Critical role of oxidized LDL receptor-1 in intravascular thrombosis in a severe influenza mouse model

Abstract

Although coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.

Abnormal Blood Coagulation and Kidney Damage in Aged Hamsters Infected with Severe Acute Respiratory Syndrome Coronavirus 2

“…This notion is supported by a previous report showing the involvement of not the virus itself but neutrophil extracellular traps (NETs) in vasculitis in the lung using the hamster COVID-19 model [25]. Recently, our group reported a critical role of LOX-1 in thrombin generation and lung thrombosis in a severe influenza mouse model [17]. As previously observed in mice infected with the influenza virus, the induction of the Olr1 gene was also detected in the lungs, liver, and aorta of hamsters after SARS-CoV-2 infection in this study.…”

“…In addition, immunohistochemistry demonstrated that LOX-1 increased in the bronchial epithelial and vascular endothelium of the lungs after infection with SARS-CoV-2. Given that the influenza-associated lung thrombosis did not occur in Olr1 knockout mice [17], it is possible that LOX-1 is also involved in promoting the thrombus formation in COVID-19.…”

“…The expression of anticoagulant factor thrombomodulin-encoding Thbd showed a tendency to be reduced by virus infection in the lungs and liver of young hamsters, whereas the basal expression of this gene in the livers of aged hamsters was low prior to infection. We also evaluated the gene expression of oxidized low-density lipoprotein receptor 1 (Olr1), which encodes lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) that is involved in prothrombotic change of the vascular wall by promoting the attachment of activated platelets to endothelial cells, endothelial dysfunction, and severe influenza-associated thrombus formation in the lung [15][16][17]. The expression of Olr1 was increased in the lung by virus infection, with similar induction levels in young and aged hamsters.…”

The elucidation of plasma lipidome profiles during severe influenza in a mouse model

“…Virus infection and sample collection were performed as previously reported 13 , 15 . PR8 virus at 50 or 500 plaque-forming units (PFU) in 50 µL phosphate-buffered saline (PBS) or PBS only (control) were intranasally inoculated into mice under inhalation anesthesia with isoflurane.…”

Role of Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in inflammation and pathogen-associated interactions

“…The ssRNA virus influenza virus A (H1N1) is hypothesized to cause thrombosis, leading to multipleorgan dysfunction [137]. A study by Ohno et al [137] showed that during a severe influenza infection in a mouse model, thrombin generation is increased and LOX-1 expression in the aorta is upregulated in contrast LOX-1 in Infectious Diseases and Inflammation to LOX-1 knockout mice. It was suggested that LOX-1 is involved in the early thrombus formation in severe influenza infections.…”