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 INFLUENZA	
  




Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
                                                                       1	
  
Influenza Disease Burden in the United States in an

                                                                                Average Year
                                                                                                              Deaths*	
  
           Hospitalizations*	
                                                                            3,000	
  to	
  49,000	
  
            117,000	
  to	
  816,000	
  


                                                                                Physician	
  visits	
  
                                                                                  ~25	
  million	
  


                                                                     Infections	
  and	
  illnesses	
  
                                                                         50	
  to	
  60	
  million	
  

        *	
  All-­‐cause	
  hospitalization	
  and	
  mortality	
  associated	
  with	
  influenza	
  virus	
  infection.	
  
Thompson WW et al. JAMA. 2003;289:179-186; Thompson WW et al. JAMA. 2004;292:1333-1340;
Couch RB. Ann Intern Med. 2000;133:992-998; Patriarca PA. JAMA. 1999;282:75-77; ACIP. MMWR. 2004;53(RR06):1-40;
MMWR. 2010; 59(33): 1057-1062.

         Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
South	
  Carolina	
  1996-­‐1997	
  DHEC	
  bulletin	
  
                             malathia	
  influenzae	
  per	
  le	
  stelle	
  




                                                                           no	
  virus	
  




             CULTURE	
                                                                influenza	
  A	
  
             	
  RESULTS	
  
                      	
  

                                                                                       influenza	
  B	
  




Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
BUSINESS	
  
  Flu	
  Combating	
  Algorithm	
  
STRATEGY	
  


   1.     Understand	
  Your	
                                                                                     *Food	
  as	
  Medicine,	
  
          Enemy	
  –	
  Virus	
  Flu	
                                                                             *Herbs	
  as	
  Medicine	
  
   2.     Understand	
  its	
  
          strategies	
  




   Build	
  a	
  Stronger	
                                                                                        *Exercise	
  as	
  Medicine	
  
   Immune	
  System.	
  
                                                                                                                   *Sleep	
  as	
  Medicine	
  
   Enhance	
  the	
  body	
  own	
  
   power	
  and	
  deffence	
  
   tools	
  .	
  
   	
  

    Use	
  ll	
  the	
  Natural	
                                                                                 Love	
  as	
  Medicine	
  
    resources	
  ito	
                                                                                            Laughter	
  asMedicine	
  
    achieve	
  a	
  safe	
  and	
                                                                                 Spiritusality	
  as	
  Medicine	
  
    healthy	
  Winter	
  




                                           Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
FLU	
  Fighting	
  
BUSINESS	
  
   Strategies	
  
STRATEGY	
  



      Missions	
  and	
  Goals	
                                     Strategic	
  planning	
                                          Implementa:on	
  
      	
                                                             Know	
  Your	
  Enemy	
                                          	
  
      Successfully	
  avoid	
  the	
  Flu	
  and	
                   Understand	
  Viruses	
                                          Arm	
  yourself	
  with	
  
      remain	
  ealthy	
  and	
  aawell	
                            and	
  all	
  there	
                                            the	
  tools	
  that	
  
      during	
  aaaaflu	
  aseason	
                                  behaviors	
  to	
  know	
                                        counteract	
  the	
  effect	
  
      	
                                                             how	
  to	
  properly	
                                          of	
  the	
  virus.	
  	
  
      	
                                                             Combat	
  Them	
                                                 	
  
                                                                     	
  
                                                                                                                    1.       Food	
  as	
  Medicine,	
  
      Build	
  a	
  Stronger	
  Immune	
               1.    Understand	
  how	
  the	
                             2.       Herbs	
  as	
  Medicine	
  
      System.	
                                              Flu	
  Is	
  transmitted	
                             3.       Exercise	
  as	
  Medicine	
  
      Enhance	
  the	
  body	
  own	
                  2.    Recognize	
  early	
                                   4.       Love	
  as	
  Medicine	
  
      power	
  and	
  deffence	
  tools	
                     Symptoms	
  of	
  the	
  Flu	
                         5.       Laughter	
  as	
  Medicine	
  
      to	
  combat	
  and	
  prevent	
  flu	
                                                                        6.       Spiritusality	
  as	
  
