Interval Between Infections and Viral Hierarchy Are Determinants of Viral Interference Following Influenza Virus Infection in a Ferret Model

Laurie, Karen; Guarnaccia, Teagan; Carolan, Louise; Yan, Aimin; Aban, Malet; Petrie, Stephen; Cao, Pengxing; Heffernan, Jane M.; McVernon, Jodie; Mosse, Jennifer; Kelso, Anne; McCaw, James M.; Barr, Ian G.

doi:10.1093/infdis/jiv260

Cited by 101 publications

(148 citation statements)

References 49 publications

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“…A modest temperature peak was detected on day 2 after infection (Fig. 1B); minimal other clinical signs were observed, consistent with previous studies with the A(H1N1)pdm09 virus (27,28). In the URT, viral RNA levels peaked at day 2 postinfection and declined thereafter, with viral clearance occurring 8 or 9 days after infection (Fig.…”

Section: Patterns Of Cytokine and Chemokine Expression Are Similar Insupporting

confidence: 90%

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Carolan

Rockman

Borg

et al. 2016

J Virol

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The burden of infection with seasonal influenza viruses is significant. Each year is typically characterized by the dominance of one (sub)type or lineage of influenza A or B virus, respectively. The incidence of disease varies annually, and while this may be attributed to a particular virus strain or subtype, the impacts of prior immunity, population differences, and variations in clinical assessment are also important. To improve our understanding of the impacts of seasonal influenza viruses, we directly compared clinical symptoms, virus shedding, and expression of cytokines, chemokines, and immune mediators in the upper respiratory tract (URT) of ferrets infected with contemporary A(H1N1)pdm09, A(H3N2), or influenza B virus. Gene expression in the lower respiratory tract (LRT) was also assessed. Clinical symptoms were minimal. Overall cytokine/chemokine profiles in the URT were consistent in pattern and magnitude between animals infected with influenza A and B viruses, and peak expression levels of interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-12p40, alpha interferon (IFN-␣), IFN-␤, and tumor necrosis factor alpha (TNF-␣) mRNAs correlated with peak levels of viral shedding. MCP1 and IFN-␥ were expressed after the virus peak. Granzymes A and B and IL-10 reached peak expression as the virus was cleared and seroconversion was detected. Cytokine/chemokine gene expression in the LRT following A(H1N1)pdm09 virus infection reflected the observations seen for the URT but was delayed 2 or 3 days, as was virus replication. These data indicate that disease severities and localized immune responses following infection with seasonal influenza A and B viruses are similar, suggesting that other factors are likely to modulate the incidence and impact of seasonal influenza. IMPORTANCEBoth influenza A and B viruses cocirculate in the human population, and annual influenza seasons are typically dominated by an influenza A virus subtype or an influenza B virus lineage. Surveillance data indicate that the burden of disease is higher in some seasons, yet it is unclear whether this is due to specific virus strains or to other factors, such as cross-reactive immunity or clinical definitions of influenza. We directly compared disease severities and localized inflammatory responses to different seasonal influenza virus strains, including the 2009 pandemic strain, in healthy naive ferrets. We found that the disease severities and the cytokine and chemokine responses were similar irrespective of the seasonal strain or the location of the infection in the respiratory tract. This suggests that factors other than the immune response to a particular virus (sub)type contribute to the variable impact of influenza virus infection in a population. Morbidity and mortality associated with human influenza virus infection are significant worldwide. Influenza is caused by three virus types (A, B, and C), among which types A and B are responsible for most of the diagnosed cases of seasonal influenza. Influenza A viruses attract the greatest attentio...

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Section: Patterns Of Cytokine and Chemokine Expression Are Similar Insupporting

confidence: 90%

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Carolan

Rockman

Borg

et al. 2016

J Virol

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“…Depletion may be due to either infection or immune-mediated protection. Either way, these models are arguably incompatible with recent evidence that the host is susceptible to reinfection with a second strain of influenza, a short period following primary exposure (43). Furthermore, as reviewed by Dobrovolny et al (39), target cell depletion in these models strongly limits viral expansion so that virus can be effectively controlled or cleared at early stage of infection even in the absence of adaptive immunity, which contradicts the experimental finding that influenza virus remains elevated in the absence of adaptive immune response (44).…”

