Macrophage metabolic reprogramming facilitates viral entry and pyroptosis

Introduction/Rationale: The respiratory virus SARS-CoV-2 has posed a significant health burden since its emergence. The virus primarily infects and replicates in epithelial cells in the respiratory tract, but SARS-CoV-2 viral RNA has also been detected in macrophages isolated from patients with COVID-19. However, how SARS-CoV-2 enters macrophages remains unclear.

Methods: To address this gap, we assessed the metabolic changes that SARS-CoV-2 induces in monocyte-derived and tissue resident macrophages and how this affects transcriptional responses and viral entry.

Results: Our studies suggest that SARS-CoV-2 triggers a TLR2-dependent pathway encompassing IRG1, an enzyme that produces the metabolite itaconate, and NRF2, a transcription factor, which is necessary for effective viral entry into macrophages. Through this mechanism, SARS-CoV-2 induces the NRF2 gene target Macrophage associated receptor with collagenous structure (MARCO) for entry. MARCO is a scavenger receptor that is basally expressed by tissue-resident macrophages and facilitates efferocytosis of unopsonized particles and pathogens. MARCO expression increases in macrophages following SARS-CoV-2 treatment in a TLR2, IRG1, and NRF2-dependent manner. Furthermore, SARS-CoV-2 is unable to effectively enter MARCO-deficient macrophages, suggesting that MARCO serves as an alternative viral entry receptor. Our data shows that MARCO is required for pyroptosis following SARS-CoV-2 infection. In vivo, pre-treatment of mice with an anti-MARCO blocking antibody reduces the severity of COVID-19. To understand how MARCO expression is regulated during infection, I determined that anti-viral type I IFN negatively regulates MARCO via inhibition of NRF2.

Conclusion: Together, these novel findings suggest that SARS-CoV-2 metabolically reprograms macrophages to induce MARCO expression and promote viral entry and pyroptosis in the absence of IFN signaling. This work identifies a novel, druggable host-pathogen interaction that dictates the severity of respiratory virus infection.