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Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection

ABSTRACT: Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from wild-type 129S6/SvEv and interferon receptor (IFNR) knockout mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203).

ORGANISM(S): Mus musculus

PROVIDER: GSE48890 | GEO | 2013/07/16

SECONDARY ACCESSION(S): PRJNA212141

REPOSITORIES: GEO

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Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection

Project description:Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from wild-type 129S6/SvEv and interferon receptor (IFNR) knockout mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Eight- to 10-week-old female wild-type and IFNR1-/- mice (on a 129S6/SvEv background) were anesthetized by intraperitoneal injection of 0.2 ml of 2,2,2-tribromoethanol in tert-amylalcohol (Avertin; Sigma-Aldrich, Milwaukee, WI). Ten times the 50% lethal dose (LD50), 3.2 × 10^4 PFU (1918) or 7 × 10^3 PFU (VN/1203), in 50 μl of infectious virus diluted in phosphate-buffered saline (PBS) was inoculated intranasally (i.n.). Lung tissue was harvested for microarray analysis from infected animals at 1, 3, and 4 days post-innoculation. For RNA isolation, lungs were frozen in individual tubes and stored in solution D (4 M guanidinium thiocyanate, 25 mM sodium citrate, 0.5% sarcosyl, 0.1 M β-mercaptoethanol). Separate microarrays were run for each infected mouse. This included 2 animals/time point for 1918 virus-infected mice (24 animals total) or 3 animals/time point for VN/1203-infected mice (36 animals total). Lung tissue from three uninfected wild type 129S6/SvEv mice was collected as a mock control. Equal masses of total RNA from the lung tissue of the three mice were pooled prior to being run on microarray. Two-channel microarrays were used to determine gene expression in the lungs. For each individual infected lung, gene expression from an infected lung was compared to gene expression from the pooled RNA from the mock control.

2013-07-16 | E-GEOD-48890 | biostudies-arrayexpress

Characterizing the transcriptomic response of mice infected with A/Anhui/01/2013 (H7N9), A/Netherlands/219/2003 (H7N7), and A/Vietnam/1203/2004 (H5N1), and a pandemic H1N1 human virus, A/Mexico/4482/2007 (H1N1)

Project description:Modulating the host response is a promising approach to treating influenza, a virus whose pathogenesis is determined in part by the host response it elicits. Though the pathogenicity of emerging H7N9 influenza virus has been reported in several animal models, these studies have not included a detailed characterization of the host response following infection. To this end, we characterized the transcriptomic response of BALB/c mice infected with H7N9 (A/Anhui/1/2013) virus and compared it to the responses induced by H5N1 (A/Vietnam/1203/2004), H7N7 (A/Netherlands/219/2003) or H1N1 (A/Mexico/4482/2009) viruses. We found that responses to the H7 subtype viruses were intermediate to those elicited by H5N1 and H1N1 early in infection, but that they evolved to resemble the H5N1 response as infection progressed. H5N1, H7N7 and H7N9 viruses were pathogenic in mice, and this pathogenicity correlated with increased cytokine response, decreased lipid metabolism and decreased coagulation signaling. This three-pronged signature has previously been observed in mice infected with pathogenic H1N1 strains such as the 1918 virus, indicating that it may be predictive of pathogenicity across multiple influenza strains. Groups of 6- to 8-week-old BALB/c mice were infected with either A/Anhui/01/2013 (H7N9), A/Netherlands/219/2003 (H7N7), A/Vietnam/1203/2004 (H5N1), or pandemic H1N1 human virus, A/Mexico/4482/2007 (H1N1). Infections were done at 10^5 PFU or time-matched mock infected. Time points were 1, 3 and 5 d.p.i. There were 4-5 infected and 3 mock infected animals/time point. Lung samples were collected for virus load and transcriptional analysis. Weight loss and animal survival were also monitored.

2014-05-27 | E-GEOD-54048 | biostudies-arrayexpress

2014-05-27 | GSE54048 | GEO

The 1918 PB2 protein, not HA, enhances the virulence of an avian influenza virus closely related to the 1918 pandemic virus through the inhibition of wnt signaling.

2015-12-31 | GSE70502 | GEO

The 1918 PB2 protein, not HA, enhances the virulence of an avian influenza virus closely related to the 1918 pandemic virus through the inhibition of wnt signaling.

Project description:The purpose of this experiment was to understand the pathogenic role of individual 1918 genes on the host response to the 1918 pandemic influenza virus. We examined reassortant avian viruses nearly identical to the pandemic 1918 virus (1918-like avian virus) carrying either the 1918 HA or PB2 gene. Both genes enhanced 1918-like avian virus replication, but only the mammalian host adaptation of the 1918-like avian virus through reassortment of the 1918 PB2 led to increased lethality in mice. We demonstrate that 1918 PB2 enhances immune and inflammatory responses concomitant with increased cellular infiltration in the lung. We also show that 1918 PB2 expression results in the repression of both canonical and non-canonical Wnt signaling pathways which are crucial for inflammation mediated lung regeneration and repair. Five- to six-week-old female BALB/c mice (Jackson Laboratory) were used for the experiments. Isoflurane-anesthetized mice were intranasally inoculated with tenfold serial dilutions (three mice per dilution) of 1918, 1918-like avian, 1918 PB2/avian and 1918 HA/avian viruses. The dose required to kill 50% of mice (MLD50) was calculated using the Reed-Muench method. For analysis of virus growth and microarray profiling mice were intranasally inoculated with 10^4 PFU of virus (n=4/virus/timepoint) or PBS (n=3/timepoint). At days 1, 2 and 4 after infection, lungs were harvested from the infected mice. Lungs were processed for RNA extraction for microarray studies and virus titer determination.

