Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

  title={Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus},
  author={Darwyn Kobasa and Steven J M Jones and Kyoko Shinya and John C. Kash and John S Copps and Hideki Ebihara and Yasuko Hatta and Jin Hyun Kim and Peter J. Halfmann and Masato Hatta and Friederike Feldmann and Judie B. Alimonti and Lisa Fernando and Yan Li and Michael G. Katze and Heinz Feldmann and Yoshihiro Kawaoka},
The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in… 

Infection with highly pathogenic H7 influenza viruses results in an attenuated proinflammatory cytokine and chemokine response early after infection.

It is shown that infection with HPAI H7 viruses resulted in a delayed and weakened production of cytokines, including the type I interferon response, compared with infections of other influenza A subtypes, including H7 virus of low pathogenicity.

Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response

Influenza A viruses of avian origin represent an emerging threat to human health as the progenitors of the next influenza pandemic as well as their induction of host innate immune responses in mammalian species, and the contribution of these responses to the disease process.

Innate immunity: 1918 — a lesson from history?

Results indicate that the ability of the 1918 virus to modulate host immune responses could have contributed to its unprecedented lethality, and highlights the need for a better understanding of the transmission of pandemic influenza viruses, their interactions with the host and their ability to modify host innate immune responses.

Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes

Compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04 suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severityof tissue damage.

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

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.

A mouse model of lethal synergism between influenza virus and Haemophilus influenzae.

It is suggested that infection with virulent strains of influenza may predispose even immunocompetent individuals to severe illness on secondary infection with H. influenzae by a mechanism that involves innate immunity, but does not require tumor necrosis factor, interleukin-6, or signaling via Toll-like receptor-4.

Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection

It is suggested that Vietnam/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of upregulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/ 1203 to disseminate to extrapulmonary organs.

Toll-like receptor pre-stimulation protects mice against lethal infection with highly pathogenic influenza viruses

It is shown that pre-stimulation of Toll-like receptors (TLRs) 2 and 4 increased resistance against influenza viruses known to induce high pathogenicity in animal models, and suggested that TLR agonists might be utilized to protect against lethality associated with highly pathogenic influenza virus infection in humans.

Innate immune responses to influenza A H5N1: friend or foe?

Pathogenesis of 1918 Pandemic and H5N1 Influenza Virus Infections in a Guinea Pig Model: Antiviral Potential of Exogenous Alpha Interferon To Reduce Virus Shedding

It is proposed that the guinea pig may serve as a useful small animal model for testing the efficacy of antiviral compounds and that α-IFN treatment may be a useful antiviral strategy against highly virulent strains with pandemic potential.



Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus

It is demonstrated that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host.

Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus

It is found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5, in contrast with smaller host immune responses as measured at the genomic level.

Lethal H5N1 influenza viruses escape host anti-viral cytokine responses

It is shown that lethal H5N1 influenza virus, unlike other human, avian and swine influenza viruses, are resistant to the antiviral effects of interferons and tumor necrosis factor α, and the nonstructural (NS) gene of H5n1 viruses is associated with this resistance.

Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus

Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were virulent in mice, and current antiviral strategies would be effective in curbing the dangers of a re-emergent 1918 or 1918-like virus.

Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus

Reverse genetics was used to generate an influenza virus bearing all eight gene segments of the pandemic virus to study the properties associated with its extraordinary virulence, and confirmed that the coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed with this pandemicirus.

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

The observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis and the focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.

Integrated Molecular Signature of Disease: Analysis of Influenza Virus-Infected Macaques through Functional Genomics and Proteomics

The previous in vivo genomics experiments with influenza virus-infected macaques were expanded, focusing on the innate immune response at day 2 postinoculation and on gene expression in affected lung tissue with viral genetic material present, to identify signature genes for early infection in whole blood.

Pathology of Human Influenza A (H5N1) Virus Infection in Cynomolgus Macaques (Macaca fascicularis)

It is suggested that the cynomolgus monkey is a suitable animal model for studying the pathogenesis of human H5N1 virus infection and that multiple-organ dysfunction syndrome in this disease may be caused by diffuse alveolar damage from virus replication in the lungs alone.

Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene.

Phylogenetic analyses suggest that the 1918 virus HA gene, although more closely related to avian strains than any other mammalian sequence, is mammalian and may have been adapting in humans before 1918.