      	
                                                                                                                     Medicine	
  
      	
  
                                                                                                                 1.       Interferon	
  Concept	
  
      Use	
  ll	
  the	
  Natural	
                    1.  Know	
  yor	
  Body	
                                 2.       Enzyme	
  
      resources	
  ito	
  achieve	
  a	
                                                                         3.       Replace	
  your	
  flora	
  
      safe	
  and	
  healthy	
  Winter	
  
                                                       2.  Know	
  Your	
                                        4.       Healthy	
  PH	
  
      	
                                                   Friends	
  


                                                                     Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
How	
  Ca	
  

                  Virus	
  


                 High	
  Mucosal	
            Cigarette	
  
                    Acidity	
                  Smoke	
  




                                                                                            • Viruses	
  like	
  	
  seeds	
  they	
  
                Poor	
  Mucosal	
                                                           cannot	
  grow	
  and	
  germinate	
  
                                               Altering	
  
                  defense	
                                                                 unless	
  all	
  they	
  have	
  opZmal	
  
                                                Flora	
  
                         	
                                                                 condiZons	
  




                    High	
  
                SuscepZbility	
  



                             	
  
                    Flu	
  develops	
  
                                          Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
The	
  Magical	
  
Network	
  


     Spirit	
  –	
  Body	
  
     -­‐	
  	
  Mind	
  



   Internal	
  Body	
  
   invironment	
  and	
  
   Immunity	
  	
  

   External	
  
   Environment:	
  
   O2,	
  Toxin	
  	
  


     Water,	
  Food,	
  
     Herbs,	
  Sun,	
  	
  



     Supplement	
  



                               Copyright	
  ©	
  2012	
  AWAREmed	
  All	
  Rights	
  Reserved.	
  
TRANSMISSION	
  
s  AEROSOL	
  
  s  100,000	
  TO	
  1,000,000	
  
      VIRIONS	
  PER	
  DROPLET	
  


s  18-­‐72	
  HR	
  INCUBATION	
  


s  SHEDDING	
  

                                       8	
  
Influenza: Who s at risk?

s  Everybody

s  People with greater risk:


  Ø ≥ 65 years old
  Ø Patients with chronic diseases
    Ø  Asthma/Lung chronic disease

    Ø  Chronic Heart Disease


  s  ≤ 5 years old
s  DECREASED	
  
    CLEARANCE	
  


s  RISK	
  BACTERIAL	
  
    INFECTION	
  


s  VIREMIA	
  RARE	
  
                            10	
  
                                     Lycke	
  and	
  Norrby	
  Textbook	
  of	
  Medical	
  Virology	
  1983	
  
RECOVERY	
  
s  INTERFERON	
  -­‐	
  SIDE	
  EFFECTS	
  INCLUDE:	
  
  s  FEVER,	
  MYALGIA,	
  FATIGUE,	
  MALAISE	
  



s  CELL-­‐MEDIATED	
  IMMUNE	
  RESPONSE	
  


s  TISSUE	
  REPAIR	
  
  s  CAN	
  TAKE	
  SOME	
  TIME	
  



                                         11	
  
interferon-­‐alpha,	
  interferon-­‐beta	
  


                                                      interferon	
  receptor	
  	
  



       induction	
  of	
  	
                   induction	
  of	
  	
                                   induction	
  of	
  a	
  
 2ʼ’5ʼ’oligo	
  A	
  synthase	
               ribonuclease	
  L	
  	
                                  protein	
  kinase	
  	
  

ds	
  RNA	
                         2ʼ’5ʼ’oligo	
  A	
                                           ds	
  RNA	
  


         activated	
                             activated	
  	
                                         activated	
  
 2ʼ’5ʼ’oligo	
  A	
  synthase	
               ribonuclease	
  L	
  	
                                  protein	
  kinase	
  	
  

