title: Adaptation of human influenza H3N2 virus in a mouse pneumonitis model: insights into viral virulence, tissue tropism and host pathogenesis.
abstract: Most pandemic influenza virus strains undergo adaptation or reassortment before they acquire the ability to cause fatal infections in a new host species. The pathologic changes and tissue tropism during virus adaptation are not fully understood. Here we investigated pathologic changes and tissue tropism by serial lung-to-lung passaging of human influenza virus strain A/Aichi/2/68 (H3N2) in a BALB/c mouse model. Enhanced pulmonary lesions and systemic virus infection were observed during adaptation. Late passage 10 (P10) virus caused extra-pulmonary spread with necrotic and inflammatory lesions in the brain, heart, spleen and intestine of infected animals, in contrast to infection with earlier passage viruses which were restricted to lungs. Non-conservative mutations in the hemagglutinin (Gly218Glu) and non-structural 1 (Asp125Gly) proteins were identified in P10 virus which exhibited high virulence. Virus growth kinetics showed enhanced replication ability of P10 virus in different cell lines. P10 virus also exhibited the ability to bind to erythrocytes of different host species. These results demonstrate extra-pulmonary spread of influenza virus during adaptation with enhanced replication ability in a new host. This mouse adaptation model may provide a basis for understanding cross-species adaptability corresponding to increased virulence of the influenza A virus, a phenomenon of relevance to the emergence of future highly pathogenic strains.
authors.affiliation: Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117597, Singapore.
authors.forename: T
authors.initials: T
authors.lastname: Narasaraju
authors.forename: M K
authors.initials: MK
authors.lastname: Sim
authors.forename: H H
authors.initials: HH
authors.lastname: Ng
authors.forename: M C
authors.initials: MC
authors.lastname: Phoon
authors.forename: N
authors.initials: N
authors.lastname: Shanker
authors.forename: S K
authors.initials: SK
authors.lastname: Lal
authors.forename: Vincent T K
authors.initials: VT
authors.lastname: Chow
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics; D054884:Host-Pathogen Interactions; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D007251:Influenza, Human / Q000473:pathology / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D009928:Organ Specificity; D011014:Pneumonia / Q000473:pathology / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics; D014774:Virulence
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins