Hierarchy among viral RNA (vRNA) segments in their role in vRNA incorporation into influenza A virions.
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The genome of influenza A viruses comprises eight negative-strand RNA segments. Although all eight segments must be present in cells for efficient viral replication, the mechanism(s) by which these viral RNA (vRNA) segments are incorporated into virions is not fully understood. We recently found that sequences at both ends of the coding regions of the HA, NA, and NS vRNA segments of A/WSN/33 play important roles in the incorporation of these vRNAs into virions. In order to similarly identify the regions of the PB2, PB1, and PA vRNAs of this strain that are critical for their incorporation, we generated a series of mutant vRNAs that possessed the green fluorescent protein gene flanked by portions of the coding and noncoding regions of the respective segments. For all three polymerase segments, deletions at the ends of their coding regions decreased their virion incorporation efficiencies. More importantly, these regions not only affected the incorporation of the segment in which they reside, but were also important for the incorporation of other segments. This effect was most prominent with the PB2 vRNA. These findings suggest a hierarchy among vRNA segments for virion incorporation and may imply intersegment association of vRNAs during virus assembly. (+info)
1918 Influenza: the mother of all pandemics.
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The "Spanish" influenza pandemic of 1918-1919, which caused approximately 50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis. (+info)
Identification of human H1N2 and human-swine reassortant H1N2 and H1N1 influenza A viruses among pigs in Ontario, Canada (2003 to 2005).
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Since 2003, three novel genotypes of H1 influenza viruses have been recovered from Canadian pigs, including a wholly human H1N2 virus and human-swine reassortants. These isolates demonstrate that human-lineage H1N2 viruses are infectious for pigs and that viruses with a human PB1/swine PA/swine PB2 polymerase complex can replicate in pigs. (+info)
Systemic suppression of interferon-gamma responses in Buruli ulcer patients resolves after surgical excision of the lesions caused by the extracellular pathogen Mycobacterium ulcerans.
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Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most common mycobacterial infection in immunocompetent humans besides tuberculosis and leprosy. We have compared by ex vivo enzyme-linked immunospot analysis interferon-gamma (IFN-gamma) responses in peripheral blood mononuclear cells (PBMC) from BU patients, household contacts, and individuals living in an adjacent M. ulcerans nonendemic region. PBMC were stimulated with purified protein derivative (PPD) and nonmycobacterial antigens such as reconstituted influenza virus particles and isopentenyl-pyrophosphate. With all three antigens, the number of IFN-gamma spot-forming units was reduced significantly in BU patients compared with the controls from a nonendemic area. This demonstrates for the first time that M. ulcerans infection-associated systemic reduction in IFN-gamma responses is not confined to stimulation with live or dead mycobacteria and their products but extends to other antigens. Interleukin (IL)-12 secretion by PPD-stimulated PBMC was not reduced in BU patients, indicating that reduction in IFN-gamma responses was not caused by diminished IL-12 production. Several months after surgical excision of BU lesions, IFN-gamma responses of BU patients against all antigens used for stimulation recovered significantly, indicating that the measured systemic immunosuppression was not the consequence of a genetic defect in T cell function predisposing for BU but is rather related to the presence of M. ulcerans bacteria. (+info)
Kupffer cell-dependent hepatitis occurs during influenza infection.
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Respiratory infections, including influenza in humans, are often accompanied by a hepatitis that is usually mild and self-limiting. The mechanism of this kind of liver damage is not well understood. In the present study, we show that influenza-associated hepatitis occurs due to the formation of inflammatory foci that include apoptotic hepatocytes, antigen-specific CD8(+) T cells, and Kupffer cells. Serum aminotransaminase levels were elevated, and both the histological and serum enzyme markers of hepatitis were increased in secondary influenza infection, consistent with a primary role for antigen-specific T cells in the pathogenesis. No virus could be detected in the liver, making this a pure example of "collateral damage" of the liver. Notably, removal of the Kupffer cells prevented the hepatitis. Such hepatic collateral damage may be a general consequence of expanding CD8(+) T-cell populations during many extrahepatic viral infections, yielding important implications for liver pathobiology. (+info)
Synchrony, waves, and spatial hierarchies in the spread of influenza.
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Quantifying long-range dissemination of infectious diseases is a key issue in their dynamics and control. Here, we use influenza-related mortality data to analyze the between-state progression of interpandemic influenza in the United States over the past 30 years. Outbreaks show hierarchical spatial spread evidenced by higher pairwise synchrony between more populous states. Seasons with higher influenza mortality are associated with higher disease transmission and more rapid spread than are mild ones. The regional spread of infection correlates more closely with rates of movement of people to and from their workplaces (workflows) than with geographical distance. Workflows are described in turn by a gravity model, with a rapid decay of commuting up to around 100 km and a long tail of rare longer range flow. A simple epidemiological model, based on the gravity formulation, captures the observed increase of influenza spatial synchrony with transmissibility; high transmission allows influenza to spread rapidly beyond local spatial constraints. (+info)
In vivo antiviral activity: defective interfering virus protects better against virulent Influenza A virus than avirulent virus.
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A defective interfering (DI) virus differs from the infectious virus from which it originated in having at least one major deletion in its genome. Such DI genomes are replicated only in cells infected in trans with homologous infectious virus and, as their name implies, they interfere with infectious virus replication and reduce the yield of progeny virus. This potent antiviral activity has been abundantly demonstrated in cell culture with many different DI animal viruses, but few in vivo examples have been reported, with the notable exception of DI Influenza A virus. A clue to this general lack of success arose recently when an anomaly was discovered in which DI Influenza A virus solidly protected mice from lethal disease caused by A/PR/8/34 (H1N1) and A/WSN/40 (H1N1) viruses, but protected only marginally from disease caused by A/Japan/305/57 (A/Jap, H2N2). The problem was not any incompatibility between the DI and infectious genomes, as A/Jap replicated the DI RNA in vivo. However, A/Jap required 300-fold more mouse infectious units to cause clinical disease than A/PR8 and it was hypothesized that it was this excess of infectivity that abrogated the protective activity of the DI virus. This conclusion was verified by varying the proportions of DI and challenge virus and showing that increasing the DI virus : infectious virus ratio in infected mice resulted in interference. Thus, counter-intuitively, DI virus is most effective against viruses that cause disease with low numbers of particles, i.e. virulent viruses. (+info)
Bacterial sinusitis and otitis media following influenza virus infection in ferrets.
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Streptococcus pneumoniae is the leading cause of otitis media, sinusitis, and pneumonia. Many of these infections result from antecedent influenza virus infections. In this study we sought to determine whether the frequency and character of secondary pneumococcal infections differed depending on the strain of influenza virus that preceded bacterial challenge. In young ferrets infected with influenza virus and then challenged with pneumococcus, influenza viruses of any subtype increased bacterial colonization of the nasopharynx. Nine out of 10 ferrets infected with H3N2 subtype influenza A viruses developed either sinusitis or otitis media, while only 1 out of 11 ferrets infected with either an H1N1 influenza A virus or an influenza B virus did so. These data may partially explain why bacterial complication rates are higher during seasons when H3N2 viruses predominate. This animal model will be useful for further study of the mechanisms that underlie viral-bacterial synergism. (+info)