Disruption of Type I Interferon Signaling Causes Sexually Dimorphic Dysregulation of Anti-Viral Cytokines
| Autor: | Byram W. Bridle, Katrina E. Allison, Khalil Karimi, Raveendra R. Kulkarni, Shayan Sharif, Maedeh Darzianiazizi |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
VSV
vesicular stomatitis virus Cytokine response medicine.medical_treatment Immunology Viremia Biochemistry Virus 03 medical and health sciences 0302 clinical medicine Interferon Sex as a biological variable medicine Immunology and Allergy Type I interferon Interferon signaling Receptor Molecular Biology ComputingMethodologies_COMPUTERGRAPHICS 030304 developmental biology 0303 health sciences Viral matrix protein business.industry Hematology RC581-607 medicine.disease IFNs Interferons 3. Good health Sexual dimorphism Type I interferon receptor IFNAR IFN-α/β receptor Cytokine Tumor necrosis factor alpha Immunologic diseases. Allergy business Research Article 030215 immunology medicine.drug |
| Zdroj: | Cytokine: X, Vol 3, Iss 2, Pp 100053-(2021) Cytokine: X |
| ISSN: | 2590-1532 |
| DOI: | 10.1016/j.cytox.2021.100053 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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