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									How does influenza virus jump
  from animals to humans?
              Haixu Tang
 School of Informatics and Computing
   Indiana University, Bloomington
Swine flu outbreak, 2009
Influenza pandemics in human history
• Spanish flu, 1918
  – Most deadly natural disaster
• Asian flu, 1957
• Hong Kong flu, 1968

• Seasonal flu: every year
  – Vaccine designed based on the observation of the
    flu strains spreading in animals
          Influenza is cause by a virus

q Orthomyxoviridae;
q a class of RNA virus using
  RNA as genetic material;
q globular article of a
  diameter ~100 nm;
q Protected by a bilayer and
  matrix proteins;
q ~500 copies of H protein
  and ~100 copies of N
  proteins;
   q used for classification
    Classification of influenza viruses
• 16 H genes and 9 genes found

• Spanish flu, 1918: H1N1
    – Most deadly natural disaster
•   Asian flu, 1957: H2N2
•   Hong Kong flu, 1968: H3N2
•   Swine flu: 2009: H1N1
•   Current pandemic threat: H5N1
•   Several hundreds of active flu strains
             Infection of flu viruses
1. Virus attached to the host
   cell;




                                        Host cell




                                        nucleus
              Infection of flu viruses
1. Virus attached to the host cell;
2. Virus swallowed up by the host
   cell;
                 Infection of flu viruses
1.   Virus is attached to the host cell;
2.   Virus is swallowed up by the host
     cell;
3.   Viral RNAs is released and enter the
     nucleus, where they are reproduced;
                 Infection of flu viruses
1.   Virus is attached to the host cell;
2.   Virus is swallowed up by the host
     cell;
3.   Viral RNAs is released and enter the
     nucleus, where they are reproduced;
4.   Fresh RNAs enter the cytosol;
                 Infection of flu viruses
1.   Virus is attached to the host cell;
2.   Virus is swallowed up by the host
     cell;
3.   Viral RNAs is released and enter the
     nucleus, where they are reproduced;
4.   Fresh RNAs enter the cytosol;
5.   Viral RNAs act as mRNA to be
     translated into proteins forming new
     virus particles;
                 Infection of flu viruses
1.   Virus is attached to the host cell;
2.   Virus is swallowed up by the host
     cell;
3.   Viral RNAs is released and enter the
     nucleus, where they are reproduced;
4.   Fresh RNAs enter the cytosol;
5.   Viral RNAs act as mRNA to be
     translated into proteins forming new
     virus particles;
6.   New virus buds off from the
     membrane of the host cell;
                 Infection of flu viruses
1.   Virus is attached to the host cell;
2.   Virus is swallowed up by the host
     cell;
3.   Viral RNAs is released and enter the
     nucleus, where they are reproduced;
4.   Fresh RNAs enter the cytosol;
5.   Viral RNAs act as mRNA to be
     translated into proteins forming new
     virus particles;
6.   New virus buds off from the
     membrane of the host cell;
             Spread of influenza viruses




http://www.healtyhype.com
      Recognition of the virus to the host
                       cell:
      hemagglutinin (H protein) vs. glycans
• On the surface of animal cells,
  there exist a heavy coat of
  glycans (sugars linked to
  proteins or lipids);
• Different animals may have
  glycans of different structures;
    – Human, pig and birds
• Different influenza virus strains
  with different hemagglutinin
  proteins (a class of glycan
  binding protein) recognize
  glycans of different structures
   Structure of glycans
                          linkage

monosaccharide
         Some basic graph theory
• Graph: modeling pairwise relation (edges)
  between subjects (nodes or vertices)
• Tree: a graph with no cycle
  – Each node in a tree has zero (leaves) or more child nodes
  – Subtree: a subset of nodes/edge
• Labels
  – Nodes: monosaccharides
  – Edges: linkage types
Animal glycans
 Hemagglutinins recognize sialylated
              glycans
• Human cells mainly
  express 2-6 linked
  sialylated glycans;
• Bird cells mainly
  express 2-3 linked
  sialylated glycans;
• Pig cells express
  both.
                         Vessel theory
  Hemagglutinin-glycan interaction is
         more complicated
• Several influenza strains were observed to be
  inconsistent with the theory
  – AV18 strain has hemagglutinin proteins recognize
    specifically 2-3 linked glycans, but are not
    transmissable in birds;
  – NY18 and Tx91 strains recognize both 2-3 and 2-6
    linked glycans, but NY18 does not transmit efficiently
    in human population, whereas Tx91 does;
  – Some chimeric H1N1 strains with high binding affinity
    to 2-6 linked glycans, but do not spread efficiently in
    human and pig.
   Experimental determination of binding
       specificities of hemagglutinins

           Interaction assay
hemagglutinin



   virus


                                 Glycan array




       The glycan motif finding problem
 The glycan motif finding problem
• Input: a set of (glycan) trees that are found to be
  recognized by a glycan binding protein (e.g.
  hemagglutinin)
• Output: a l-treelet that is over-represented in the
  input set

• l-treelet: a tree of a fixed small size l (e.g. l=4).
• Over-representation: number of trees in the input
  set containing the treelet is much higher than the
  expected number in a random set of trees
Exhaustive counting of treelets
Finding over-represented treelets




                               Many 4-treelets
                               appear in ALL
                               input glycan trees.



                  Glycans are not random!
    The glycan motif finding problem
         A different formulation
• Input: a positive set of (glycan) trees that are found
  to be recognized by a glycan binding protein (e.g.
  hemagglutinin) and a negative set of glycan trees
  that are found NOT to be recognized by the same
  protein
• Output: a l-treelet that is over-represented in the
  input positive set than the negative set

• Over-representation: number of trees in the
  positive set containing the treelet is much higher
  than the number of trees in the negative set
Contingency table
Fisher’s exact test: significance test of
    the over-represented treelets
                P=0.05     M glycans printed on the array
                           N positive, M-N negative
                           ni+ positives contain the treelet
                           ni- negatives contain the treelet


                                         +          -
                P=0.15         +         ni+      N-ni+
                               -         ni-     M-N-ni-
              Glycan patterns found to be
              recognized by hemagglutinin
   • R. Sasisekharan and colleagues show is the
     pattern recognized by human influenza
     hemagglutinin, but not recognized by avian
     influenza hemagglutinin;
   • 2-6 linked sialylated glycans with long
     oligosaccharide branch (with multiple lactosamine
     repeats) are predominantly expressed in the
     human upper respratory epithelial cells
   • Indeed, the binding specificity of hemagglutinin to
     2-6 linked sialylated glycans is not sufficient for the
     spread of the influenza viruses in human
     populations.
Chandrasekaran A, et al. Nat Biotechnol , 2008; 26:107–113.
             Spread of influenza viruses




http://www.healtyhype.com

								
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