Autophagy receptor P62 regulates SARS-CoV-2-induced inflammation in COVID-19
2023
Authors:
Stevanović, DanijelaPaunović, Verica
Vučićević, Ljubica
Misirkić Marjanović, Maja
Perović, Vladimir
Ristić, Biljana
Bošnjak, Mihajlo
Mandić, Miloš
Harhaji-Trajković, Ljubica
Janjetović, Kristina
Kosić, Milica
Lalošević, Jovan
Nikolić, Miloš
Bonači-Nikolić, Branka
Trajković, Vladimir
Contributors
Dobrivojević, ZoranaDocument Type:
Conference object (Published version)
,
© 2023 by the Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
Metadata
Show full item recordAbstract:
Introduction: Since the interaction between autophagy and virus-induced inflammation is complex,
we investigated the interplay between autophagy and inflammation in COVID-19 patients and THP-1
cells expressing SARS-Cov2 proteins NSP5 and ORF3a.
Methods: Autophagy markers in blood from 19 control subjects and 26 COVID-19 patients at hospital
admission and one week later were measured by ELISA, while cytokine levels were examined by flow cytometric bead immunoassay. The level of p62 in cells and its concentration in cell culture supernatants
was measured by immunoblot/ELISA. The mRNA levels of proinflammatory cytokines were measured
by RT-qPCR.
Results: IFN-α, TNF, IL-6, IL-8, IL-17, IL-33, and IFN-γ were elevated in COVID-19 patients at both time
points, whereasIL-10 and IL-1β were elevated at admission and one week later, respectively. Autophagy
markers LC3 and ATG5 were unchanged in COVID-19. The concentration of autophagic cargo receptor
p62 was significantly lower and positively correlated with TNF, IL-10, IL-17, and IL-33 at hospital admission, returning to normal levels after one week. The expression of SARS-CoV-2 proteins NSP5 or ORF3a
in THP-1 cells caused an autophagy-independent decrease/autophagy-inhibition-dependent increase
of intracellular and secreted p62. This was associated with an NSP5-mediated decrease inTNF/IL-10 mRNA
and an ORF3a-mediated increase inTNF/IL-1β/IL-6/IL-10/IL-33 mRNA levels. A genetic knockdown of p62
mimicked the immunosuppressive effect of NSP5, while a p62 increase in autophagy-deficient cells mirrored the immunostimulatory action of ORF3a.
Conclusion: The autophagy receptor p62 is reduced in acute COVID-19, and the balance between autophagy-independent decrease and autophagy blockade-dependent increase of p62 levels could affect
SARS-CoV-induced inflammation.
Keywords:
inflammation; COVID19; p62; NSP; ORF3aFunding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200110 (University of Belgrade, Faculty of Medicine) (RS-MESTD-inst-2020-200110)
- TACTICIAN – Targeting Autophagy to Combat SARS-CoV2-induced Immune Dysregulation (RS-ScienceFundRS-Fond_2020_COVID19-7552006)
In:
- Dobrijević Z, editor. Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia. Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade ; 2023. p. 76. (Trends in Molecular Biology; Special Issue).