The 1918 Influenza Virus

By: Mahshid Far

The 1918 Influenza Virus

The influenza epidemic; an explosion

waiting to happen!
 The 1918 Influenza Virus
Major Topics
• Historical Backgrounds
• Review Innate Immunity & its
Components
• General Characteristics of The
Influenza Virus
• Article
• Conclusion
 Historical Background
• “influenza”: from Medieval Latin
influentia:the belief that epidemics were due
to the influence of the stars
• AKA: "Spanish Flu" or "La Grippe"
• The 1918 Influenza epidemic
• Resulted in about 50 million deaths
worldwide
• An estimated 675,000 Americans died:
ten times as many as in the world war
 The Year 1918: year of suffering
& death & yet of peace …

An emergency hospital for influenza patients

Historical Backgrounds cont’d

As noted in the Journal of the American Medical

Association final edition of 1918:

• "The 1918 has gone: a year momentous as the

termination of the most cruel war in the annals of
the human race; a year which marked, the end at
least for a time, of man's destruction of man;
unfortunately a year in which developed a most
fatal infectious disease causing the death of
hundreds of thousands of human beings. Medical
science for four and one-half years devoted itself
to putting men on the firing line and keeping them
there. Now it must turn with its whole might to
combating the greatest enemy of all--infectious
disease," (12/28/1918).
 Historical Backgrounds cont’d
In 1918 children would skip rope to the rhyme (Crawfor

I had a little bird, Its name was Enza.

I opened the window,
And in-flu-enza.
• Video
 Historical Backgrounds cont’d
• Historically, the 20th century saw 3 pandemics of influenza:
• 1918 influenza pandemic
at least 675,000 U.S. deaths
up to 50 million deaths worldwide
• 1957 influenza pandemic
at least 70,000 U.S. deaths
1-2 million deaths worldwide
• 1968 influenza pandemic
about 34,000 U.S. deaths
700,000 deaths worldwide
Historical Backgrounds cont’d

Death due
to influenza
Innate Immunity & Components
• Innate Immunity
Ready to go.
Physical barriers
-skin
-mucus membrane
Chemical barriers
-Acid pH of stomach
Cellular response
-phagocytic cells
-NK cells
 Innate Immunity & Components
Innate Immunity
• Phagocytic Cells • Granular Cells
-monocyte -NK cells
-neutrophils -eosinophill
-machrophage -mast cells
• Function: phagocytosis -basophil
of microorganisms & • *Function: cause an
other particles inflammatory response
Cytokines: soluble signaling molecules…i.e., IL 6
Produced: by variety of cells, ex: macrophages
Function: activation, inhibition, inflammation etc,…
 Innate Immunity & Components
IL 6
• A group of cytokine
• Produced by:
-monocytes
-macrophages
-Th2 cells
-stromal cells
• Activate B Cells
-differentiate & proliferate into
plasma cells to release Abs
-acute phase response
*physiological Δ’s after infections:
inflammation, fever, etc,…
Innate Immunity & Components
IL 8
• A group of cytokine
• Produced by:
-macrophages
-endothelial cells
• Target the neutrophils
• Direct elimination of pathogens via
chemotaxis
Structural Characteristics of Influenza virus
 Structural Characteristics of Influenza virus
• an orthomxyvirus
• Round or elongated
• Genome consist of: 8 segments of single
stranded RNA (except type C virus)
• Enveloped virus
• Surface proteins: glycoprotein “spikes”
>hemagglutinin: HA (80%)
*allows the virus to "stick" to a cell and initiate infection
>neuraminidase: NA (20%)
*enables newly formed viruses to exit the host cell
Structural Characteristics of Influenza virus
3 types of Influenza Virus:
Type A:
• Found in: ducks, chickens, pigs, whales, & in humans.
• Major cause of pandemics and epidemics
• The 1918 Influenza Virus

Type B:
• normally is only found in humans & responsible for
many localized outbreaks

Type C:
Found in: humans, pigs, dogs & causes mild respiratory
infections, but does not spark epidemics
• often nonsymptomatic
 Morphological Differences

Type A & B Type C

 Disease Caused by Influenza virus
Symptoms:
• Acute febrile respiratory tract infection
• Rapid onset of fever, sore throat, cough
• Abdominal pain & vomiting in children

Transmission:
• inhalation of aerosol droplets

Risk Factors:
• Adult w/ flue syndrome, elderly, children, & immune-
compromised individual

Mechanism:
• Symptoms caused by cytokine response to infection
• Ab’s against HA & NA important for protection
• Recovery depends on interferon and cell-mediated IR
• Type A undergoes antigenic Δ’s

video
Aberrant innate immune response in lethal infection
of macaques with the 1918 influenza virus.