                         ATP	
                                                                                          ATP	
  


                                                                                         phosphorylated	
  initiation	
  
         2ʼ’5ʼ’oligo	
  A	
  
                                                                                              factor	
  (eIF-­‐2)	
  



                                             mRNA	
  degraded	
  	
                    inhibition	
  of	
  protein	
  synthesis	
  	
  
                                                                      12	
  
ORTHOMYXOVIRUSES	
  
                                                           HA	
  -­‐	
  hemagglutinin	
  	
  	
  

                                                                               NA	
  -­‐	
  neuraminidase	
  


                                                                        helical	
  nucleocapsid	
  (RNA	
  plus	
  	
  
                                                                        NP	
  protein)	
  	
  	
  	
  	
  

                                                                              lipid	
  bilayer	
  membrane	
  	
  

                                                                              polymerase	
  complex	
  



                                                                        M1	
  protein	
  

type	
  A,	
  B,	
  C	
  :	
  NP,	
  M1	
  protein	
  	
  	
  	
  
sub-­‐types:	
  HA	
  or	
  NA	
  protein	
  
                                                               13	
  
ORTHOMYXOVIRUSES	
  

pleomorphic	
  
influenza	
  types	
  A,B,C	
  
febrile,	
  respiratory	
  illness	
  
     with	
  systemic	
  
     symptoms	
  
	
  

                                                  http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html	
  




                                         14	
  
CAUSE:	
  	
  	
  RNA	
  Virus	
  
  s  file:///Users/outreach/                         s  	
  	
  	
  	
  The	
  influenza	
  virus,	
  
      Desktop/DESKTOP                                      commonly	
  known	
  as	
  the	
  
      %202008/curr                                         flu,	
  is	
  an	
  infectious	
  
      %20project/Image-­‐3D                                disease	
  of	
  birds	
  and	
  
      %20Influenza%20virus	
                                mammals	
  caused	
  by	
  RNA	
  
                                                           viruses.	
  	
  Commonly	
  
                                                           confused	
  with	
  a	
  cold,	
  the	
  
                                                           flu	
  is	
  a	
  much	
  more	
  
                                                           severe	
  disease	
  and	
  
http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png	
  caused	
  by	
  a	
  different	
  

                                                           virus.	
  
Key Influenza A Viral Features



            Two Surface proteins(major antigens)
             s  Hemagglutinin (HA)
            HA
                 s  Site of attachment to host cells
                 •  Antibody to HA is protective

             s  Neuraminadase (NA)
              •  Helps release virions from cells
             NA Antibody to NA can help modify disease
              • 
       17          severity
INFLUENZA	
  A	
  PANDEMICS	
  




               19	
  
Type A influenza
                          16 HA subtypes
cannot be eradicated
                           9 NA subtypes




                                 α2-6Gal
                                 α2-3Gal
                α2-3Gal




              α2-6Gal
              α2-3Gal            α2-6Gal
where	
  do	
   new 	
  HA	
  and	
  NA	
  
                 come	
  from?	
  
s  13	
  types	
  HA	
  
s  	
  	
  9	
  types	
  NA	
  
    s  all	
  circulate	
  in	
  birds	
  

s  pigs	
  
    s  avian	
  and	
  human	
  




                                              21	
  
where	
  do	
   new 	
  HA	
  and	
  NA	
  
          come	
  from?	
  




                     22	
  
Reassortment
Pandemic Influenza 2009 - Natural history of swine influenza	

                  North American Swine Influenza            Eurasian Swine Influenza
                         (~last 12 years)

                                                trH3N2	


                        trH3N2	


cH1N1	
  
                                                trH1N2	




 H3N2	

               cH1N1	
  
                                                trH1N1	




                PB2 = North Am. Avian
 H1N1	

        PB1 = Human
                PA = North Am. Avian                            PB2 = H3N2 swine
                HA = Human                                      PB1 = H3N2 swine
                         2009 swine-like H1N1
                NP = Classical swine                            PA = H3N2 swine
                              American flu
                NA = Human                                      HA = Classical swine
                M = Classical swine                             NP = Classical swine
                NS = Classical swine                            NA = Eurasian swine
                                                                M = Eurasian swine
                                                                NS = Classical swine
1918
                          H1N1 Spanish flu
                          >20 million deaths



