SARS-CoV-2 spike proteins bind to HS and interfere with factor H function. Coincubating 5 µg/mL His-tagged SARS-CoV-2 spike proteins with 2 mg/mL HS solution completely blocked the binding of S1 subunit (A) and S2 subunit (B) to TF1PIGAnull cells. Supplementing NHS with 10 µg of purified factor H protein significantly inhibited C5b-9 (C) and C3c deposition (D) triggered by 20 µg/mL S1 in APC-specific buffer. Addition of 10 µg of purified factor H also significantly inhibited the S2-induced C5b-9 deposition (E) and C3c deposition (F) in APC-specific buffer. All experiments were repeated at least 3 times. Unpaired Student t test P values indicate statistical significance (*P < .05, **P < .01, ***P < .001, ****P < .0001). FH, purified factor H protein; NaHS, HS sodium solution.