Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity, 2022, Briquez &

[SNT Gatchaman]

Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity
Briquez PS, Rouhani SJ, Yu J, Pyzer AR, Trujillo J, Dugan HL, Stamper CT, Changrob S, Sperling AI, Wilson PC, Gajewski TF, Hubbell JA, Swartz MA

Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation, and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme 2 (ACE2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide.

Here, we show that a significant proportion of hospitalized patients with COVID-19 developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or receptor-binding domain (RBD), to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.

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[SNT Gatchaman]

Hospitalised patients, severe disease.

[SARS-CoV-2] infects cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of its Spike protein. ACE2 is an enzyme expressed on the surfaces of alveolar epithelial cells and vascular endothelial cells, among others, that plays an important role in regulating blood pressure (BP) by converting the vasoconstrictive peptide angiotensin II (AngII) to the vasopressor peptide angiotensin-(1-7).

It is known that SARS-CoV-2 infection can lead to dysregulation of vascular tension, endothelial inflammation, and enhanced thrombosis, presumably through enhancing endocytosis of ACE2 and thereby lowering its cell surface presence. Here, we sought to explore whether SARS-CoV-2 infection might induce autoantibodies against the peptide AngII. We hypothesized that the simultaneous binding of SARS-CoV-2 and AngII to ACE2 might lead to their cophagocytosis by antigen-presenting cells, thus providing a strong immune adjuvant (the virus molecules) to the self-peptide AngII, leading to an anti-AngII autoimmune response. Moreover, we asked whether some epitope mimicry might exist between a domain on the Spike protein and AngII, based on their shared binding to ACE2.

We conducted observational studies using serum of hospitalized patients with COVID-19 and determined that such autoantibodies are indeed induced, independently of anti-RBD levels. Instead, their presence and levels were strongly correlated with BP dysregulation and poor oxygenation. We lastly demonstrated cross-reactivity of some antibodies between AngII and the Spike protein, suggesting immune epitope homology between these molecules.