Histamine Potentiates SARS-CoV-2 Spike Protein Entry Into Endothelial Cells

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes coronavirus disease (COVID-19) is one of the most serious global health crises in recent history. COVID-19 patient symptoms range from life-threatening to mild and asymptomatic, which presents unique problems in identifying, quarantining, and treating the affected individuals. The emergence of unusual symptoms among survivors, now referred to as “Long COVID”, is concerning, especially since much about the condition and the treatment of it is still relatively unknown. Evidence so far also suggests that some of these symptoms can be attributed to vascular inflammation. Although famotidine, the commonly used histamine H2 receptor (H2R) blocker, was shown to have no antiviral activity, recent reports indicate that it could prevent adverse outcomes in COVID-19 patients. Histamine is a classic proinflammatory mediator, the levels of which increase along with other cytokines during COVID-19 infection. Histamine activates H2R signaling, while famotidine specifically blocks H2R activation. Investigating the effects of recombinant SARS-CoV-2 spike protein S1 Receptor-Binding Domain (Spike) on ACE2 expression in cultured human coronary artery endothelial cells, we found that the presence of histamine potentiated spike-mediated ACE2 internalization into endothelial cells. This effect was blocked by famotidine, protein kinase A inhibition, or by H2 receptor protein knockdown. Together, these results indicate that histamine and histamine receptor signaling is likely essential for spike protein to induce ACE2 internalization in endothelial cells and cause endothelial dysfunction and that this effect can be blocked by the H2R blocker, famotidine.

Increase in venous thromboembolism in SARS‐CoV‐2 infected lung tissue: proteome analysis of lung parenchyma, isolated endothelium, and thrombi

“…Histamine has been found to induce proinflammatory cytokines and provoking endothelial damage in COVID19. [51][52][53] Our results are in line with these findings and imply increased mast cell activity, which may contribute to pulmonary fibrosis and thrombosis in COVID-19. 54,55 Upregulation of arginase (ARG1) in COVID-19 patients may also contribute to organ failure and pulmonary fibrosis.…”

Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19

“…1A ): neuropilin-1 (NRP1), which is a promoter of virus entry in the presence of ACE2 and TMPRESS2 [ 78 , 79 ], scavenger receptor B type 1 (SR-B1) [ 80 , 81 ] and extracellular vimentin [ 82 ], which facilitate ACE2-dependent virus entry; CD147 [ 83 ] and αvβ3 integrin [ 84 ], which mediate virus entry by endocytosis; and liver/lymph node-specific ICAM-3 grabbing nonintegrin (L-SIGN), which are highly expressed on human liver sinusoidal endothelial cells and serve as the virus receptor [ 85 ]. Histamine also contributes to the entry of spike protein into ECs [ 86 ]. Moreover, nucleocapsid protein (NP), which is one of the most crucial structural components of SARS-CoV-2 activates human ECs through toll-like receptor (TLR) 2/nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling [ 87 ].…”

Hypoxia induces purinergic receptor signaling to disrupt endothelial barrier function

“…Surface biotinylation was performed as we have done previously for intact arteries and endothelial cells ( Leo et al, 2021 ; Raghavan and Leo, 2022 ). Briefly, live endothelial cells were the first subject to in vitro hypoxia for 90 min, followed by 24 h reoxygenation.…”