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

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;



nucleus, where they are reproduced;4. Fresh RNAs enter the cytosol;



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;



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


4

4

3 6

3 62


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

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

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