                          1957
                          H2N2 Asian Flu

Pandemic influenza strains contain
                          ~2 million deaths



  genes from the avian reservoir
                          1968
                          H3N2 Hong Kong Flu
                          ~700,000 deaths



                          1977
           ?              H1N1 Russian Flu




                           2009
                           H1N1 American Flu
Neuraminidase Inhibitors
Surface glycoprotein genes                      “Tamiflu” “Relenza”	

      HA and NA
                                                          X
                                                        Release
        HA        NA
      Master donor                                                   ER - Golgi
      strain genes
                                                                                       AAAA	
  
    PB2      PB1 PA                                                                      AAAA	
  
                                                                                                AAAA	
  

        NP        M

             NS                 Packaging and Budding
 Transfection of plasmids
        into cells
                                                                       Nucleus
                                                                                    AAAA	
  
                                                                                                            X
                                                                                                           IFN	
  
                                                                         AAAA	
  
                                                                  Host mRNAs
   Receptor binding and Entry



                                                        Uncoating


                  Amantadine                  X+
                                              H
                                                           Endocytosis
                  “Symmetrel”
                  “Flumadine”
Influenza virus Reverse Genetics

                      viral protein

                                         translation
          cap                                                    AAAA
  mRNA


RNA polymerase II (pol II)

      pIICMV                                                    pABGH
                     ATG--------- viral cDNA -------TAA
            tI                                            pIh

                                         RNA polymerase I (pol I)

    (-) vRNA                                              ppp
                3‘                                        5‘
why	
  do	
  we	
  not	
  have	
  influenza	
  
                   B	
  pandemics?	
  	
  	
  	
  
s  so	
  far	
  no	
  shifts	
  have	
  
    been	
  recorded	
  

s  no	
  animal	
  reservoir	
  
    known	
  




                                            28	
  
Spreading	
  
Fig.	
  13.11	
  
Anatomy	
  of	
  Nose	
  and	
  Sinuses	
  
Anatomy	
  of	
  Nose	
  &	
  Sinuses,	
  
             cont.	
  
Fusion Schematic
     Fusion	
  Schematic	
  
  1)	
  HA	
  binds	
  a	
  cell	
  GP	
  at	
  a	
  
  Sialic	
  Acid	
  Binding	
  Site	
  




                         http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt	
  
Fusion Schematic
     Fusion	
  Schematic	
  
  1)	
  HA	
  binds	
  a	
  cell	
  GP	
  at	
  a	
  
  Sialic	
  Acid	
  Binding	
  Site	
  




                                                                    Low	
  pH	
  



                      2)	
  Clathrin-­‐Coated	
  pit	
  
                      endocytoses	
  virion	
  




                         http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt	
  
Fusion Schematic
     Fusion	
  Schematic	
  
  1)	
  HA	
  binds	
  a	
  cell	
  GP	
  at	
  a	
  
  Sialic	
  Acid	
  Binding	
  Site	
                                                        3)	
  Conformational	
  Change:	
  
                                                                                             Hydrophobic	
  binding	
  of	
  HA	
  
                                                                                             to	
  vesicle	
  membrane	
  


                                                                    Low	
  pH	
  



                      2)	
  Clathrin-­‐Coated	
  pit	
  
                      endocytoses	
  virion	
  




                         http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt	
  
Fusion Schematic
     Fusion	
  Schematic	
  
  1)	
  HA	
  binds	
  a	
  cell	
  GP	
  at	
  a	
  
  Sialic	
  Acid	
  Binding	
  Site	
                                                        3)	
  Conformational	
  Change:	
  
