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1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans.

ABSTRACT: To study bacterial co-infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72?h later. Co-infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co-infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co-infected mice. Lung sections of SP-positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co-infection-positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co-infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis.

SUBMITTER: Walters KA

PROVIDER: S-EPMC4789761 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans.

Walters Kathie-Anne KA D'Agnillo Felice F Sheng Zong-Mei ZM Kindrachuk Jason J Schwartzman Louis M LM Kuestner Rolf E RE Chertow Daniel S DS Golding Basil T BT Taubenberger Jeffery K JK Kash John C JC

The Journal of pathology 20151014 1

To study bacterial co-infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co-infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co-infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed ex ...[more]

PMID: 26383585

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Project description:BACKGROUND:Increasing our knowledge of past influenza pandemic patterns in different regions of the world is crucial to guide preparedness plans against future influenza pandemics. Here, we undertook extensive archival collection efforts from three representative cities of Peru-Lima in the central coast, Iquitos in the northeastern Amazon region, Ica in the southern coast-to characterize the temporal, age and geographic patterns of the 1918-1920 influenza pandemic in this country. MATERIALS AND METHODS:We analyzed historical documents describing the 1918-1920 influenza pandemic in Peru and retrieved individual mortality records from local provincial archives for quantitative analysis. We applied seasonal excess mortality models to daily and monthly respiratory mortality rates for 1917-1920 and quantified transmissibility estimates based on the daily growth rate in respiratory deaths. RESULTS:A total of 52,739 individual mortality records were inspected from local provincial archives. We found evidence for an initial mild pandemic wave during July-September 1918 in Lima, identified a synchronized severe pandemic wave of respiratory mortality in all three locations during November 1918-February 1919, and a severe pandemic wave during January 1920-March 1920 in Lima and July-October 1920 in Ica. There was no recrudescent pandemic wave in 1920 in Iquitos. Remarkably, Lima experienced the brunt of the 1918-1920 excess mortality impact during the 1920 recrudescent wave, with all age groups experiencing an increase in all cause excess mortality from 1918-1919 to 1920. Middle age groups experienced the highest excess mortality impact, relative to baseline levels, in the 1918-1919 and 1920 pandemic waves. Cumulative excess mortality rates for the 1918-1920 pandemic period were higher in Iquitos (2.9%) than Lima (1.6%). The mean reproduction number for Lima was estimated in the range 1.3-1.5. CONCLUSIONS:We identified synchronized pandemic waves of intense excess respiratory mortality during November 1918-February 1919 in Lima, Iquitos, Ica, followed by asynchronous recrudescent waves in 1920. Cumulative data from quantitative studies of the 1918 influenza pandemic in Latin American settings have confirmed the high mortality impact associated with this pandemic. Further historical studies in lesser studied regions of Latin America, Africa, and Asia are warranted for a full understanding of the global impact of the 1918 pandemic virus.

Project description:2018 marks the 100-year anniversary of the 1918 influenza pandemic, which killed ~50 million people worldwide. The severity of this pandemic resulted from a complex interplay between viral, host, and societal factors. Here, we review the viral, genetic and immune factors that contributed to the severity of the 1918 pandemic and discuss the implications for modern pandemic preparedness. We address unresolved questions of why the 1918 influenza H1N1 virus was more virulent than other influenza pandemics and why some people survived the 1918 pandemic and others succumbed to the infection. While current studies suggest that viral factors such as haemagglutinin and polymerase gene segments most likely contributed to a potent, dysregulated pro-inflammatory cytokine storm in victims of the pandemic, a shift in case-fatality for the 1918 pandemic toward young adults was most likely associated with the host's immune status. Lack of pre-existing virus-specific and/or cross-reactive antibodies and cellular immunity in children and young adults likely contributed to the high attack rate and rapid spread of the 1918 H1N1 virus. In contrast, lower mortality rate in in the older (>30 years) adult population points toward the beneficial effects of pre-existing cross-reactive immunity. In addition to the role of humoral and cellular immunity, there is a growing body of evidence to suggest that individual genetic differences, especially involving single-nucleotide polymorphisms (SNPs), contribute to differences in the severity of influenza virus infections. Co-infections with bacterial pathogens, and possibly measles and malaria, co-morbidities, malnutrition or obesity are also known to affect the severity of influenza disease, and likely influenced 1918 H1N1 disease severity and outcomes. Additionally, we also discuss the new challenges, such as changing population demographics, antibiotic resistance and climate change, which we will face in the context of any future influenza virus pandemic. In the last decade there has been a dramatic increase in the number of severe influenza virus strains entering the human population from animal reservoirs (including highly pathogenic H7N9 and H5N1 viruses). An understanding of past influenza virus pandemics and the lessons that we have learnt from them has therefore never been more pertinent.

Dataset Information

1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans.

Publications

1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans.

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