2015-12-31 | E-GEOD-70502 | biostudies-arrayexpress

Viral determinants in H5N1 influenza A virus enable productive infection of HeLa cells

Project description:Influenza A virus (IAV) is a human respiratory pathogen that causes yearly global epidemics, and sporadic pandemics due to human adaptation of pathogenic strains. Efficient replication of IAV in different species is, in part, dictated by its ability to exploit the genetic environment of the host cell. To investigate IAV tropism in human cells, we evaluated the replication of IAV strains in a diverse subset of epithelial cell lines. HeLa cells were refractory to growth of human H1N1 and H3N2, and low pathogenic avian influenza (LPAIs) viruses. Interestingly, a human isolate of the highly pathogenic avian influenza (HPAI) virus H5N1 successfully propagated in HeLa cells to levels comparable to a human lung cell line. Heterokaryon cells generated by fusion of HeLa and permissive cells supported H1N1 growth, suggesting the absence of a host factor(s) required for replication of H1N1, but not H5N1, in HeLa cells. The absence of this factor(s) was mapped to reduced nuclear import, replication, and translation, and deficient viral budding. Using reassortant H1N1:H5N1 viruses, we found that the combined introduction of nucleoprotein (NP) and hemagglutinin (HA) from H5N1 was necessary and sufficient to enable H1N1 growth. Overall, this study suggests the absence of one or more cellular factors in HeLa cells that results in abortive replication of H1N1, H3N2, and LPAI viruses, but can be circumvented upon introduction of H5N1 NP and HA. Further understanding of the molecular basis of this restriction will provide important insights into virus-host interactions that underlie IAV pathogenesis and tropism.

2019-11-21 | GSE140759 | GEO

1918 pandemic influenza virus and pneumococcus co-infection results in activation of coagulation and widespread pulmonary microvascular thrombosis in mice and humans

Project description:To study the effects of secondary bacterial infection during 1918 pandemic H1N1 influenza virus infection, BALB/c mice were inoculated with the fully reconstructed 1918 influenza virus followed by inoculation with pneumococcus 72h later. To study the effects of secondary bacterial infection during 1918 pandemic H1N1 influenza virus infection, BALB/c mice were inoculated with the fully reconstructed 1918 influenza virus followed by inoculation with pneumococcus 72h later.

2015-09-20 | E-GEOD-70445 | biostudies-arrayexpress

An ultrasensitive mechanism regulates influenza virus-induced inflammation

Project description:Whole-genome, time-course data was developed from the lungs of influenza infected mice to better characterize the dynamics of the host immune response during infection. Lung for microarray studies were obtained from female, five-week old C57BL/6Js infected with influenza viruses. Forty-two animals per group were inoculated with 10^5 PFU of A/Kawasaki/UTK-4/09 H1N1 virus [Kawasaki], A/California/04/09 (H1N1) virus (pH1N1) [SOIV], A/Vietnam/1203/04 H5N1 virus (H5N1), 10^3 PFU A/Vietnam/1203/04 H5N1 virus (H5N1) [VN1203] or mock-infected with PBS. Spanning the first week of the infections, three animals per infection group were sacrificed at 14 predetermined time points, lungs isolated and the homogenate was used to assess changes in genes expression over time and between infections.

2015-06-12 | E-GEOD-63786 | biostudies-arrayexpress

Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.

Project description:This study revealed important similarities but also critical differences between the H5N1 and 1918-reassortant viruses, highlighting aspects of the host–pathogen interface caused by highly virulent influenza viruses. Animals assigned to 4 experimental groups (n = 8) matched for age, weight, and sex, were inoculated by intratracheal, intranasal, tonsillar, and conjunctival routes with a total of 107 pfu of A/Vietnam/1203/2004 (H5N1) virus, A/Texas/36/91 (H1N1) virus or reassortants of this virus containing either 2 (HA, NA) or 3 (HA, NA, NS) genes from the 1918 virus. Two animals per group were scheduled for sacrifice on days 1, 2, 4, and 7. Two additional animals were used as uninfected control animals and killed on day 7. Oligoarray analyses consisted of comparing array profiles of individual lung samples (with representative pathology and degree of infection) from infected animals to pooled equal masses of mRNA from all lung lobes of 7 reference cynomolgus macaques obtained through the tissue program of the University of Washington National Primate Research Center. There are 2 technical array replicates fro each sample.

2011-11-01 | E-GEOD-33351 | biostudies-arrayexpress

An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets [ferret]

Project description:Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics as well as from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is comprised of four beta-propiolactone-inactivated low pathogenicity avian influenza A virus subtypes of H1N9, H3N8, H5N1, or H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to mock vaccinated animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.

2022-07-21 | GSE205840 | GEO

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