Whereas our data confirm that the Spike protein induces SARS-CoV-2-associated hyperinflammation in MΦ by binding to TLR4, infection with viable SARS-CoV-2 may cause a more exaggerated TLR4-mediated response or possibly engage with additional inflammatory pathways, such as TLR3 and TLR7/9 mediated responses through cellular pathogen recognition of viral and/or cellular RNA. The gene discussed is TLR3; the disease is infection.