Autophagy Receptor p62 Regulates SARS-CoV-2-Induced Inflammation in COVID-19
Verica Paunovic,
Ljubica Vucicevic,
Maja Misirkic Marjanovic,
Vladimir Perovic,
Biljana Ristic,
Mihajlo Bosnjak,
Milos Mandic,
Danijela Stevanovic,
Ljubica Harhaji-Trajkovic,
Jovan Lalosevic,
Milos Nikolic,
Branka Bonaci-Nikolic,
Vladimir Trajkovic
Affiliations
Verica Paunovic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Ljubica Vucicevic
Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11000 Belgrade, Serbia
Maja Misirkic Marjanovic
Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11000 Belgrade, Serbia
Vladimir Perovic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Biljana Ristic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Mihajlo Bosnjak
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Milos Mandic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Danijela Stevanovic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
Ljubica Harhaji-Trajkovic
Department of Neurophysiology, Institute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11000 Belgrade, Serbia
Jovan Lalosevic
Clinic of Dermatovenereology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
Milos Nikolic
Clinic of Dermatovenereology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
Branka Bonaci-Nikolic
Faculty of Medicine, University of Belgrade, Dr. Subotica 8, 11000 Belgrade, Serbia
Vladimir Trajkovic
Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia
As autophagy can promote or inhibit inflammation, we examined autophagy-inflammation interplay in COVID-19. Autophagy markers in the blood of 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 antiviral IFN-α and proinflammatory TNF, IL-6, IL-8, IL-17, IL-33, and IFN-γ were elevated in COVID-19 patients at both time points, while IL-10 and IL-1β were increased at admission and one week later, respectively. Autophagy markers LC3 and ATG5 were unaltered in COVID-19. In contrast, 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 monocytes caused an autophagy-independent decrease or autophagy-inhibition-dependent increase, respectively, of intracellular/secreted p62, as confirmed by immunoblot/ELISA. This was associated with an NSP5-mediated decrease in TNF/IL-10 mRNA and an ORF3a-mediated increase in TNF/IL-1β/IL-6/IL-10/IL-33 mRNA levels. A genetic knockdown of p62 mimicked the immunosuppressive effect of NSP5, and a p62 increase in autophagy-deficient cells mirrored the immunostimulatory action of ORF3a. In conclusion, the proinflammatory autophagy receptor p62 is reduced inacute COVID-19, and the balance between autophagy-independent decrease and autophagy blockade-dependent increase of p62 levels could affect SARS-CoV-induced inflammation.
