14 subtypes of hemagluttin. Each of these subtypes are greater than 30 different than the other
subtypes. Subtypes are just called H1- H14.
A lot of hemagluttin depends on the virus surface. Virus will change its hemagluttin to hide it away from
the attack from the immune system.
Ex: H1N1- hemagluttin 1: has been under attack from humans for almost 8-9 years.
Synthesis of hemagluttin:
HA1 binds to the host cell:
HA 2 is required for virus release after uptake
Antibodies are against hemagluttin to prevent infection
Neuroaminidase 9 subtypes: N1 -> N9
Antigenic drift- change in the viral genome due to mutation.
-> Mutation rate is high in influenza A because error RNA dependent RNAP
-> Base substitution : instead of U it’s a C -> small insertion/ deletion mutation
-> Responsible for year to year changes in particular flu type
H1N1 (2009)
2009, virus shown up in Mexico -> extremely pathogenic -> 30% kill rate.
Antigenic shift- change in viral genome composition due to mixing and matching
In order for antigenic shift to happen, somewhere in the world, there has to be a cell and this cell get infected by virus.
New pandemic causes severe diseases: human can’t fight it so the disease progressively spreads throughout the world.
Due to the fact that the new virus hasn’t been in human population. Therefore, there’s no immunity for it.
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H1N1 has been around since 2009. However, rapid spread is even more extreme than H1N1
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The virus of these pandemic diseases come from antigenic shift or direct transfer from animal sources.
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Bird flu (H5N1): originated from Hongkong. This particular isn’t in human.It’s very ineffective to human. It doesn’t stick to human’s lung cells. However,
farmers that work with chicken with H5N1 can transfer to farmers handling them -> symptoms: get really sick
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Less severe symptoms and spread is usually cause by antigenic drift
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Natural history of influenza
1918 toward end of WW1 and cause 20-40 million deaths in two years. Strange because it killed young adults -> immune overreaction (cytokine strain)
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Little is known about the virus before except for knowing it is H1N1. This virus is still out there in low levels.
However, we currently have the sequence of the genome. The genome is made of RNA (super unstable). It’s really hard to keep the RNA sample to
synthesize.
1957: H2N2
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1968: H3N2
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1977: Re-introduction of H1N1 virus. Less virulent than the 1918 version.
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1997: H5N1 bird flu shows up in Hongkong. Example of direct transfer between animals and humans.
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2009: new strand of H1N1 from antigenic shift.
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Every two to four years: bad flu year. 2018 is specifically a bad flu year. More people get sick -> epidemic because of drift
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Reservoirs of flu virus:
Largest reservoir are in waterfowl : duck, shorebird
-> GI infection
H1-> h14
N1-> N9
-> been around long enough to rarely cause disease
Waterfowl can pass these pathogen to domestic birds (chicken , turkey ) very often fatal to the bird. Only H5 and H7 subtypes are
seen. -> Human can inherit these pathogen. However, H5N1 is not easily passed between humans to humans. Human is susceptible to a
limited number of virus (H1N1, H2N2, H3N2, H5N1, H7xx)
Waterfowl can also pass to swine which is susceptible to H1N1 and H3N2 diseases. Swine can also get the virus from domestic birds.
Swine can also deliver their virus to human. And human can pass virus to swine. Human and swine can exchange the virus. About 10%
of swine farmers/ workers have antibodies to swine flu from pigs.
Example: rural China and Southeast Asia are more susceptible to be the host of H1N1 and H3N2 diseases. 2009 pandemic is interesting
bc it happened in Mexico.
Sources of pandemics:
H5N1 -> 1957
New viral pathogen causing disease showed up in Hongkong
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-> new influenza H5N1 -> suggested that it was coming from birds.
-> shorebirds -> ducks, chickens (very pathogenic) -> pass to humans in Hongkong (extremely bad) - 18 people had H5N1
and 6 died and about 6 times higher than the 1918 influenza. -> poor passage but it could improve due to antigenic drift
-> no global immunity to H5N1: the start of new pandemic
-> Hongkong authority regulates that all chicken in Hongkong are killed. -> two millions chicken -> effective!!!!!! The
pandemic appears to die out. But it shows up again in 2002 in Hongkong. And this spread beyond chicken -> dosmetic and
wild bird died all over the world because of H5N1: bird pandemic.
Similar thing happened in the Netherlands: H7N7, H7N3.
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World Health Organization and CDC is the two organizations that focus on public health issues such as vaccines
H3N2 has been around in 1968 and drifting
MMWR -morbidity and mortality weekly report
-> determine vaccinations, make vaccinations in the spring for the following year
Flu vaccine - trivalent , 3 strains, the vaccine is actually inactivated virus.
2 influenza A, 1 influenza B. This year, it is 2A and 2B.
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Vaccine itself -> takes 6 months to make -> make enough doses. Mono valent vaccine -> 1 strain:
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+ Make with virus injected into chicken eggs
+ The virus grows in the egg
+Particles harvested , purified, combined, adjuvant
+Virus sometimes is very virulent -> the egg doesn’t release enough particles to be used -> can’t be used for vaccines
Virus can make with tissue cells:
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+very fast and effective
Influenza B (H1N1) :
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1950 and Soviet release descendants, Mexican 2009 H1N1 in vaccine until 2018
H3N2 ->
Poliovirus ->
Viral Infection
Friday,)May)11,)2018
9:18)AM
Document Summary
Viral binding absorption -> virus associates with its host to start the infection. > association is specific and vital or essential for infection. > antibodies drugs or host mutations that alter this step prevent infection. Ex: p lambda- infects e. coli through maltose transport. Hiv infects white blood cells called t4 lymphocytes: hiv binds to cd4 (surface molecules of t4 lymphocytes). If there is no cd4, hiv can"t infect the white blood cells. There is another co-receptor called ccr5 and it"s also on the surface of t4 lymphocytes. The ccr5 32 misses 32 bp and inactivated the infection process of hiv. Europeans don"t have ccr5 32 (receptor for chemokines) For example, influenza vaccine prevents virus from host cell. After binding: virus goes into the host (eukaryotic virus) , or virus genome gets injected into the host (bacterial virus) Once it"s inside the host, genome comes out of the capsid and released out to cytoplasm from the capsid.
