close

Вход

Забыли?

вход по аккаунту

?

How does influenza virus jump from animals to humans

код для вставкиСкачать
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
Lipid Bilayer
пЃ± Orthomyxoviridae;
пЃ± a class of RNA virus using
RNA as genetic material;
пЃ± globular article of a
diameter ~100 nm;
пЃ± Protected by a bilayer and
matrix proteins;
пЃ± ~500 copies of H protein
and ~100 copies of N
proteins;
пЃ± used for classification
Hemagglutinin (H)
Neuraminidase (N)
matrix protein
RNA/protein
complex
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.
2.
3.
Virus is attached to the host cell;
Virus is swallowed up by the host
cell;
Viral RNAs is released and enter the
nucleus, where they are reproduced;
Infection of flu viruses
1.
2.
3.
4.
Virus is attached to the host cell;
Virus is swallowed up by the host
cell;
Viral RNAs is released and enter the
nucleus, where they are reproduced;
Fresh RNAs enter the cytosol;
Infection of flu viruses
1.
2.
3.
4.
5.
Virus is attached to the host cell;
Virus is swallowed up by the host
cell;
Viral RNAs is released and enter the
nucleus, where they are reproduced;
Fresh RNAs enter the cytosol;
Viral RNAs act as mRNA to be
translated into proteins forming new
virus particles;
Infection of flu viruses
1.
2.
3.
4.
5.
6.
Virus is attached to the host cell;
Virus is swallowed up by the host
cell;
Viral RNAs is released and enter the
nucleus, where they are reproduced;
Fresh RNAs enter the cytosol;
Viral RNAs act as mRNA to be
translated into proteins forming new
virus particles;
New virus buds off from the
membrane of the host cell;
Infection of flu viruses
1.
2.
3.
4.
5.
6.
Virus is attached to the host cell;
Virus is swallowed up by the host
cell;
Viral RNAs is released and enter the
nucleus, where they are reproduced;
Fresh RNAs enter the cytosol;
Viral RNAs act as mRNA to be
translated into proteins forming new
virus particles;
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
6
6
4
4
2
2
6
4
4
2
4
3
6
4
2
2
4
4
4
2
2
6
3
4
3
3
4
6
4
4
2
4
4
6
4
2
4
2
2
6
3
2
4
3
4
2
3
6
6
Finding over-represented treelets
2
4
4
3
6
6
4
2
6
4
4
2
2
4
2
2
3
4
4
2
2
6
6
4
4
3
4
6
2
4
3
2
6
6
3
4
6
4
2
4
3
4
6
2
6
3
6
3
4
4
4
3
2
2
2
4
4
6
4
3
2
2
6
2
4
6
4
2
4
2
6
4
4
2
4
3 or 6
4
2
3
6
3
core
structure
6
3 or 6
3 or 6
4
4
2
3
6
3
6
3 or 6
4
2
3
3
4
4
4
4
4
High-mannose
ASN-X-Ser/Thr
Complex
N-glycans
6
6
4
ASN-X-Ser/Thr
Many 4-treelets
appear in ALL
input glycan trees.
ASN-X-Ser/Thr
hybrid
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
2
6
positive
2
4
4
2
2
6
4
4
2
2
4
4
6
4
3
2
4
2
2
2
2
6
3
2
4
4
4
4
6
+
-
+
3
0
-
0
3
4
3
6
6
4
2
2
6
2
4
2
3
6
6
3
2
4
3
3
sample
4
4
4
6
6
4
6
6
4
2
4
4
2
4
3
4
4
6
2
2
3
6
3
4
6
4
2
6
6
4
4
2
2
4
6
3
negative
3
6
sample
4
6
3
6
2
2
2
2
3
6
4
4
4
4
3
+
-
+
3
3
-
0
0
6
4
4
3
4
4
Fisher’s exact test: significance test of
the over-represented treelets
P=0.05
positive
sample
6
6
6
4
4
4
6
2
2
2
4
4
2
2
3
4
4
2
2
6
4
+
-
+
3
0
-
0
3
2
2
4
3
6
6
4
2
2
2
6
3
6
4
4
4
4
3
6
4
sample
6
4
4
2
2
6
3
negative
3
-
+
3
2
-
0
1
6
2
2
6
+
4
6
2
2
6
3
3
6
4
4
4
4
+
-
+
n i+
N-ni+
-
ni-
M-N-ni-
4
P=0.15
6
M glycans printed on the array
N positive, M-N negative
ni+ positives contain the treelet
ni- negatives contain the treelet
3
6
4
4
4
2
Glycan patterns found to be
recognized by hemagglutinin
6
• 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.
4
2
Chandrasekaran A, et al. Nat Biotechnol , 2008; 26:107–113.
Spread of influenza viruses
http://www.healtyhype.com
Документ
Категория
Презентации
Просмотров
6
Размер файла
1 116 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа