Oseltamivir Inhibits H7 Influenza Virus Replication in Mice Inoculated by the Ocular Route

Belser, Jessica A.; Sleeman, Katrina; Pearce, Melissa B.; Katz, Jacqueline M.; Gubareva, Larisa V.; Tumpey, Terrence M.

doi:10.1128/aac.06101-11

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…While our results in the ferret model agree with previous work demonstrating reduced viral loads in ocular tissue of oseltamivir-treated mice (Belser et al, 2012b), the efficacy of oseltamivir specifically within human ocular tissue has not been studied. We examined the susceptibility of influenza viruses to oseltamivir carboxylate in primary human corneal epithelial cells (HCEpiC) and compared with the human bronchial epithelial cell line Calu-3 and MDCK cells.…”

Section: Resultssupporting

confidence: 84%

“…The majority of antiviral drugs available to treat viral conjunctivitis are targeted towards herpesvirus and adenovirus infection; ocular disease caused by RNA viruses such as influenza or RSV currently lack commercially available antiviral drug treatments (Skevaki et al, 2011). The high bioavailability of oseltamivir following oral administration (Davies, 2010; Wattanagoon et al, 2009) likely contributes to the reduced viral titers observed in ocular tissue following ocular inoculation of either mice or ferrets with influenza viruses (Belser et al, 2012b). Our finding that oseltamivir reduces influenza virus titers in human ocular cells in a dose-dependent manner is in agreement with these studies (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study from our laboratory demonstrated that oseltamivir inhibits H7 influenza virus replication in mice inoculated by the ocular route, with reductions in morbidity, mortality, and viral titers in both respiratory and ocular tissues in antiviral-treated mice (Belser et al, 2012b). However, there remains a need to better understand the capacity of currently available antiviral treatments to both inhibit virus spread from ocular sites to the respiratory tract and mitigate ocular disease caused by influenza virus infection.…”

Section: Introductionmentioning

confidence: 99%

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Oseltamivir inhibits influenza virus replication and transmission following ocular-only aerosol inoculation of ferrets

et al. 2015

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Ocular exposure to influenza virus represents an alternate route of virus entry capable of establishing a respiratory infection in mammals, but the effectiveness of currently available antiviral treatments to limit virus replication within ocular tissue or inhibit virus spread from ocular sites to the respiratory tract is poorly understood. Using an inoculation method that delivers an aerosol inoculum exclusively to the ocular surface, we demonstrate that oral oseltamivir administration following ocular-only aerosol inoculation with multiple avian and human influenza viruses protected ferrets from a fatal and systemic infection, reduced clinical signs and symptoms of illness, and decreased virus transmissibility to susceptible contacts when a respiratory infection was initiated. The presence of oseltamivir further inhibited influenza virus replication in primary human corneal epithelial cells. These findings provide critical experimental evidence supporting the use of neuraminidase inhibitors during outbreaks of influenza virus resulting in ocular disease or following ocular exposure.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oseltamivir inhibits influenza virus replication and transmission following ocular-only aerosol inoculation of ferrets

et al. 2015

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“…vir against new and emerging strains of influenza is frequently tested in mice and other animal species and is used as a predictor for efficacy in humans (12)(13)(14)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)), but we demonstrate here that evaluation of antiviral efficacy in in vitro assays as well as in vivo analyses in other animal species should be assessed collectively to ensure that an accurate understanding of antiviral efficacy for humans will be predicted.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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During the first wave of the 2009 pandemic, caused by a H1N1 influenza virus (pH1N1) of swine origin, antivirals were the only form of therapeutic available to control the proliferation of disease until the conventional strain-matched vaccine was produced. Oseltamivir is an antiviral that inhibits the sialidase activity of the viral neuraminidase (NA) protein and was shown to be effective against pH1N1 viruses in ferrets. Furthermore, it was used in humans to treat infections during the pandemic and is still used for current infections without reported complication or exacerbation of illness. However, in an evaluation of the effectiveness of oseltamivir against pH1N1 infection, we unexpectedly observed an exacerbation of disease in virus-infected mice treated with oseltamivir, transforming an otherwise mild illness into one with high morbidity and mortality. In contrast, an identical treatment regime alleviated all signs of illness in mice infected with the pathogenic mouse-adapted virus A/WSN/33 (H1N1). The worsened clinical outcome with pH1N1 viruses occurred over a range of oseltamivir doses and treatment schedules and was directly linked to a reduction in NA enzymatic activity. Our results suggest that the suppression of NA activity with antivirals may exacerbate disease in a host-dependent manner by increasing replicative fitness in viruses that are not optimally adapted for replication in that host. IMPORTANCEHere, we report that treatment of pH1N1-infected mice with oseltamivir enhanced disease progression, transforming a mild illness into a lethal infection. This raises a potential pitfall of using the mouse model for evaluation of the therapeutic efficacy of neuraminidase inhibitors. We show that antiviral efficacy determined in a single animal species may not represent treatment in humans and that caution should be used when interpreting the outcome. Furthermore, increased virulence due to oseltamivir treatment was the effect of a shift in the hemagglutinin (HA) and neuraminidase (NA) activity balance. This is the first study that has demonstrated that altering the HA/NA activity balance by reduction in NA activity can result in an increase in virulence in any animal model from nonpathogenic to lethal and the first to demonstrate a situation in which treatment with a NA activity inhibitor has an effect opposite to the intended therapeutic effect of ameliorating the infection.

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“…The murine model of ocular inoculation described here currently represents the most stringent in vivo model available to study the ocular tropism possessed by H7 subtype viruses. The use of models such as this has permitted the investigation of antiviral drugs to mitigate viral replication and spread following H7 ocular exposure (Belser et al, 2012b), underscoring the need for well-characterized mammalian models to examine the diversity of influenza virus exposure routes and disease presentations.…”

Section: Discussionmentioning

confidence: 99%

Role of H7 hemagglutinin in murine infectivity of influenza viruses following ocular inoculation

et al. 2017

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H7 subtype influenza viruses have demonstrated an ocular tropism in humans, causing conjunctivitis and not respiratory symptoms in many infected individuals. However, the molecular determinants which confer ocular tropism are still poorly understood. Here, we used a murine model of ocular inoculation to demonstrate that H7 influenza viruses are more likely to cause infection following ocular exposure than are non-H7 subtype viruses. We included investigation regarding the potential role of several properties of influenza viruses with murine infectivity following ocular inoculation, including virus lineage, pathogenicity, and HA cleavage site composition. Furthermore, we examined the potential contribution of internal proteins to murine ocular infectivity. These studies establish a link between H7 subtype viruses and the risk of heightened infectivity in a mammalian species following ocular exposure, and support the development of non-traditional inoculation methods and models to best understand the human risk posed by influenza viruses of all subtypes.

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Oseltamivir Inhibits H7 Influenza Virus Replication in Mice Inoculated by the Ocular Route

Cited by 11 publications

References 25 publications

Oseltamivir inhibits influenza virus replication and transmission following ocular-only aerosol inoculation of ferrets

Oseltamivir inhibits influenza virus replication and transmission following ocular-only aerosol inoculation of ferrets

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Role of H7 hemagglutinin in murine infectivity of influenza viruses following ocular inoculation

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