INFLUENZA VIRUS

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INFLUENZA VIRUS
INFLUENZA VIRUS
CDC WEBSITE
http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm
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‘FLU’
True influenza
influenza virus A or influenza virus B
(or influenza virus C infections - much milder)

Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often inaccurately called ‘flu’
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South Carolina 1996-1997 DHEC bulletin
http://www.state.sc.us/dhec/LAB/labbu017.htm
no virus
influenza A
influenza B
CULTURE
RESULTS
malathia influenzae per le stelle
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THE IMPACT OF INFLUENZA
PANDEMICS
Deaths:
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THE IMPACT OF INFLUENZA
In the US, 1979-2001, on average:

41,000 deaths per year

290,000 hospitalizations per year

Dushoff et al, Am J Epidemiol. (2006)163:181
Nichol et al, J Infect. Diseases (2006)194:S111

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THE IMPACT OF INFLUENZA
recently some increase in morbidity and mortality - possible factors?
more elderly people
CF patients live longer
more high risk neonates
more immunosuppressed patients
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ORTHOMYXOVIRUSES
http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html
pleomorphic
influenza types A,B,C
febrile, respiratory illness with systemic symptoms
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ORTHOMYXOVIRUSES
type A, B, C : NP, M1 protein
sub-types: HA or NA protein
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TRANSMISSION
AEROSOL
100,000 TO 1,000,000 VIRIONS PER DROPLET

18-72 HR INCUBATION

SHEDDING
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NORMAL TRACHEAL MUCOSA
3 DAYS POST-INFECTION
7 DAYS POST-INFECTION
Lycke and Norrby Textbook of Medical Virology 1983
Ramphal et al., INFECTION AND IMMUNITY 1979 25:992-997 (mouse)
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DECREASED CLEARANCE

RISK BACTERIAL INFECTION

VIREMIA RARE
Lycke and Norrby Textbook of Medical Virology 1983
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RECOVERY
INTERFERON - SIDE EFFECTS INCLUDE:
FEVER, MYALGIA, FATIGUE, MALAISE

CELL-MEDIATED IMMUNE RESPONSE

TISSUE REPAIR
CAN TAKE SOME TIME
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An immunological diversion
INTERFERON
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INTERFERON
time course of virus production will vary from virus to virus
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INTERFERON
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INTERFERON
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INTERFERON
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INTERFERON
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INTERFERON
THE VIRUSES ARE COMING!
http://www.paulreverehouse.org/midnight.html
PAUL REVERE
http://www.mfa.org/collections/one_hour/6.htm
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TYPES OF INTERFERON
TYPE I
Interferon-alpha (leukocyte interferon, about 20 related proteins)
- leukocytes, etc
Interferon-beta (fibroblast interferon)
- fibroblasts, epithelial cells, etc
TYPE II
Interferon-gamma (immune interferon)
- certain activated T-cells, NK cells
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INDUCTION OF INTERFERON
interferon-alpha and interferon-beta
induced by
viral infection (especially RNA viruses)
double stranded RNA
certain bacterial components
- strong anti-viral properties
interferon-gamma
- antigens, mitogenic stimulation of lymphocytes
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INTERFERON
induces variety of proteins in target cells

many consequences, not all fully understood
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INTERFERON-ALPHA AND INTERFERON-BETA
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interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
induction of
protein kinase R (PKR)
2’5’oligo A
induction of
ribonuclease L
activated
ribonuclease L
ATP
activated
protein kinase R
activated
2’5’oligo A synthase
ATP
2’5’oligo A
mRNA degraded
phosphorylated initiation factor (eIF-2)
inhibition of protein synthesis
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interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
induction of
protein kinase R (PKR)
2’5’oligo A
induction of
ribonuclease L
activated
ribonuclease L
ATP
ds RNA
ds RNA
activated
protein kinase R
activated
2’5’oligo A synthase
ATP
2’5’oligo A
mRNA degraded
phosphorylated initiation factor (eIF-2)
inhibition of protein synthesis
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interferons
only made when needed
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OTHER EFFECTS OF INTERFERONS

ALL TYPES
INCREASE MHC I EXPRESSION
CYTOTOXIC T-CELLS
ACTIVATE NK CELLS
CAN KILL VIRALLY INFECTED CELLS
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OTHER EFFECTS OF INTERFERONS
INTERFERON-GAMMA
INCREASES MHC II EXPRESSION ON APC
HELPER T-CELLS
INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES
INTRINSIC
EXTRINSIC
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THERAPEUTIC USES OF INTERFERONS
ANTI-VIRAL
e.g. interferon-alpha is currently approved for certain cases of acute and chronic HCV and chronic HBV
MACROPHAGE ACTIVATION
interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis
ANTI-TUMOR
have been used in e.g. melanoma, Kaposi’s sarcoma, CML
MULTIPLE SCLEROSIS
interferon-beta

