Mechanisms and consequences of coinfections with influenza virus and SARS-CoV-2
File(s)
Author(s)
Reuss, Dorothee
Type
Thesis
Abstract
Co-circulation of different viruses can lead to coinfections resulting in competitive or cooperative virus-virus interactions which impact virus epidemiology and disease severity, posing a challenge for public health. Coinfection with influenza A virus (IAV) and first-wave SARS-CoV-2 resulted in more severe lung damage in animals and has been linked to more severe disease in people. Interactions between more recent variants of SARS-CoV-2 and IAV, and between SARS-CoV-2 and IBV are understudied.
IBV pre-infection decreased SARS-CoV-2 viral yields, and vice versa, by inducing interferon (IFN)-mediated immune responses in Calu-3 cells. Similar competitive interactions were observed in sequential coinfections of seasonal IAV, live attenuated influenza vaccine (LAIV) and Omicron BA.5 in ex vivo primary human airway epithelial (HAE) cells. Bulk RNA-sequencing of coinfected versus single infected HAEs revealed that Omicron BA.5 and IAV H3N2 induced specific subsets of interferon-stimulated genes (ISGs) 24 hours post-infection. NR4A1 was one of 4 ISGs uniquely induced by Omicron BA.5 but not IAV. Overexpression of NR4A1 resulted in increased SARS-CoV-2 but decreased IAV titres by negatively impacting influenza virus entry.
In vivo, enhanced disease severity and pathological changes were observed in hamsters sequentially coinfected with Omicron EG.5.1 followed by IAV H1N1, despite EG.5.1 interfering with IAV replication. Sequential infection with the same virus pair in the reversed order did not worsen disease outcome nor impact EG.5.1 replication, indicating the order of viruses in sequential confection in vivo matters greatly for the disease outcome.
Previous studies have reported that older SARS-CoV-2 variants exerted little interference with influenza virus replication. In contrast, newer SARS-CoV-2 variants such as Omicron BA.1 and BA.5, which have evolved different immune evasion strategies and control of IFN responses, affected influenza replication through ISG expression. These interactions likely impact influenza epidemiology and vaccine effectiveness, and ongoing monitoring as the viruses continue to evolve is advisable.
IBV pre-infection decreased SARS-CoV-2 viral yields, and vice versa, by inducing interferon (IFN)-mediated immune responses in Calu-3 cells. Similar competitive interactions were observed in sequential coinfections of seasonal IAV, live attenuated influenza vaccine (LAIV) and Omicron BA.5 in ex vivo primary human airway epithelial (HAE) cells. Bulk RNA-sequencing of coinfected versus single infected HAEs revealed that Omicron BA.5 and IAV H3N2 induced specific subsets of interferon-stimulated genes (ISGs) 24 hours post-infection. NR4A1 was one of 4 ISGs uniquely induced by Omicron BA.5 but not IAV. Overexpression of NR4A1 resulted in increased SARS-CoV-2 but decreased IAV titres by negatively impacting influenza virus entry.
In vivo, enhanced disease severity and pathological changes were observed in hamsters sequentially coinfected with Omicron EG.5.1 followed by IAV H1N1, despite EG.5.1 interfering with IAV replication. Sequential infection with the same virus pair in the reversed order did not worsen disease outcome nor impact EG.5.1 replication, indicating the order of viruses in sequential confection in vivo matters greatly for the disease outcome.
Previous studies have reported that older SARS-CoV-2 variants exerted little interference with influenza virus replication. In contrast, newer SARS-CoV-2 variants such as Omicron BA.1 and BA.5, which have evolved different immune evasion strategies and control of IFN responses, affected influenza replication through ISG expression. These interactions likely impact influenza epidemiology and vaccine effectiveness, and ongoing monitoring as the viruses continue to evolve is advisable.
Version
Open Access
Date Issued
2025-06-20
Date Awarded
01/11/2025
License URL
Advisor
Barclay, Wendy
Thompson, Catherine
Tregoning, John
Sponsor
UK Health Security Agency (Great Britain)
National Institute for Health Research (Great Britain)
Medical Research Council (Great Britain)
Grant Number
MR/W005611/1
NIHR203323
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)