Trajectories of gene expression, seasonal influenza, and within-host seasonal immunity: transfer value to covid-19

  1. Eiliv Lund
  2. Marit Holden
  3. Lill-Tove Rasmussen Busund
  4. Igor Snapkov
  5. Nikita Shvetsov
  6. Lars Holden

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Abstract

As a novel approach we will combine trajectories or longitudinal studies of gene expression with information on annual influenza epidemics. Seasonality of gene expression in immune cells from blood could be a consequence of within-host seasonal immunity interacting with the seasonal pandemics of influenza (flu) in temperate regions and, thus, with potential valuable analogy transfer to the proposed seasonal development of covid-19.

Here we operationalized within-host immunity as genes with both a significant seasonal term and a significant flu term in the sine-cosine model. Information on gene expression was based on microarray using RNase buffered blood samples collected randomly from a population-based cohort of Norwegian middle-aged women in 2003-2006, The Norwegian Women and Cancer (NOWAC) study. The unique discovery (N=425) and replication (N=432) design were based on identical sampling and preprocessing. Data on proportion of sick leaves due to flu, and the flu intensities per week was obtained from the National Institute of Public Health, giving a semi-ecological analysis.

The discovery analysis found 2942 (48.1%) significant genes in a generalized seasonal model over four years. For 1051 within-host genes both the seasonal and the flu term were significant. These genes followed closely the flu intensities. The trajectories showed slightly more genes with a maximum in early winter than in late summer. Moving the flu intensity forward in time indicated a better fit 3-4 weeks before the observed influenza. In the replication analyses, 369 genes (35.1% of 1051) were significant. Exclusion of genes with unknown functions and with more than a season in difference reduced the number of genes in the discovery dataset to 305, illustrating the variability in the measurements and the problem in assessing weak biological relationships. Thus, we found for the first time a clear seasonality in gene expression with marked responses to the annual seasonal influenza in a unique discovery – replication design. Hypothetically, this could support the within-host seasonal immunity concept.

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    SciScore for 10.1101/2022.03.01.22271679: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The study design has some limitations. The discovery and the replication samples were run on two different microarrays. The discovery set used Illumina H-6 with six blood samples on the chip, compared to the 12 blood samples on the Illumina Hu-12 in the replication. The shift was due to the sudden stop in the production of Illumina Hu-6. Hu-6 had approximately twice as many probes per gene as Hu-12 (Appendix Figure A). It might be that the reduction in probe numbers per gene reduced the sensibility of the microarray. Still a reasonable test-retest result was obtained. The original NOWAC study invited only women since it was based on hypotheses related to female reproduction, oral contraception, and hormonal replacement therapy. The age span included mainly women in their middle age. Due to the original design of building a biobank for functional genomics the study covered only four years. On the other hand, the sampling was independent of any knowledge of seasonal influenza. A major issue in the interpretation of the findings is the lack of knowledge about many basic aspects of the antibody response to the influenza A virus (15). This makes it difficult to test specific hypotheses. Preliminary analyses of the gene expression did not support any specific hypothesis. This could be due to lack of knowledge of the biological relationship between host and viruses. A major strength of this study was the completely random assignment for blood sampling regardless of place of living i...

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  2. Version published to 10.1101/2022.03.01.22271679 on medRxiv