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Viral response to host immune system
Viruses may :
block interferon binding
inhibit function of interferon-induced proteins
inhibit NK function
interfere with MHC I or MHC II expression
block complement activation
inhibit apoptosis
etc!
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SIDE EFFECTS OF INTERFERONS

FEVER
MALAISE
FATIGUE
MUSCLE PAINS
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BACK TO INFLUENZA
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SYMPTOMS
FEVER
HEADACHE
MYALGIA
COUGH
RHINITIS
OCULAR SYMPTOMS
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INTERFERON
time course of virus production will vary from virus to virus
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PROTECTION AGAINST
RE-INFECTION

IgG and IgA
IgG less efficient but lasts longer

antibodies to both HA and NA important
antibody to HA more important (can neutralize)
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CLINICAL FINDINGS

SEVERITY
VERY YOUNG
ELDERLY
IMMUNO-COMPROMISED
HEART OR LUNG DISEASE
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PULMONARY COMPLICATIONS
CROUP (YOUNG CHILDREN)
PRIMARY INFLUENZA VIRUS PNEUMONIA
SECONDARY BACTERIAL INFECTION
Streptococcus pneumoniae
Staphlyococcus aureus
Hemophilus influenzae
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NON-PULMONARY COMPLICATIONS
myositis (rare, > in children, > with type B)
cardiac complications
recent studies report encephalopathy
2002/2003 season studies of patients younger than 21 yrs in Michigan - 8 cases (2 deaths)
liver and CNS
Reye’s syndrome
peripheral nervous system
Guillian-Barré syndrome
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Reye’s syndrome
liver - fatty deposits
brain - edema
vomiting, lethargy, coma
risk factors
youth
certain viral infections (influenza, chicken pox)
aspirin
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Guillian-Barré syndrome
peripheral nervous system involved

1976/77 swine flu vaccine
35,000,000 doses
354 cases of GBS
28 GBS-associated deaths
recent vaccines much lower risk
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MORTALITY

MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH
BACTERIAL PNEUMONIA
CARDIAC FAILURE

90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE
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DIAGNOSIS
ISOLATION
NOSE, THROAT SWAB
GROW IN TISSUE CULTURE OR EGGS
SEROLOGY
PCR
RAPID TESTS
provisional - clinical picture + outbreak
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HA protein - attachment, fusion
inside of virion
membrane
=antibody
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NA protein - neuraminidase
inside of virion
membrane
=antibody
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ANTIGENIC DRIFT
HA and NA accumulate mutations
RNA virus

immune response no longer protects fully

sporadic outbreaks, limited epidemics
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ANTIGENIC SHIFT
“new” HA or NA proteins

pre-existing antibodies do not protect

may get pandemics
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INFLUENZA A PANDEMICS
Ryan et al., in Sherris Medical Microbiology
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where do “new” HA and NA come from?
~16 types HA
~9 types NA
all circulate in birds
pigs
can be infected by avian and human influenza viruses

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Where do “new” HA and NA come from?
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Where do “new” HA and NA come from
- can ‘new’ bird flu directly infect humans?
Bird flu H5N1?
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H5N1 – in birds
Avian H5N1 has spread to humans
So far human cases in Asia and Africa
387 cases (12-1-03 through 09-10-08)
245 (63%) fatal
Have been a few instances where may have spread human-to-human
So far no sustained spread in humans

Surveillance continues
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why do we not have influenza B pandemics?
so far no shifts have been recorded
no animal reservoir known
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SURVEILLANCE
http://www.csiro.au/science/AIatAAHL.html
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% typed cases
influenza season
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CDC: http://www.cdc.gov/mmwr/pdf/rr/rr57e717.pdf
actual percentage of deaths
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VACCINE
‘BEST GUESS’ OF MAIN ANTIGENIC TYPES
CURRENTLY TRIVALENT
type A - H1N1
type A - H3N2
type B
each year choose which strain of each subtype is the best to use for optimal protection
(The 2008–09 trivalent vaccine virus strains are A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Florida/4/2006-like)

