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Research Article

Virus–virus interactions impact the population dynamics of influenza and the common cold

Sema Nickbakhsh, Colette Mair, View ORCID ProfileLouise Matthews, View ORCID ProfileRichard Reeve, Paul C. D. Johnson, Fiona Thorburn, Beatrix von Wissmann, Arlene Reynolds, James McMenamin, Rory N. Gunson, and View ORCID ProfilePablo R. Murcia
  1. aMRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH Glasgow, United Kingdom;
  2. bSchool of Mathematics and Statistics, College of Science and Engineering, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
  3. cBoyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
  4. dThe Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, G51 4TF Glasgow, United Kingdom;
  5. ePublic Health, NHS Greater Glasgow and Clyde, G12 0XH Glasgow, United Kingdom;
  6. fHealth Protection Scotland, NHS National Services Scotland, G2 6QE Glasgow, United Kingdom;
  7. gWest of Scotland Specialist Virology Centre, NHS Greater Glasgow and Clyde, G31 2ER Glasgow, United Kingdom

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PNAS December 26, 2019 116 (52) 27142-27150; first published December 16, 2019; https://doi.org/10.1073/pnas.1911083116
Sema Nickbakhsh
aMRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH Glasgow, United Kingdom;
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Colette Mair
aMRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH Glasgow, United Kingdom;
bSchool of Mathematics and Statistics, College of Science and Engineering, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
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Louise Matthews
cBoyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
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  • ORCID record for Louise Matthews
  • For correspondence: louise.matthews@glasgow.ac.uk Pablo.Murcia@glasgow.ac.uk
Richard Reeve
cBoyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
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Paul C. D. Johnson
cBoyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom;
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Fiona Thorburn
dThe Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, G51 4TF Glasgow, United Kingdom;
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Beatrix von Wissmann
ePublic Health, NHS Greater Glasgow and Clyde, G12 0XH Glasgow, United Kingdom;
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Arlene Reynolds
fHealth Protection Scotland, NHS National Services Scotland, G2 6QE Glasgow, United Kingdom;
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James McMenamin
fHealth Protection Scotland, NHS National Services Scotland, G2 6QE Glasgow, United Kingdom;
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Rory N. Gunson
gWest of Scotland Specialist Virology Centre, NHS Greater Glasgow and Clyde, G31 2ER Glasgow, United Kingdom
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Pablo R. Murcia
aMRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH Glasgow, United Kingdom;
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  • ORCID record for Pablo R. Murcia
  • For correspondence: louise.matthews@glasgow.ac.uk Pablo.Murcia@glasgow.ac.uk
  1. Edited by Burton H. Singer, University of Florida, Gainesville, FL, and approved November 12, 2019 (received for review June 27, 2019)

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    Fig. 1.

    Temporal patterns of viral respiratory infections detected among patients in Glasgow, United Kingdom, 2005 to 2013. (A) Percentage of patients diagnosed with a single viral infection (white), a viral coinfection (gray), or determined to be virus-negative (black) by multiplex RT-PCR in each calendar month from 2005 to 2013 (6-mo intervals depicted by vertical lines; Jan = January, Jul = July). (B) Relative virus prevalences in each calendar month, from 2005 to 2013; note total virus counts may sum to more than those informing single infection prevalences due to coinfections, and test frequency denominators vary slightly across viruses. During the first wave of the United Kingdom’s influenza A pandemic [A(H1N1)pdm09] in 2009, infections with influenza A virus were relatively more prevalent among the patient population than noninfluenza virus infections (highlighted by black box). RV = rhinoviruses (A–C); IAV = influenza A virus (H1N1 and H3N2); IBV = influenza B virus; RSV = respiratory syncytial virus; CoV = human coronaviruses (229E, NL63, HKU1); AdV = human adenoviruses; MPV = human metapneumovirus; PIV3 = parainfluenza 3 virus; PIV1 = parainfluenza 1 virus; PIV4 = parainfluenza 4 virus; PIV2 = parainfluenza 2 virus. See also Table 1. Virus groups are listed in descending order of their total prevalence.

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    Fig. 2.

    Comparative prevalences of viral infections detected among patients in Glasgow, United Kingdom, 2005 to 2013. Prevalence was measured as the proportion of patients testing positive to a given virus among those tested in each month. (A and B) Asynchronous seasonality, explained by negative epidemiological interactions. (C and D) Synchronous seasonality, explained by positive epidemiological interactions. ρ = significant correlation coefficients from Bayesian multivariate disease mapping analysis of viral infection time series shown in Fig. 3. See Table 1 for a full description of the viruses.