Section: Introductionmentioning

confidence: 84%

On the Role of CD8+ T Cells in Determining Recovery Time from Influenza Virus Infection

et al. 2016

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Myriad experiments have identified an important role for CD8+ T cell response mechanisms in determining recovery from influenza A virus infection. Animal models of influenza infection further implicate multiple elements of the immune response in defining the dynamical characteristics of viral infection. To date, influenza virus models, while capturing particular aspects of the natural infection history, have been unable to reproduce the full gamut of observed viral kinetic behavior in a single coherent framework. Here, we introduce a mathematical model of influenza viral dynamics incorporating innate, humoral, and cellular immune components and explore its properties with a particular emphasis on the role of cellular immunity. Calibrated against a range of murine data, our model is capable of recapitulating observed viral kinetics from a multitude of experiments. Importantly, the model predicts a robust exponential relationship between the level of effector CD8+ T cells and recovery time, whereby recovery time rapidly decreases to a fixed minimum recovery time with an increasing level of effector CD8+ T cells. We find support for this relationship in recent clinical data from influenza A (H7N9) hospitalized patients. The exponential relationship implies that people with a lower level of naive CD8+ T cells may receive significantly more benefit from induction of additional effector CD8+ T cells arising from immunological memory, itself established through either previous viral infection or T cell-based vaccines.

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“…This phenomenon has been shown experimentally in animal models (1)(2)(3), as well as in humans given the live-attenuated IAV vaccine in clinical studies (4)(5)(6)(7), and has been postulated as a major factor in determining the rate of IAV antigenic drift (8). This temporary immunity has also been observed epidemically when the respiratory syncytial virus season was delayed as a result of the 2009 pandemic IAV outbreak occurring earlier than is normally seen with seasonal strains (9)(10)(11).…”

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confidence: 85%

Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity

Hamilton

Sachs

Lim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A brief window of antigen-nonspecific protection has been observed after influenza A virus (IAV) infection. Although this temporary immunity has been assumed to be the result of residual nonspecific inflammation, this period of induced immunity has not been fully studied. Because IAV has long been characterized as a cytopathic virus (based on its ability to rapidly lyse most cell types in culture), it has been a forgone conclusion that directly infected cells could not be contributing to this effect. Using a Cre recombinase-expressing IAV, we have previously shown that club cells can survive direct viral infection. We show here not only that these cells can eliminate all traces of the virus and survive but also that they acquire a heightened antiviral response phenotype after surviving. Moreover, we experimentally demonstrate temporary nonspecific viral immunity after IAV infection and show that surviving cells are required for this phenotype. This work characterizes a virally induced modulation of the innate immune response that may represent a new mechanism to prevent viral diseases.influenza virus | RNA sequencing | alternative cell fate | antiviral immunity T here have been reports of a short period after influenza A virus (IAV) infection during which subsequent respiratory viral infection is restricted. This phenomenon has been shown experimentally in animal models (1-3), as well as in humans given the live-attenuated IAV vaccine in clinical studies (4-7), and has been postulated as a major factor in determining the rate of IAV antigenic drift (8). This temporary immunity has also been observed epidemically when the respiratory syncytial virus season was delayed as a result of the 2009 pandemic IAV outbreak occurring earlier than is normally seen with seasonal strains (9-11). Although observations of influenza-induced temporary immunity are well documented, how this protection is established is unknown.We have previously shown that respiratory epithelial cells (principally club cells) are infected by IAV and are capable of clearing infection and surviving for long periods in vivo (12). These surviving cells, characterized by an inflammatory transcriptional profile, contributed to bronchiolar epithelium damage. However, it was unclear why these cells would prolong an inflammatory state beyond the resolution of infection.In this report, we test the hypothesis that cells surviving IAV infection are involved in protecting the host from subsequent viral respiratory infections. We reasoned that the turnover of "survivor cells" could explain the temporary nature of IAVinduced antiviral immunity. We show that the cells that survive direct IAV infection are reprogrammed and exhibit an increased antiviral response to secondary infection and type I IFN. We also show that the overall immune response to secondary infection is different from the response to the primary infection. Finally, we demonstrate temporary, antigen-nonspecific viral immunity in the mouse model and show that surviving cells are required for this pr...

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Interval Between Infections and Viral Hierarchy Are Determinants of Viral Interference Following Influenza Virus Infection in a Ferret Model

Cited by 101 publications

References 49 publications

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

On the Role of CD8+ T Cells in Determining Recovery Time from Influenza Virus Infection

Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity

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