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VACCINE
inactivated (trivalent inactivated influenza vaccine, TIV)
egg grown
some formulations licensed for children

reassortant, trivalent live vaccine (live attenuated vaccine, LAIV)
egg grown
for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years
also approved for healthy children 24-59 months old without a history of recurrent wheezing
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CDC
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Annual vaccination against influenza is recommended for any adult who wants to reduce the risk for becoming ill with influenza or of transmitting it to others
Vaccination also is recommended for all adults in the following groups, because these persons are either at high risk for influenza complications, or are close contacts of persons at higher risk:
persons aged >50 years (from public health point of view, easier to target by age than by high-risk condition, which may not have been discovered)
women who will be pregnant during the influenza season
persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological or metabolic disorders (including diabetes mellitus)
persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus)
persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration
residents of nursing homes and other chronic-care facilities
health-care personnel
household contacts and caregivers of children aged <5 years and adults aged>50 years, with particular emphasis on vaccinating contacts of children aged <6 months
household contacts and caregivers of persons with medical conditions that put them at high risk for severe complications from influenza
2008: ADULT VACCINATION
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Vaccination of all children aged 6 months–18 years should begin before or during the 2008–09 influenza season if feasible, but no later than during the 2009–10 influenza season.
Children and adolescents at high risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children and adolescents. Recommendations for these children have not changed. Children and adolescents at higher risk for influenza complication are those:
aged 6 months–4 years
who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological or metabolic disorders (including diabetes mellitus)
who are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus)
who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration
who are receiving long-term aspirin therapy who therefore might be at risk for experiencing Reye syndrome after influenza virus infection
who are residents of chronic-care facilities
who will be pregnant during the influenza season
2008: CHILDREN AND ADOLESCENTS AGED
6 MONTHS - 18 YEARS
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PREVENTION - DRUGS
ZANAMIVIR (NA)
types A and B
OSELTAMIVIR (NA)
types A and B (some resistance, but most strains sensitive)
RIMANTADINE (M2)
type A only
AMANTADINE (M2)
type A only
2005 to present
high levels of resistance of influenza A viruses to amantidine and rimantidine, so these drugs not recommended until resistance drops
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TREATMENT - DRUGS

ZANAMIVIR (NA)
types A and B, needs to be given early
OSELTAMIVIR (NA)
types A and B, needs to be given early
(some resistance, but most strains sensitive)
resistant strains currently still sensitive to zanamivir

RIMANTADINE (M2)
type A only, needs to be given early
currently resistance problems so not recommended
AMANTADINE (M2) –
type A only, needs to be given early
currently resistance problems so not recommended
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NA protein - neuraminidase
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OTHER TREATMENT
REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS)

BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY
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TYPE A

++++
yes
yes
yes
shift, drift
yes
(sensitive)
sensitive
2


severity of illness
animal reservoir
human pandemics
human epidemics
antigenic changes
segmented genome
amantadine, rimantidine
zanamivir,oseltamivir
surface glycoproteins
TYPE B

++
no
no
yes
drift
yes
no effect
sensitive
2
TYPE C

+
no
no
no (sporadic)
drift
yes
no effect

(1)
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the end...............
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A Rondelay (Without Cadenza) By The Virion Of Influenza (by Edwin D. Kilbourne)
Now you have me―sucrose-banded,
Enveloped and negative-stranded
Spiked and cleaved and slightly dented
Into pieces eight, segmented―
Without mercy I`ve been strained
Through filters―then been bromelained, and
Torn apart by each detergent
With a haste unseemly, urgent―
All my helices displayed
Just to show you how I`m made.
My polypeptides have been mapped
My hemagglutinin unwrapped―
All my sequences are clear―
All the way from Arg to Ser.
With techniques sharp and newly honed
My very genes have now been cloned―
Transplanted to an alien host
Wherein my evanescent ghost
As solitary as an elf
Has managed to express myself.
And scientists have labored nights
To probe my antigenic sites
Some fresh from school with new diplomas
(Aided by their hybridomas)
Scramble up trimeric slopes
Counting all my epitopes


And every Ph.D. or pupil
Utterly devoid of scruple
Mates me with complete abandon―
Asks, then, why my genes are random
Can I kiss and never tell
When genotyped upon a gel?
Which, if inspected with acuity
Will document my promiscuity―
Must you write, in fat reports
How flagrantly I reassort?
No boundaries have my misbehavin`
Horsey set or duck or avian―
In other moments less sublime
You`ve put my perils before swine!
And yet in 1981
Despite the work that has been done
The epidemics come and go
As regular as winter snow.
And people cough and people die
And all of you still wonder why.
I`m so perverse and ever mutable
And so eternally unscrutable.
But think about just what you`d do
If there were really
No more flu!
http://www.cdc.gov/eid/content/14/2/359.htm?s_cid=eid359_e
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2005
2006
2007
adapted from http://www.cdc.gov/flu/weekly/fluactivity.htm
2005-2006 season to Oct 13th 2007