Spike mimicry of thrombopoietin may induce thrombocytopenia in COVID-19

Nunez-Castilla, Janelle; Stebliankin, Vitalii; Baral, Prabin; Balbin, Christian A; Sobhan, Masrur; Cickovski, Trevor; Mondal, Ananda Mohan; Narasimhan, Giri; Chapagain, Prem; Mathee, Kalai; Siltberg-Liberles, Jessica

Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. Previous studies have shown that antibodies that cross-react with thrombopoietin, a regulator of platelet production, can induce thrombocytopenia which is characterized by low platelet count. Thrombocytopenia is associated with increased mortality in COVID-19 patients and is a rare side effect following vaccination against SARS-CoV-2. Here we show molecular mimicry between the Spike protein from SARS-CoV-2, the causative agent of COVID-19, and human thrombopoietin. Our computational analyses identify a shared five-amino acid long sequence motif (TQLPP) with similar structure and antibody-binding properties for these proteins, strongly indicative of molecular mimicry with potential for cross-reactivity. Our results are supported by reports of the presence of antibodies against epitopes containing TQLPP in both COVID-19 and pre-pandemic patient samples, indicating antibody cross-reactivity between Spike and a human protein. Since the Spike protein is the antigenic component of the SARS-CoV-2 vaccines, altering the motif may reduce the risk for thrombocytopenia and improve long-term protection against evolving variants. Our findings highlight the importance of considering peptide-level molecular mimicry when developing therapeutic interventions and designing vaccines to avoid potential autoimmune reactions.