Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Josset, Laurence; Belser, Jessica A.; Pantin‐Jackwood, Mary J.; Chang, Jean; Chang, Stewart T.; Belisle, Sarah E.; Tumpey, Terrence M.; Katze, Michael G.

doi:10.1128/jvi.00563-12

Cited by 56 publications

(79 citation statements)

References 54 publications

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“…In the absence of prior host adaptation, inoculation of mice with pH1N1 virus generally results in nonlethal infection that is resolved around day 8 post-infection. There is low morbidity (<10% total body weight) and moderate bronchiolitis observed in the lung, despite efficient viral replication throughout infection [10]. Alteration of viral PB1-F2 and NS1 proteins marginally impacted viral pathogenesis [11,12] and did not affect viral control of innate immune responses during pH1N1 infection in mice [13].…”

Section: Introductionmentioning

confidence: 99%

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

Belisle

Tchitchek

et al. 2012

BMC Genomics

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BackgroundThe 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this we have performed a comparative transcriptomic analysis of acute phase responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine.ResultsDespite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. We found genes associated with the retinoid X receptor (RXR) signaling pathway known to control pro-inflammatory and metabolic processes that were differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns varied among the three species.ConclusionsBy comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another.

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Section: Introductionmentioning

confidence: 99%

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

Belisle

Tchitchek

et al. 2012

BMC Genomics

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“…3). Previously, we showed that unabated antiviral and inflammatory responses associated with the recruitment of proinflammatory monocytes and macrophages results in increased viral virulence (35). Here, we show that in addition to the recruitment of granulocytes and agranulocytes into the lung, 1918 PB2 promotes the infiltration and activation of NK cells following infection.…”

Section: Network Analysis Identifies the Relationship Between Inflammmentioning

confidence: 61%

“…Previously, we reported that the early inflammatory response to IAV infection can severely impact the disease outcome (35). To better understand whether 1918 PB2 contributes to these detrimental responses, we focused on genes upregulated immediately following IAV infection at day 1 p.i.…”

Section: Pb2 Is a Key Driver Of Inflammatory Responses Enhancing Immumentioning

confidence: 99%

“…To predict immune cell composition, we utilized microarray data available from Mouse GeneAtlas v3 (GEO accession number GSE10246) as previously described (35). A Fisher exact test was used to determine enrichment scores for each module relative to the expression of DE genes in our data set enrichment scores (ES) were reported as Ϫlog 10 (P value), and the cutoff for significant enrichment was set at ES ϭ 1.3.…”

Section: Cells and Virusesmentioning

confidence: 99%

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The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice

Forero

Tisoncik-Go

Watanabe

et al. 2016

J Virol

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The 1918 A nnual influenza epidemics cause significant morbidity and mortality. On occasion, novel influenza A strains emerge that are capable of producing severe respiratory disease on a global scale (1). The 1918-1919 pandemic was an unprecedented event, with an estimated 40 to 50 million deaths worldwide (2, 3). Sequence analysis indicates that the 1918 pandemic influenza virus is avian in origin (4-8) and 1918 viral genes are highly homologous to those of circulating avian influenza H1N1 viruses (9). In a recent study, a reconstructed virus comprised of avian influenza viral segments with high homology to the 1918 virus was shown to be pathogenic in ferrets and mice. Specific amino acid changes in PB2 and PA viral polymerase proteins, in combination with amino acid changes in the hemagglutinin (HA) viral glycoprotein, resulted in the "1918-like avian virus" efficiently transmitting between ferrets via the respiratory droplet route (9). Host-adaptive changes in polymerase and NP genes enhancing avian influenza virus replicative fitness are well documented (10, 11). In particular, PB2 627K has become a genomic signature of host adaptation, which was present in the 1918 pandemic influenza virus PB2 gene, though novel host adaptive mutations continue to be characterized in the ribonucleoprotein complex (12-14). These humanadaptive changes may confer efficient replication of avian influ-

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“…Many genes associated with inflammation are strongly upregulated following influenza infection of mice, especially following highly virulent viruses (Boon et al 2011; Josset et al 2012; Kash et al 2006; Korth et al 2013; Trammell and Toth 2008). Many of these genes are differentially regulated in different mouse strains (Alberts et al 2010; Ding et al 2008), with susceptible strains showing a more robust inflammatory response to influenza infection than do the more resistant strains (Alberts et al 2010; Boon et al 2011; Srivastava et al 2009; Trammell et al 2012), suggesting that at least one reason for differential influenza susceptibility may be variations in immune responses.…”

Section: Host Genetics Influencing Susceptibility To Influenzamentioning

confidence: 99%

Molecular Determinants of Influenza Virus Pathogenesis in Mice

Kamal

Katz

York

2014

Influenza Pathogenesis and Control - Volume I

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Mice are widely used for studying influenza virus pathogenesis and immunology because of their low cost, the wide availability of mouse-specific reagents, and the large number of mouse strains available, including knockout and transgenic strains. However, mice do not fully recapitulate the signs of influenza infection of humans: transmission of influenza between mice is much less efficient than in humans, and influenza viruses often require adaptation before they are able to efficiently replicate in mice. In the process of mouse adaptation, influenza viruses acquire mutations that enhance their ability to attach to mouse cells, replicate within the cells, and suppress immunity, among other functions. Many such mouse-adaptive mutations have been identified, covering all 8 genomic segments of the virus. Identification and analysis of these mutations have provided insight into the molecular determinants of influenza virulence and pathogenesis, not only in mice but also in humans and other species. In particular, several mouse-adaptive mutations of avian influenza viruses have proved to be general mammalian-adaptive changes that are potential markers of pre-pandemic viruses. As well as evaluating influenza pathogenesis, mice have also been used as models for evaluation of novel vaccines and anti-viral therapies. Mice can be a useful animal model for studying influenza biology as long as differences between human and mice infections are taken into account.

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Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Cited by 56 publications

References 54 publications

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice

Molecular Determinants of Influenza Virus Pathogenesis in Mice

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