Disruption of type I interferon signaling causes sexually dimorphic dysregulation of anti-viral cytokines. Issue 2 (June 2021)

• Record Type: Journal Article
• Authors: Darzianiazizi, Maedeh; Allison, Katrina E.; Kulkarni, Raveendra R.; Sharif, Shayan; Karimi, Khalil; Bridle, Byram W.
• Is Part Of: Cytokine. Volume 3:Issue 2(2021)
• Publication Date: 2021-06
• Subjects: IFNs Interferons -- IFNAR IFN-α/β receptor -- VSV vesicular stomatitis virus; Type I interferon -- Type I interferon receptor -- Interferon signaling -- Cytokine response -- Sex as a biological variable
• DOI: 10.1016/j.cytox.2021.100053
• Languages: English
• ISSNs: 2590-1532

Abstract

Graphical abstract: Highlights: Mice infected with rVSVΔm51 became sick if IFNARs were blocked with an antibody. Morbidity was greater in females than males. Cytokines induced by rVSV during IFNAR blockade were most dysregulated in females. IFNAR signaling in females reduced cytokine responses to rVSV and avoided morbidity. Neutrophils may regulate cytokine responses to rVSV when IFNAR signaling is impaired. Impaired type I IFN responses can dysregulate cytokine responses to viruses. Abstract: Type I interferons (IFNs) play a crucial role in the establishment of an antiviral state via signaling through their cognate type I IFN receptor (IFNAR). In this study, a replication-competent but highly attenuated strain of VSV (rVSVΔm51) carrying a deletion at position 51 of the matrix protein to remove suppression of anti-viral type I IFN responses was used to explore the effect of disrupted IFNAR signaling on inflammatory cytokine responses in mice. The kinetic responses of interleukin-6, tumor necrosis factor-α and interleukin-12 were evaluated in virus-infected male and female mice with or without concomitant antibody-mediated IFNAR-blockade. Unlike controls, both male and female IFNAR-blocked mice showed signs of sickness by 24-hours post-infection. Female IFNAR-blocked mice experienced greater morbidity as demonstrated by a significant decrease in body temperature. This was not the case for males. In addition, females with IFNAR-blockade mounted prolonged and exaggerated systemic inflammatory cytokine responses to rVSVΔm51. This was in stark contrast to controls with intact IFNAR signaling and males with IFNAR-blockade; they were able to down-regulate virus-induced inflammatory cytokine responses by 24-hours post-infection. Exaggerated cytokine responses in females with impaired IFNAR signaling was associated with more effective control of viremia than their male counterparts. However, the trade-off was greater immune-mediated morbidity. The results of this study demonstrated a role for IFNAR signaling in the down-regulation of antiviral cytokine responses, which was strongly influenced by sex. Our findings suggested that the potential to mount toxic cytokine responses to a virus with concomitant disruption of IFNAR signaling was heavily biased towards females.