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    Fig. 3.

    Negative and positive interactions among influenza and noninfluenza viruses at population scale. Significant unadjusted correlations from bivariate cross-correlation analysis applying Spearman’s rank method to monthly viral infection prevalences are shown in gray, with negative and positive correlations indicated by − and +, respectively, and noncorrelated virus pairs in white. Significant support for virus–virus interactions based on correlations derived from Bayesian disease mapping analysis adjusting for fluctuations in testing frequency, temporal autocorrelation, and alternative drivers of correlated seasonality are shown in blue (negative) and red (positive).

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    Fig. 4.

    Host-scale interactions among influenza and noninfluenza viruses. (A) Statistically supported negative (OR < 1) and positive (OR > 1) virus–virus interactions based on uncorrected P < 0.05 from multivariable logistic regression analysis. Line widths are proportional to the absolute value of the maximum log OR estimated per virus pair. Two interactions (RV/IAV and AdV/PIVB) retained strong statistical support (P < 0.001) following Holm’s correction to control the familywise error rate. (B) Test of the global null hypothesis: QQ plot of the observed P value distribution from 20 pairwise tests among the 5 remaining virus groups (IBV, CoV, MPV, RSV, and PIVA; green line), compared to the P value distribution expected under the global null hypothesis of no interactions (purple dashed line). The distribution of QQ lines simulated from the global null hypothesis using 10,000 permutations is shown in gray. See Table 1 for a full description of the viruses. Due to comparatively low infection frequencies, parainfluenza viruses were regrouped into PIVA (PIV1 and PIV3; human respiroviruses) and PIVB (PIV2 and PIV4; human rubulaviruses).

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    Fig. 5.

    Mathematical ODE models simulating the impact of viral interference on the cocirculatory dynamics of a seasonal influenza-like virus and a ubiquitous common cold-like virus. (A) Percentage decrease in the minimum daily incidence of common cold-like virus infections during peak influenza-like virus activity for varying interaction strengths and refractory periods. (B) Asynchronous incidences of influenza-like virus (in red) and common cold-like infections in the presence (blue) and absence (green) of interference with the influenza like virus. This example assumes a strong interaction (φ = 1) and 7-d refractory period shown over 10 simulated years. The R0s of these viruses assuming a completely susceptible homogeneous population are 1.6 (virus 1) and 2 (virus 2). The model supports the hypothesis that temporary nonspecific protection elicited by influenza explains the periodic decline in rhinovirus frequency during peak influenza activity (Fig. 2A).

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    Table 1.

    Details of virus detections by multiplex real-time RT-PCR assays

    AbbreviationVirus nomenclature according to the International Committee on Taxonomy of Viruses
    RVRhinoviruses (A–C)
    IAVInfluenza A virus*
    IBVInfluenza B virus
    RSV(Formerly) respiratory syncytial virus†
    CoVHuman coronaviruses (229E, NL63, HKU1)
    AdV(Formerly) human adenoviruses‡
    MPVHuman metapneumovirus
    PIV3(Formerly) human parainfluenza 3 virus§
    PIV1(Formerly) human parainfluenza 1 virus§
    PIV4(Formerly) human parainfluenza 4 virus¶
    PIV2(Formerly) human parainfluenza 2 virus¶
    • ↵* A generic assay detecting seasonal H3N2 and H1N1 subtypes and one specific to A(H1N1)pdm09.

    • ↵† (Currently) human orthopneumovirus.

    • ↵‡ (Currently) human mastadenoviruses (A–G).

    • ↵§ (Currently) human respiroviruses (1 and 3).

    • ↵¶ (Currently) human rubulaviruses (2 and 4).

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Virus–virus interactions impact the population dynamics of influenza and the common cold
Sema Nickbakhsh, Colette Mair, Louise Matthews, Richard Reeve, Paul C. D. Johnson, Fiona Thorburn, Beatrix von Wissmann, Arlene Reynolds, James McMenamin, Rory N. Gunson, Pablo R. Murcia
Proceedings of the National Academy of Sciences Dec 2019, 116 (52) 27142-27150; DOI: 10.1073/pnas.1911083116

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Virus–virus interactions impact the population dynamics of influenza and the common cold
Sema Nickbakhsh, Colette Mair, Louise Matthews, Richard Reeve, Paul C. D. Johnson, Fiona Thorburn, Beatrix von Wissmann, Arlene Reynolds, James McMenamin, Rory N. Gunson, Pablo R. Murcia
Proceedings of the National Academy of Sciences Dec 2019, 116 (52) 27142-27150; DOI: 10.1073/pnas.1911083116
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