                                                                                             Hydrophobic	
  binding	
  of	
  HA	
  
                                                                                             to	
  vesicle	
  membrane	
  


                                                                    Low	
  pH	
  



                      2)	
  Clathrin-­‐Coated	
  pit	
  
                      endocytoses	
  virion	
  



            4)	
  RNPs	
  are	
  released	
  into	
  
            cytoplasm	
  for	
  replication	
  
            and	
  transcription	
  (vRNA	
  and	
  
            mRNA)	
  




                         http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt	
  
Cellular	
  targets	
  
B)	
  Inhibitors	
  of	
  cellular	
  factors	
  that	
  regulate	
  the	
  virus	
  life	
  cycle	
  	
  	
  

           Hillaire	
  et	
  al.	
  (P-­‐452)	
  Collectin	
  pSP-­‐D	
  
           Nicol	
  et	
  al.	
  (P-­‐449)	
  FLUPEP	
  

                                              DAS181                                   Budding	
  
                   Adsorption	
  
                                              "



                                                                                Packaging	
  
       Entry                             Posttranslational                      Actin
                                         Processing                             Rab 11
      Endocytosis                           Translation	
  
       Rabs, V-type ATPases
       PKC
        Fusion and
        Release	
  
                                                                               RNP-
                                                         mRNA  	
              Export
                                                        vRNA (-)      	
       CRM1
                                                                               Hsc70
                       Import
                      Importins
                                                         cRNA (+)       	
     NUP153

                      NUPs
Cellular	
  targets	
  
            Viral	
  penetration	
  of	
  cellular	
  barriers	
  is	
  controlled	
  	
  
            by	
  cellular	
  signaling	
  cascades	
  



                                                                                              Budding	
  
                                Adsorption	
  
RTKs (e.g. EGFR)
Eierhoff et al. (2010)
PLoS Pathog (in press)
                                                                                       Packaging	
  
                    PI3K                         Posttranslational                      Raf/MEK/ERK
                                                 Processing
                     Entry                                                              Pleschka et al. (2001) Nat Ce
                    Endocytosis                     Translation	
                       IKK/NF-kB
                                                                                        Wurzer et al. (2004) Cell Micr
                                                                                        Wurzer et al. (2003) EMBO J.
                     Fusion and
                     Release	
  
                                                                                      RNP-
                                                                mRNA  	
              Export
                                                               vRNA (-)      	
  
                                     Import
                                                                cRNA (+)       	
  
INTERFERON	
  




      41	
  
INTERFERON	
  


                            antiviral	
  state	
  




antiviral	
  state	
                                 antiviral	
  state	
  




                            antiviral	
  state	
  
                                         42	
  
INTERFERON	
  


                            antiviral	
  state	
  




antiviral	
  state	
                                 antiviral	
  state	
  




                            antiviral	
  state	
  
                                         43	
  
INTERFERON	
  


                            antiviral	
  state	
  




antiviral	
  state	
                                 antiviral	
  state	
  




                            antiviral	
  state	
  
                                         44	
  
INTERFERON	
  
THE	
  VIRUSES	
  ARE	
  COMING!	
  




                                          PAUL	
  REVERE	
  
                                          http://www.mfa.org/collections/one_hour/6.htm	
  
              45	
  
     http://www.paulreverehouse.org/midnight.html	
  
Echinecea	
  
Elder	
  Berry	
  
Fruits	
  
Garlic	
  
Bee	
  Propolis	
  
Olive	
  Leaf	
  
Education	
  and	
  Awareness	
  
s  Consult their physician before taking other medication, including
    OTCs



s Good hygiene
s Antiviral drugs are not cures but help manage
   symptoms
Flu how to combat it naturally?

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Flu how to combat it naturally?

