How does influenza virus jump from animals to humans?
Haixu TangSchool 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 virusLipid B ilayer
matrix protein
RNA/proteincomplex
Hemagglutinin (H)
Neuraminidase (N)
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
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
Host cell
nucleus
1. Virus attached to the host cell;
Infection of flu viruses
1. Virus attached to the host cell;2. Virus swallowed up by the host
cell;
Infection of flu viruses1. 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 viruses1. 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 viruses1. 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 viruses1. 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 viruses1. 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
monosaccharide
linkage
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
hemagglutinin
virus
Interaction assay
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
4
4
3 6
2
4
6
2
4
6
2
4 4
4
3 6
4
4 2
4
6
4
4
4
3 6
4
2
4
3
2
3 6
2
3 6
23
2
4
6
2
4
2
4
2
6
2
4
Finding over-represented treelets
4
4
3 6
2
4
6
2
4
6
2
4
4
4
3 6
2 2
4
6
2
4
4
6
2
4
4
4
3 6
2
4
6
2
4
3 6
2
2
6
2
4
6
4
4
4
6
2
4
3
2
4
3 63 6
2
3 6
2
4
4
3
3
2
4
6
2
4
2
4
2
4
2
4
A S N -X-S e r/ Th r
4
4
3 6
3 62
A S N -X-S e r/ Th r
4
4
3 6
3 62
A S N -X-S e r/ Th r
4
4
3 6
3 62
4
3 o r 6
4
3 o r 63 o r 6
4 4
3 o r 6
H ig h -m a n n o s e C o m p le x h yb rid
N -g lyca n s
co re s tru ctu re Glycans are not random!
Many 4-treelets appear in ALL input glycan trees.
The glycan motif finding problemA 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
6
2
4
6
4
4
4
6
2
4
3
2
4
3 63 6
2
3 6
2
4
4
3
3
2
4
6
2
4
2
4
2
4
2
4
4
4
3 6
2
4
6
n e g a tiv e
4
4
3 6
4
4
3 6
2
3 6
2
4
6
2
4
6
3 6
2 2
4
4
3 6
2
4
6
2
4
6
2
4
p o s itiv e
4
4
3 6
2 2
4
6
2
4
4
6
2
4
4
4
3 6
2
4
6
2
4
3 6
2
26
2
4
+
+
s a m p le
-
-
3
30
0
+
+
s a m p le
-
-
3
00
34
4
3
Fisher’s exact test: significance test of the over-represented treelets
4
4
3 6
2
4
6
n e g a tiv e
4
4
3 6
4
4
3 6
2
3 6
2
4
6
2
4
6
3 6
2 2
4
4
3 6
2
4
6
2
4
6
2
4
p o s itiv e
4
4
3 6
2 2
4
6
2
4
4
6
2
4
4
4
3 6
2
4
6
2
4
3 6
2
2
6
2
4
+
+
s a m p le
-
-
3
30
0
+
+
s a m p le
-
-
3
10
22
4
6
+ -
+ ni+ N-ni
+
- ni- M-N-ni
-
M glycans printed on the arrayN positive, M-N negativeni
+ positives contain the treeletni
- negatives contain the treelet
P=0.05
P=0.15
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.
6
2
4
Chandrasekaran A, et al. Nat Biotechnol , 2008; 26:107–113.
Spread of influenza viruses
http://www.healtyhype.com
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