Vol 445| 18 January 2007doi:10.1038/nature05495

 Why study the 1918 Influenza
Virus?
• It affects all of us!
• In US alone: 36,000 deaths and 114,000
people hospitalized every year
• Social stress Weakens IS  vulnerable toward the virus

Social
Stress
 Hypothesis

“The ability of influenza viruses to

modulate host immune responses, such
as that demonstrated for the avian
H5N1 influenza viruses, may be a
feature shared by the virulent influenza
viruses.”
 Method
• 1918 virus genes constructed using:
Plasmid-Based Reverse Genetic
• Researchers manipulate the influenza genome in
any desired way
• cloning a virus into units of DNA that can then be
mutated
• each one of the 8 segments can be cloned into a
plasmid DNA unit.
• Those units, in plasmid DNA form, are then very
easy to manipulate
• allowing scientists to investigate the genetic
markers that give a virus the potential to cross
the species barrier
• After the outbreak of avian influenza in Hong
Kong in 1997
 Method Cont’d

• Pulse oximetry
• Measures the
lung function
 Method Cont’d

• Macaques chosen as nonhuman primate

model (n=10)
*7 infected w/ the 1918 virus
*3 infected w/ the K173
• All 1918 virus-infected animals became
symptomatic 24 hrs post infection

acute respiratory distress syndrome

Method Cont’d

On day 8 post-
infections all animals
were euphonized due to
severity of symptoms
 Symptoms of animals infected w/ the 1918 virus & K173 virus

1918 Virus K173 Virus

• Respiratory signs
Increased heat rate • Very mild clinical signs
•
• Decrease in lung function • Virus isolated from upper
• in blood O2 saturation: up to 36% respiratory tissues only (3,6)
• Virus present at both upper and lower • Virus isolated from tonsil (8)
respiratory tissues on days (3,6,8) • Alveolar damage (3)
• 60-90% of lung tissues affected by • Lung healing by (6,8)
sever lesions (6,8)
• H2O & blood filled infections reduced • Thickening of alveolar walls
the lung function • & no Ags
• Alveolar damage + viral Ags (3)
• Worsening of alveolar damage +
Ag
• In lungs of a K173-
virus-infected animal
• peribronchiolitis
with lymph follicle
formation was
detected throughout
the lung
• Mild thickening of
the alveolar wall was
observed in the
• middle lobes, but
antigen was not
detected
Most areas of the lungs of a
1918-virus-infected animal
contained consolidated lesions
Viral antigen (brown) was detected
in the large regenerative alveolar
cells and the bronchiolar epithelial
cells in lesions
 Chemokines of 1918 virus & K173
1918 virus K173
• IL 6 post-infection • Increase in expression
• IL 6 & CCL11 after Day 8 for type I IFN
• Delay in activities of IL 8 & CXCL11 • Decrease regulation by
• CXCL6 & CXCL1recruitment of day 6&8
nuetrophils
• Induced less fewer • Major genes for
IFNαalteration of antiviral activation of antiviral
response response are induced
• Reduced sensitivity to IFN response
• Genes that active antiviral response:
*DDX58
*IFIH1
Not activated for this virus
 Microarry Analysis
To investigate the regulation of the
host response to the 1918 virus,
we considered the global gene
expression profiles in bronchi, a lower
respiratory tissue with substantial
replication of both viruses
Interpretation of the Microarry analysis
1918 virus K173 virus
• Relative consistency in • More dynamic gene
gene expression from expression
Day 3 through 8 • Highest at day 3 post
• Immune response related infection
genes higher through the • But dramatic activation of
course of infection genes involved in cellular
• This results in metabolism on days 6-8
meaning that tissues are
healing after clearance of
virus

Red: up regulation
Green: down regulation
 Results
• 1918 virus may show reduced sensitivity
to type I IFN response
• IFIH1 & DDX58 genes were induced in
K173 BUT not in 1918 virus
• NS1 protein of virulent virus can
modulate the IFN mediated antiviral
response
 Summery of Results
• The 1918 virus cause alteration of immune
system:
• virus NS1 protein could be responsible for the
low levels of DC maturation after influenza
virus infection.
• The NS1 protein is an important virulence
factor associated with the suppression of
innate immunity via the inhibition of type I
interferon (IFN) production in infected cells.
 Conclusion
• We still don’t know much!
• Need to find the exact mechanism in
which the NS1 protein alters the innate
immune response
• possibilities?
 Results vaccine dev’t
• Killed vaccine against annual strains of
influenza A and B viruses
• Live, attenuated influneza A and B
vaccine (nasal spray)
• Antiviral drugs: amantadine,
rimantadine, etc…