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How does influenza virus jump from animals to humans? Haixu Tang School of Informatics and Computing Indiana University, Bloomington.

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Presentation on theme: "How does influenza virus jump from animals to humans? Haixu Tang School of Informatics and Computing Indiana University, Bloomington."— Presentation transcript:

1 How does influenza virus jump from animals to humans? Haixu Tang School of Informatics and Computing Indiana University, Bloomington

2 Swine flu outbreak, 2009

3 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

4 Influenza is cause by a virus Orthomyxoviridae; a class of RNA virus using RNA as genetic material; globular article of a diameter ~100 nm; Protected by a bilayer and matrix proteins; ~500 copies of H protein and ~100 copies of N proteins; used for classification

5 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

6 Infection of flu viruses Host cell nucleus 1.Virus attached to the host cell;

7 Infection of flu viruses 1.Virus attached to the host cell; 2.Virus swallowed up by the host cell;

8 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;

9 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;

10 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;

11 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;

12 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;

13 Spread of influenza viruses

14 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

15 Structure of glycans monosaccharide linkage

16 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

17 Animal glycans

18 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

19 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.

20 Experimental determination of binding specificities of hemagglutinins hemagglutinin virus Interaction assay Glycan array The glycan motif finding problem

21 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

22 Exhaustive counting of treelets

23 Finding over-represented treelets Glycans are not random! Many 4-treelets appear in ALL input glycan trees.

24 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

25 Contingency table

26 Fishers exact test: significance test of the over-represented treelets +- +ni+ni+ N-n i + -ni-ni- M-N-n i - M glycans printed on the array N positive, M-N negative n i + positives contain the treelet n i - negatives contain the treelet P=0.05 P=0.15

27 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.

28 Spread of influenza viruses


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