2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice

Otte, Anna; Gabriel, Gülşah

doi:10.4161/viru.2.6.18148

Cited by 27 publications

(30 citation statements)

References 22 publications

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“…pdm09 virus causes significant lethality in this mouse species without prior adaptation contrasting to the BALB/c species (Otte and Gabriel, 2011). The severely compromised fitness demonstrated in mice and in vitro for our double E119D/H275Y and single E119D mutants is also in agreement with a detrimental impact on NA velocity (Vmax), affinity (Km) (L'Huillier et al, 2015) and cell surface activity induced by these changes.…”

Section: Discussionsupporting

confidence: 64%

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

et al. 2016

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Keyword: Influenza A(H1N1)pdm09 Resistance Neuraminidase E119D Zanamivir a b s t r a c tWe recently isolated an influenza A(H1N1)pdm09 E119D/H275Y neuraminidase (NA) variant from an immunocompromised patient who received oseltamivir and zanamivir therapies. This variant demonstrated cross resistance to zanamivir, oseltamivir, peramivir and laninamivir. In this study, the viral fitness of the recombinant wild-type (WT), E119D and E119D/H275Y A(H1N1)pdm09 viruses was evaluated in vitro and in experimentally-infected C57BL/6 mice and guinea pigs. In replication kinetics experiments, viral titers obtained with the E119D and E119D/H275Y recombinants were up to 2-and 4-log lower compared to the WT virus in MDCK and ST6GalI-MDCK cells, respectively. Enzymatic studies revealed that the E119D mutation significantly decreased the surface NA activity. In experimentallyinfected mice, a 50% mortality rate was recorded in the group infected with the WT recombinant virus whereas no mortality was observed in the E119D and E119D/H275Y groups. Mean lung viral titers on day 5 post-inoculation for the WT (1.2 ± 0.57 Â 10 8 PFU/ml) were significantly higher than those of the E119D (9.75 ± 0.41 Â 10 5 PFU/ml, P < 0.01) and the E119D/H275Y (1.47 ± 0.61 Â 10 6 PFU/ml, P < 0.01) groups. In guinea pigs, comparable seroconversion rates and viral titers in nasal washes (NW) were obtained for the WT and mutant index and contact groups. However, the D119E reversion was observed in most NW samples of the E119D and E119D/H275Y animals. In conclusion, the E119D NA mutation that could emerge in A(H1N1)pdm09 viruses during zanamivir therapy has a significant impact on viral fitness and such mutant is unlikely to be highly transmissible.

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Section: Discussionsupporting

confidence: 64%

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

et al. 2016

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“…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: 49%

“…In order to assess the prevalence of HH15-specific amino acids in human 2009 pH1N1 isolates, we have per- formed a database analysis ( Table 1). The obtained amino acid frequencies were then differentiated according to previously defined pandemic phases (16,23). In general, HH15-specific amino acids were less frequent in the early pandemic phase and became most prevalent with frequencies from 52.16% to 100%, with the exception of PB2 340N and PA 118V at the postpandemic phase.…”

Section: Resultsmentioning

confidence: 99%

“…For each protein, the same analysis pipeline was applied: first duplicate isolates for same strains and then isolates with missing sampling times were removed. After alignment of the sequences with MUSCLE (21) and manual curation of the alignments with JalView (22), the sequences were binned by their isolation date into four pandemic phases, adopting definitions used in the literature (16,23). For the HA protein, the H1 numbering based on the sequence was used (42).…”

Section: Methodsmentioning

confidence: 99%

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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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“…The clinical isolate of pandemic 2009H1N1 IAV shows host-specific pathogenicity in mice. 40 Intranasal IAV infection caused exaggerated neutrophil influx into the lungs of RhoA/B dKO mice within 24 hours, which was fivefold higher than the influx in RhoB KO 2 mice ( Figure 6A). These neutrophils were highly activated, leading to increased BAL protein content and MPO release ( Figure 6B-C).…”

Section: Absence Of Rho Rescues From Lethal Iav Infectionmentioning

confidence: 99%

RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

Jennings¹,

Strengert²,

Hayes³

et al. 2014

Blood

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2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice

Cited by 27 publications

References 22 publications

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

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

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