Differential Host Determinants Contribute to the Pathogenesis of 2009 Pandemic H1N1 and Human H5N1 Influenza A Viruses in Experimental Mouse Models

Otte, Anna; Sauter, Martina; Alleva, Lisa M.; Baumgarte, Sigrid; Klingel, Karin; Gabriel, Gülşah

doi:10.1016/j.ajpath.2011.03.041

Cited by 56 publications

(62 citation statements)

References 32 publications

(40 reference statements)

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“…Viral sequence analysis highlighted that 2009 pH1N1 influenza viruses do not harbor previously identified markers of mammalian adaptation and/or pathogenesis, suggesting that novel and yet still largely unrecognized sites must have contributed to severe disease outcome in humans (3). This was further supported by studies using various animal models where 2009 pH1N1 influenza virus infection was more severe in mice, ferrets, and nonhuman primates compared to seasonal influenza viruses (2,(13)(14)(15). In C57BL/6J mice (15,16) and the nonhuman primate model (14), even differences in virulence were observed among the 2009 H1N1 virus variants that circulated during the pandemic.…”

supporting

confidence: 53%

“…This was further supported by studies using various animal models where 2009 pH1N1 influenza virus infection was more severe in mice, ferrets, and nonhuman primates compared to seasonal influenza viruses (2,(13)(14)(15). In C57BL/6J mice (15,16) and the nonhuman primate model (14), even differences in virulence were observed among the 2009 H1N1 virus variants that circulated during the pandemic. These data support the concept that 2009 pH1N1 influenza viruses not only possess previously unrecognized markers predictive of human adaptation and pathogenesis but also differ in their pathogenic potential.…”

supporting

confidence: 50%

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Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice

Otte

Sauter

Daxer

et al. 2015

J Virol

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During the 2009 H1N1 influenza pandemic, infection attack rates were particularly high among young individuals who suffered from pneumonia with occasional death. Moreover, previously reported determinants of mammalian adaptation and pathogenicity were not present in 2009 pandemic H1N1 influenza A viruses. Thus, it was proposed that unknown viral factors might have contributed to disease severity in humans. In this study, we performed a comparative analysis of two clinical 2009 pandemic H1N1 strains that belong to the very early and later phases of the pandemic. We identified mutations in the viral hemagglutinin (HA) and the nucleoprotein (NP) that occurred during pandemic progression and mediate increased virulence in mice. Lethal disease outcome correlated with elevated viral replication in the alveolar epithelium, increased proinflammatory cytokine and chemokine responses, pneumonia, and lymphopenia in mice. These findings show that viral mutations that have occurred during pandemic circulation among humans are associated with severe disease in mice. IMPORTANCEIn this study, novel determinants of 2009 pandemic H1N1 influenza pathogenicity were identified in the viral hemagglutinin (HA) and the nucleoprotein (NP) genes. In contrast to highly pathogenic avian influenza viruses, increased virulence in mice did not correlate with enhanced polymerase activity but with reduced activity. Lethal 2009 pandemic H1N1 infection in mice correlated with lymphopenia and severe pneumonia. These studies suggest that molecular mechanisms that mediate 2009 pandemic H1N1 influenza pathogenicity are distinct from those that mediate avian influenza virus pathogenicity in mice.T he first pandemic of the 21st century was caused by a novel influenza A virus strain of the H1N1 subtype that contained gene segments from both North American and Eurasian swine lineages (1-3). In the beginning, the 2009 H1N1 influenza pandemic was considered to be relatively mild as the majority of cases underwent an uncomplicated or even an asymptomatic infection course. However, this was partially revoked since infection attack rates were highest among the younger age groups, in contrast to seasonal influenza, where mostly the elderly are affected (4-7). During the pandemic in 2009, a disproportionately high number of young adults were hospitalized due to pneumonia and eventually died (6-9). Retrospective modeling estimates that during the first 12 months of the pandemic, approximately 80% of the overall 201,200 respiratory and additional 83,300 cardiovascular deaths occurred in people younger than 65 years (10). This age-specific mortality pattern among younger individuals has been captured by the "years-of-life-lost" metric (11) as a more accurate parameter to measure pandemic burden. In the United States, the number of years of life lost within the first months of the pandemic was estimated to range between the impact of the more virulent H3N2 influenza epidemics and that of the 1968 Hong Kong pandemic (12).Subsequently, it was postulated that ...

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supporting

confidence: 53%

supporting

confidence: 50%

Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice

Otte

Sauter

Daxer

et al. 2015

J Virol

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“…Neutrophils recovered from lungs 72 hours after IAV challenge showed enhanced CRAMP expression ( Figure 6G) and a 200% increase of intracellular viral matrix protein 1 (M1) ( Figure 6H). Although IAV titers did not correlate with disease outcome in WT mice, 24 a significant reduction in virus load was detected in lung tissue obtained from RhoA/B dKO mice ( Figure 6I). , and RhoA/B dKO mice.…”

Section: Absence Of Rho Rescues From Lethal Iav Infectionmentioning

confidence: 99%

“…Mice were challenged via intranasal installation (in) with 30 mg/kg CXCL1, 1 mg/kg fMLF, 1 mg/kg LPS, 10 7 E coli, or 10 6 pfu/kg IAV Hamburg/05/09 (pHH05) 24 in PBS. At indicated time points, bronchoalveolar lavage (BAL) was analyzed for cytokines using the multiplex-fluorokine assay (R&D Systems), for NET formation by Sytox Green (5 mM) fluorometry, for type I IFNs, and for virus load as described.…”

Section: In Vivo Lung Modelsmentioning

confidence: 99%

RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

Jennings¹,

Strengert²,

Hayes³

et al. 2014

Blood

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“…For example, in a study of host factors involved in the pathogenesis of pH1N1 virus influenza, BALB/c mice, which have a Th-2 bias, were shown to be less suitable than C57Bl/6 mice, which have a Th-1 bias. 116 Neither strain might be as suitable as DBA/2J mice, which have a more intense inflammatory response to influenza virus infection. [117][118][119] Investigators should also consider testing immunomodulatory agents in mice that have the same highrisk conditions as humans; e.g., pregnancy, 62 obesity 120 and cardiovascular disease.…”

Section: Acknowledgmentsmentioning

confidence: 99%

The controversy over H5N1 transmissibility research

Fedson¹,

Opal

2013

Human Vaccines & Immunotherapeutics

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Differential Host Determinants Contribute to the Pathogenesis of 2009 Pandemic H1N1 and Human H5N1 Influenza A Viruses in Experimental Mouse Models

Cited by 56 publications

References 32 publications

Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice

Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice

RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

The controversy over H5N1 transmissibility research

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