Impact of Pregnancy on Intra-Host Genetic Diversity of Influenza A Viruses in Hospitalised Women: A Retrospective Cohort Study.

Gregory Destras,Bruno Simon,Martine Valette,Bruno Lina,Pascal Gaucherand,Maxime Pichon,Pierre-Adrien Bolze,Gil Dubernard,Laurence Josset,Vanessa Escuret

doi:10.3390/jcm8111974

Abstract

Characterising dynamics of Influenza A Viruses (IAV) within-host evolution is an active field of research which may lead to a better understanding of viral pathogenesis. Using a pregnant mouse model, a study has recently suggested that immune modulation during pregnancy could promote the emergence of IAV quasispecies with increased virulence. Herein, we assess the clinical relevance of these findings in humans. We studied IAV intra-host diversity (ihD) in pregnant (n = 36) and non-pregnant (n = 23) women hospitalized in Lyon for IAV infection (01/2015–05/2018). Whole IAV genomes present in nasopharyngeal samples were sequenced in duplicate to analyze reproducible intra-host single nucleotide variants (ihSNV). Counts, relative frequencies and locations of ihSNV were used as indicators of ihD. The median ihSNV/kb counts per segment were between 0 and 1.3. There was >81% ihSNV at relative frequencies between 1–5% for H1N1 and >51% for H3N2 IAV. No significant difference was noted between pregnant and non-pregnant women when considering all or only non-synonymous ihSNV. Seven convergent non-synonymous ihSNV were found; none were significantly associated with pregnancy. These results suggest that modulation of the immune system during pregnancy in humans does not impact IAV ihD, in contrast to mice.

Highlights

Due to its error-prone polymerase, RNA eight-segmented influenza A viruses (IAV) acquire genetic diversity when replicating [1]
Using allogeneic pregnant mice infected with human A(H1N1)pdm09, Engels et al suggested that immune modifications of both innate and adaptive immunity during pregnancy could drive the emergence of convergent non-synonymous mutations (Q223R on HA according to HA1 numbering, R211K on NS1, and R54N on NEP) associated with fatal outcomes [3]
* Number of women with the same intra-host single nucleotide variants (ihSNV) on total number of women that were analysed at that position; ** HA1 numbering; NS-ihSNV: Non-Synonymous intra-host diversity. In this cohort of 59 patients, we found no evidence of a specific impact of pregnancy on IAV ihD in humans

Summary

Introduction

Due to its error-prone polymerase, RNA eight-segmented influenza A viruses (IAV) acquire genetic diversity when replicating [1]. Using allogeneic pregnant mice infected with human A(H1N1)pdm, Engels et al suggested that immune modifications of both innate and adaptive immunity during pregnancy could drive the emergence of convergent non-synonymous mutations (Q223R on HA according to HA1 numbering, R211K on NS1, and R54N on NEP) associated with fatal outcomes [3]. They postulated that this mechanism could explain why pregnant women are more at risk of developing severe influenza. To examine the clinical relevance of these findings, we assessed IAV ihD in women according to pregnancy status and its potential impact on fostering severe forms

Methods

Results

Conclusion