  • 1.  INFLUENZA   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.   1  
  • 2. Influenza Disease Burden in the United States in an Average Year Deaths*   Hospitalizations*   3,000  to  49,000   117,000  to  816,000   Physician  visits   ~25  million   Infections  and  illnesses   50  to  60  million   *  All-­‐cause  hospitalization  and  mortality  associated  with  influenza  virus  infection.   Thompson WW et al. JAMA. 2003;289:179-186; Thompson WW et al. JAMA. 2004;292:1333-1340; Couch RB. Ann Intern Med. 2000;133:992-998; Patriarca PA. JAMA. 1999;282:75-77; ACIP. MMWR. 2004;53(RR06):1-40; MMWR. 2010; 59(33): 1057-1062. Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 3. South  Carolina  1996-­‐1997  DHEC  bulletin   malathia  influenzae  per  le  stelle   no  virus   CULTURE   influenza  A    RESULTS     influenza  B   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 4. BUSINESS   Flu  Combating  Algorithm   STRATEGY   1.  Understand  Your   *Food  as  Medicine,   Enemy  –  Virus  Flu   *Herbs  as  Medicine   2.  Understand  its   strategies   Build  a  Stronger   *Exercise  as  Medicine   Immune  System.   *Sleep  as  Medicine   Enhance  the  body  own   power  and  deffence   tools  .     Use  ll  the  Natural   Love  as  Medicine   resources  ito   Laughter  asMedicine   achieve  a  safe  and   Spiritusality  as  Medicine   healthy  Winter   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 5. FLU  Fighting   BUSINESS   Strategies   STRATEGY   Missions  and  Goals   Strategic  planning   Implementa:on     Know  Your  Enemy     Successfully  avoid  the  Flu  and   Understand  Viruses   Arm  yourself  with   remain  ealthy  and  aawell   and  all  there   the  tools  that   during  aaaaflu  aseason   behaviors  to  know   counteract  the  effect     how  to  properly   of  the  virus.       Combat  Them       1.  Food  as  Medicine,   Build  a  Stronger  Immune   1.  Understand  how  the   2.  Herbs  as  Medicine   System.   Flu  Is  transmitted   3.  Exercise  as  Medicine   Enhance  the  body  own   2.  Recognize  early   4.  Love  as  Medicine   power  and  deffence  tools   Symptoms  of  the  Flu   5.  Laughter  as  Medicine   to  combat  and  prevent  flu   6.  Spiritusality  as     Medicine     1.  Interferon  Concept   Use  ll  the  Natural   1.  Know  yor  Body   2.  Enzyme   resources  ito  achieve  a   3.  Replace  your  flora   safe  and  healthy  Winter   2.  Know  Your   4.  Healthy  PH     Friends   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 6. How  Ca   Virus   High  Mucosal   Cigarette   Acidity   Smoke   • Viruses  like    seeds  they   Poor  Mucosal   cannot  grow  and  germinate   Altering   defense   unless  all  they  have  opZmal   Flora     condiZons   High   SuscepZbility     Flu  develops   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 7. The  Magical   Network   Spirit  –  Body   -­‐    Mind   Internal  Body   invironment  and   Immunity     External   Environment:   O2,  Toxin     Water,  Food,   Herbs,  Sun,     Supplement   Copyright  ©  2012  AWAREmed  All  Rights  Reserved.  
  • 8. TRANSMISSION   s  AEROSOL   s  100,000  TO  1,000,000   VIRIONS  PER  DROPLET   s  18-­‐72  HR  INCUBATION   s  SHEDDING   8  
  • 9. Influenza: Who s at risk? s  Everybody s  People with greater risk: Ø ≥ 65 years old Ø Patients with chronic diseases Ø  Asthma/Lung chronic disease Ø  Chronic Heart Disease s  ≤ 5 years old
