Pathogenicity of different PR8 influenza A virus variants in mice is determined by both viral and host factors

Błażejewska, Paulina; Koscinski, Lukasz; Viegas, Nuno; Anhlan, Darisuren; Ludwig, Stephan; Schughart, Klaus

doi:10.1016/j.virol.2010.12.047

Cited by 74 publications

(106 citation statements)

References 49 publications

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“…We noted a small, but significant, difference in the viral load of A/J and B6 mice only at day 3 postinfection. This similar pattern of viral load between resistant and susceptible strains of mice is not in line with previous research (49,50), in which susceptible mouse strains had higher viral loads throughout infection. In contrast to viral loads, A/J mice showed significantly increased expression of cytokines and chemokines, principally Kc, Tnf-a, and Mcp-1, compared with B6 mice.…”

Section: Functional Dissection Of Susceptibility In Our Mouse Modelsupporting

confidence: 51%

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

Boivin

Pothlichet

Skamene

et al. 2012

The Journal of Immunology

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Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.

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Section: Functional Dissection Of Susceptibility In Our Mouse Modelsupporting

confidence: 51%

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

Boivin

Pothlichet

Skamene

et al. 2012

The Journal of Immunology

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“…This surveillance is critical for vaccine selection (23), as HA and NA are the major targets for vaccine-induced protective immunity (18). Since the virulence of influenza viruses is a multigenic trait (7,8,21), surveillance of additional viral genes may allow us to better predict the severity of infections associated with circulating influenza viruses (45). Furthermore, a description of distinct contributions of viral virulence factors toward deadly superinfections will FIG 4 Survival after secondary challenge.…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Swine Influenza A Virus PB1-F2 Phenotypes That Contribute to Superinfection with Gram-Positive Respiratory Pathogens

Weeks-Gorospe

Hurtig

Iverson

et al. 2012

J Virol

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A combination of viral, bacterial, and host factors contributes to the severity and overall mortality associated with influenza virus-bacterium superinfections. To date, the virulence associated with the recently identified influenza virus protein PB1-F2 has been largely defined using models of primary influenza virus infection, with only limited assessment in models of Streptococcus pneumoniae superinfection. Specifically, these studies have incorporated isogenic viruses that differ in the PB1-F2 expressed, but there is still knowledge to be gained from evaluation of natural variants derived from a nonhuman host species (swine). Using this rationale, we developed the hypothesis that naturally occurring viruses expressing variants of genes, like the PB1-F2 gene, can be associated with the severity of secondary bacterial infections. To test this hypothesis, we selected viruses expressing variants in PB1-F2 and evaluated outcomes from superinfection with three distinct Gram-positive respiratory pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes. Our results demonstrate that the amino acid residues 62L, 66S, 75R, 79R, and 82L, previously proposed as molecular signatures of PB1-F2 virulence for influenza viruses in the setting of bacterial superinfection, are broadly associated with enhanced pathogenicity in swine in a bacterium-specific manner. Furthermore, truncated PB1-F2 proteins can preferentially increase mortality when associated with Streptococcus pyogenes superinfection. These findings support efforts to increase influenza virus surveillance to consider viral genotypes that could be used to predict increased severity of superinfections with specific Gram-positive respiratory pathogens.

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“…The infectivity of virus used for infection of mice was determined as described previously (80,81). Virus titers were determined using a focus-forming unit (FFU) assay.…”

Section: Glycan Array Analysis (I) Preparation Of Virusesmentioning

confidence: 99%

Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice

Yang

Punyadarsaniya

Lambertz

et al. 2017

J Virol

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The natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precisioncut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized ␣2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with ␣2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190ϩHA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.IMPORTANCE Swine play an important role in the interspecies transmission of influenza viruses. Avian influenza A viruses (IAV) of the H9N2 subtype have successfully infected hosts from different species but have not established a stable lineage. We have analyzed the adaptation of IAV-H9N2 virus to target cells of a new host by passaging the virus three times in differentiated porcine respiratory epithelial cells. Among the four mutations detected, the two HA mutations were analyzed by generating recombinant viruses. Depending on the infection system used, the mutations differed in their phenotypic expression, e.g., sialic acid binding activity, replication kinetics, plaque size, and pathogenicity in inbred mice. However, none of the mutations affected the ciliary activity which serves as a virulence marker. Thus, early

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Pathogenicity of different PR8 influenza A virus variants in mice is determined by both viral and host factors

Cited by 74 publications

References 49 publications

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

Naturally Occurring Swine Influenza A Virus PB1-F2 Phenotypes That Contribute to Superinfection with Gram-Positive Respiratory Pathogens

Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice

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