Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.
Ontology highlight
ABSTRACT:
ORGANISM(S): Macaca mulatta Macaca fascicularis
PROVIDER: GSE33351 | GEO | 2011/11/01
SECONDARY ACCESSION(S): PRJNA148857
REPOSITORIES: GEO
Similar Datasets
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
Project description:The goal of this experiment was to examine the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus to determine the role of hemagglutinin (HA) and the viral RNA polymerase complex of 1918 virus toward pathogenesis and abberant host responses in mice.
2013-02-23 | GSE44595 | GEO
Project description:The goal of this experiment was to examine the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus to determine the role of hemagglutinin (HA) and the viral RNA polymerase complex of 1918 virus toward pathogenesis and abberant host responses in mice. Six- to eight-week-old female BALB/c mice were anesthetized and inoculated with 50 μl of phosphate-buffered saline (PBS; Mock) or with 10^6 pfu of virus in a 50 μl volume. There are a total of six biological conditions: wild-type 1918 virus (A/Brevig Mission/1/1918; 1918), wild-type K173 virus (A/Kawasaki/173/2001; K173), three reassortant viruses between 1918 and K173 viruses [1918HA/K173, 1918PB1/K173, and 1918(3P+NP)/K173], and mock-infected control animals. Nine animals per virus group were inoculated, and whole lungs were collected at 1, 3 and 5 days post-inoculation from three animals per virus group per time point. Two of three mice inoculated with 1918 virus and 1918HA/K173 virus died by day 5 post-inoculation. Six animals were inoculated with PBS. Whole lungs from two mock-infected animals per time point were collected and served as the uninfected reference. All samples were processed for lung gene expression analysis using oligonucleotide microarrays. Technical replicates were performed for 9 samples.
2013-02-23 | E-GEOD-44595 | biostudies-arrayexpress
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).
2013-07-16 | GSE48890 | GEO
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.
2015-12-31 | GSE70502 | GEO
Project description:The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.
| S-EPMC2642661 | biostudies-literature
Project description:Background. The pathogenesis of influenza A virus subtype H5N1 (hearafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses. Methods. To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006), and evaluated cytokine expression in human macrophages. Results. Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice. Conclusions. These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans.
2012-09-30 | GSE40711 | GEO
Project description:Occasional transmission of highly pathogenic avian H5N1 influenza viruses to humans causes severe pneumonia with high mortality. To better understand the mechanisms via which H5N1 viruses induce severe disease in humans, we infected cynomolgus macaques with six different H5N1 strains isolated from human patients and compared their pathogenicity and the global host responses to the virus infection. Although all H5N1 viruses replicated in the respiratory tract, there was substantial heterogeneity in their replicative ability and in the disease severity induced, which ranged from asymptomatic to fatal. A comparison of global gene expression between severe and mild disease cases indicated that interferon-induced up-regulation of genes related to innate immunity, apoptosis, and antigen processing/presentation in the early phase of infection was limited in severe disease cases, although interferon expression was up-regulated in both severe and mild cases. Furthermore, co-expression analysis of microarray data, which reveals the dynamics of host responses during the infection, demonstrated that the limited expression of these genes early in infection led to a failure to suppress virus replication and to the hyperinduction of genes related to immunity, inflammation, coagulation, and homeostasis in the late phase of infection, resulting in a more severe disease. Our data suggest that the attenuated interferon-induced activation of innate immunity, apoptosis, and antigen presentation in the early phase of H5N1 virus infection leads to subsequent severe disease outcome. Bronchial brushes for microarray studies were obtained from female cynomolgus macaques infected with influenza viruses. Three animals per group were inoculated with one of three H5N1 influenza viruses (VN3028II, VN30259 or VN3040). The early phase of infection refers to timepoints Pre (prior to infection), 1, and 3 days post-infection. The late phase of infection refers to days 5 and 7 post-infection. Samples collected prior to infection (labeled as Pre) served as control data for each infection group.
2014-05-27 | E-GEOD-57970 | biostudies-arrayexpress
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
Project description:Background. The pathogenesis of influenza A virus subtype H5N1 (hearafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses. Methods. To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006), and evaluated cytokine expression in human macrophages. Results. Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice. Conclusions. These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans. Human monocyte-derived macrophages were mock-infected, or infected with IDN3006, VN3028IIcl2, or IDN3006/cl2PA at a multiplicity of infection (MOI) of 2. At 6 hours post-infection (hpi), the cells were harvested and subjected to microarray analysis (three technical replicates per each group).
2012-09-30 | E-GEOD-40711 | biostudies-arrayexpress