  • 10. s  DECREASED   CLEARANCE   s  RISK  BACTERIAL   INFECTION   s  VIREMIA  RARE   10   Lycke  and  Norrby  Textbook  of  Medical  Virology  1983  
  • 11. RECOVERY   s  INTERFERON  -­‐  SIDE  EFFECTS  INCLUDE:   s  FEVER,  MYALGIA,  FATIGUE,  MALAISE   s  CELL-­‐MEDIATED  IMMUNE  RESPONSE   s  TISSUE  REPAIR   s  CAN  TAKE  SOME  TIME   11  
  • 12. interferon-­‐alpha,  interferon-­‐beta   interferon  receptor     induction  of     induction  of     induction  of  a   2ʼ’5ʼ’oligo  A  synthase   ribonuclease  L     protein  kinase     ds  RNA   2ʼ’5ʼ’oligo  A   ds  RNA   activated   activated     activated   2ʼ’5ʼ’oligo  A  synthase   ribonuclease  L     protein  kinase     ATP   ATP   phosphorylated  initiation   2ʼ’5ʼ’oligo  A   factor  (eIF-­‐2)   mRNA  degraded     inhibition  of  protein  synthesis     12  
  • 13. ORTHOMYXOVIRUSES   HA  -­‐  hemagglutinin       NA  -­‐  neuraminidase   helical  nucleocapsid  (RNA  plus     NP  protein)           lipid  bilayer  membrane     polymerase  complex   M1  protein   type  A,  B,  C  :  NP,  M1  protein         sub-­‐types:  HA  or  NA  protein   13  
  • 14. ORTHOMYXOVIRUSES   pleomorphic   influenza  types  A,B,C   febrile,  respiratory  illness   with  systemic   symptoms     http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html   14  
  • 15.
  • 16. CAUSE:      RNA  Virus   s  file:///Users/outreach/ s         The  influenza  virus,   Desktop/DESKTOP commonly  known  as  the   %202008/curr flu,  is  an  infectious   %20project/Image-­‐3D disease  of  birds  and   %20Influenza%20virus   mammals  caused  by  RNA   viruses.    Commonly   confused  with  a  cold,  the   flu  is  a  much  more   severe  disease  and   http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png  caused  by  a  different   virus.  
  • 17. Key Influenza A Viral Features Two Surface proteins(major antigens) s  Hemagglutinin (HA) HA s  Site of attachment to host cells •  Antibody to HA is protective s  Neuraminadase (NA) •  Helps release virions from cells NA Antibody to NA can help modify disease •  17 severity
  • 18.
  • 20. Type A influenza 16 HA subtypes cannot be eradicated 9 NA subtypes α2-6Gal α2-3Gal α2-3Gal α2-6Gal α2-3Gal α2-6Gal
  • 21. where  do   new  HA  and  NA   come  from?   s  13  types  HA   s     9  types  NA   s  all  circulate  in  birds   s  pigs   s  avian  and  human   21  
  • 22. where  do   new  HA  and  NA   come  from?   22  
  • 24. Pandemic Influenza 2009 - Natural history of swine influenza North American Swine Influenza Eurasian Swine Influenza (~last 12 years) trH3N2 trH3N2 cH1N1   trH1N2 H3N2 cH1N1   trH1N1 PB2 = North Am. Avian H1N1 PB1 = Human PA = North Am. Avian PB2 = H3N2 swine HA = Human PB1 = H3N2 swine 2009 swine-like H1N1 NP = Classical swine PA = H3N2 swine American flu NA = Human HA = Classical swine M = Classical swine NP = Classical swine NS = Classical swine NA = Eurasian swine M = Eurasian swine NS = Classical swine
  • 25. 1918 H1N1 Spanish flu >20 million deaths 1957 H2N2 Asian Flu Pandemic influenza strains contain ~2 million deaths genes from the avian reservoir 1968 H3N2 Hong Kong Flu ~700,000 deaths 1977 ? H1N1 Russian Flu 2009 H1N1 American Flu
  • 26. Neuraminidase Inhibitors Surface glycoprotein genes “Tamiflu” “Relenza” HA and NA X Release HA NA Master donor ER - Golgi strain genes AAAA   PB2 PB1 PA AAAA   AAAA   NP M NS Packaging and Budding Transfection of plasmids into cells Nucleus AAAA   X IFN   AAAA   Host mRNAs Receptor binding and Entry Uncoating Amantadine X+ H Endocytosis “Symmetrel” “Flumadine”
