tetano
Editor, Senior Moderator
J Gen Virol
. 2026 Nov;107(11):002360.
doi: 10.1099/jgv.0.002360.
Prema Mono Nair 1 2 , Yi Zhang 3 , Malcolm R Starkey 1 2 4 , Haw Tatt Jhong 1 2 , Kamal Dua 1 2 , Oliwia O Bolimowska 3 , Alaina J Ammit 5 6 7 , Andrew R Clark 3 , Philip M Hansbro 1 2 8
Affiliations Expand
In common with many other viruses, influenza A viruses (IAVs) activate the mitogen-activated protein kinase (MAPK) p38 pathway. This signalling pathway is strongly implicated in the pro-inflammatory cytokine storm that underlies morbidity and mortality in response to highly pathogenic IAV strains. We previously reported that MAPK p38 increased the expression of many inflammatory mediators via the phosphorylation and inactivation of the mRNA-destabilizing protein tristetraprolin (TTP). Hence, mice expressing a non-phosphorylatable form of endogenous TTP protein were strongly protected against inflammatory effects of polymicrobial sepsis or endotoxaemia. Here, we used the same minimally genetically modified mouse strain (Zfp36aa/aa) to investigate responses to a viral mimetic in vitro or IAV infection in vivo. When challenged in vitro with the viral mimetic poly(I:C), Zfp36aa/aa macrophages underexpressed several TTP-regulated inflammatory mediators. When infected with a pathogenic IAV strain, Zfp36aa/aa mice also under-expressed TTP-regulated inflammatory mediators. Strikingly, expression of type I and III IFNs and IFN-regulated antiviral genes was spared or enhanced in Zfp36aa/aa macrophages or mice. Consistent with these observations, Zfp36aa/aa mice cleared the pathogen more rapidly and were partially resistant to virus-induced airway pathology. These findings suggest that modulating TTP phosphorylation may exert anti-inflammatory effects whilst sparing or enhancing antiviral responses in the context of pathogenic IAV infection.
Keywords: MAPK p38; cytokine storm; inflammation; influenza A virus; tristetraprolin.
. 2026 Nov;107(11):002360.
doi: 10.1099/jgv.0.002360.
Mitogen-activated protein kinase p38-dependent phosphorylation of tristetraprolin enhances inflammatory and impairs antiviral responses to influenza virus
Prema Mono Nair 1 2 , Yi Zhang 3 , Malcolm R Starkey 1 2 4 , Haw Tatt Jhong 1 2 , Kamal Dua 1 2 , Oliwia O Bolimowska 3 , Alaina J Ammit 5 6 7 , Andrew R Clark 3 , Philip M Hansbro 1 2 8
Affiliations Expand
- PMID: 43019005
- PMCID: PMC13759190
- DOI: 10.1099/jgv.0.002360
Abstract
In common with many other viruses, influenza A viruses (IAVs) activate the mitogen-activated protein kinase (MAPK) p38 pathway. This signalling pathway is strongly implicated in the pro-inflammatory cytokine storm that underlies morbidity and mortality in response to highly pathogenic IAV strains. We previously reported that MAPK p38 increased the expression of many inflammatory mediators via the phosphorylation and inactivation of the mRNA-destabilizing protein tristetraprolin (TTP). Hence, mice expressing a non-phosphorylatable form of endogenous TTP protein were strongly protected against inflammatory effects of polymicrobial sepsis or endotoxaemia. Here, we used the same minimally genetically modified mouse strain (Zfp36aa/aa) to investigate responses to a viral mimetic in vitro or IAV infection in vivo. When challenged in vitro with the viral mimetic poly(I:C), Zfp36aa/aa macrophages underexpressed several TTP-regulated inflammatory mediators. When infected with a pathogenic IAV strain, Zfp36aa/aa mice also under-expressed TTP-regulated inflammatory mediators. Strikingly, expression of type I and III IFNs and IFN-regulated antiviral genes was spared or enhanced in Zfp36aa/aa macrophages or mice. Consistent with these observations, Zfp36aa/aa mice cleared the pathogen more rapidly and were partially resistant to virus-induced airway pathology. These findings suggest that modulating TTP phosphorylation may exert anti-inflammatory effects whilst sparing or enhancing antiviral responses in the context of pathogenic IAV infection.
Keywords: MAPK p38; cytokine storm; inflammation; influenza A virus; tristetraprolin.