  • 27. Influenza virus Reverse Genetics viral protein translation cap AAAA mRNA RNA polymerase II (pol II) pIICMV pABGH ATG--------- viral cDNA -------TAA tI pIh RNA polymerase I (pol I) (-) vRNA ppp 3‘ 5‘
  • 28. why  do  we  not  have  influenza   B  pandemics?         s  so  far  no  shifts  have   been  recorded   s  no  animal  reservoir   known   28  
  • 30.
  • 31.
  • 33. Anatomy  of  Nose  and  Sinuses  
  • 34. Anatomy  of  Nose  &  Sinuses,   cont.  
  • 35. Fusion Schematic Fusion  Schematic   1)  HA  binds  a  cell  GP  at  a   Sialic  Acid  Binding  Site   http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt  
  • 36. Fusion Schematic Fusion  Schematic   1)  HA  binds  a  cell  GP  at  a   Sialic  Acid  Binding  Site   Low  pH   2)  Clathrin-­‐Coated  pit   endocytoses  virion   http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt  
  • 37. Fusion Schematic Fusion  Schematic   1)  HA  binds  a  cell  GP  at  a   Sialic  Acid  Binding  Site   3)  Conformational  Change:   Hydrophobic  binding  of  HA   to  vesicle  membrane   Low  pH   2)  Clathrin-­‐Coated  pit   endocytoses  virion   http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt  
  • 38. Fusion Schematic Fusion  Schematic   1)  HA  binds  a  cell  GP  at  a   Sialic  Acid  Binding  Site   3)  Conformational  Change:   Hydrophobic  binding  of  HA   to  vesicle  membrane   Low  pH   2)  Clathrin-­‐Coated  pit   endocytoses  virion   4)  RNPs  are  released  into   cytoplasm  for  replication   and  transcription  (vRNA  and   mRNA)   http://ubik.microbiol.washington.edu/microm-­‐pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt  
  • 39. Cellular  targets   B)  Inhibitors  of  cellular  factors  that  regulate  the  virus  life  cycle       Hillaire  et  al.  (P-­‐452)  Collectin  pSP-­‐D   Nicol  et  al.  (P-­‐449)  FLUPEP   DAS181 Budding   Adsorption   " Packaging   Entry Posttranslational Actin Processing Rab 11 Endocytosis Translation   Rabs, V-type ATPases PKC Fusion and Release   RNP- mRNA   Export vRNA (-)   CRM1 Hsc70 Import Importins cRNA (+)   NUP153 NUPs
  • 40. Cellular  targets   Viral  penetration  of  cellular  barriers  is  controlled     by  cellular  signaling  cascades   Budding   Adsorption   RTKs (e.g. EGFR) Eierhoff et al. (2010) PLoS Pathog (in press) Packaging   PI3K Posttranslational Raf/MEK/ERK Processing Entry Pleschka et al. (2001) Nat Ce Endocytosis Translation   IKK/NF-kB Wurzer et al. (2004) Cell Micr Wurzer et al. (2003) EMBO J. Fusion and Release   RNP- mRNA   Export vRNA (-)   Import cRNA (+)  
  • 41. INTERFERON   41  
  • 42. INTERFERON   antiviral  state   antiviral  state   antiviral  state   antiviral  state   42  
  • 43. INTERFERON   antiviral  state   antiviral  state   antiviral  state   antiviral  state   43  
  • 44. INTERFERON   antiviral  state   antiviral  state   antiviral  state   antiviral  state   44  
  • 45. INTERFERON   THE  VIRUSES  ARE  COMING!   PAUL  REVERE   http://www.mfa.org/collections/one_hour/6.htm   45   http://www.paulreverehouse.org/midnight.html  
  • 46.
  • 47.
  • 48.
  • 49.
  • 50.
  • 51.
  • 58. Education  and  Awareness   s  Consult their physician before taking other medication, including OTCs s Good hygiene s Antiviral drugs are not cures but help manage symptoms