The role of Neuropilin-1 in COVID-19

Abstract

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.

miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells

“…Intriguingly, brain endothelial cells show a distinct pro-inflammatory response when exposed to SARS-CoV-2 spike protein subunits [65] and infected vascular endothelial cells have been shown to spread SARS-CoV-2 to glial cells in the central nervous system [66]. Furthermore, COVID-19 has been associated with a wide spectrum of neurological symptoms and Neuropilin-1 has been proposed as a key factor in the neurological manifestation of COVID-19 by enhancing the entry of SARS-CoV-2 into the brain [66][67][68][69][70][71].…”

Neuropilin 1: A Novel Entry Factor for SARS-CoV-2 Infection and a Potential Therapeutic Target

“… 1 It is encoded by the NRP1 gene located on the 10p11.22 human chromosome locus and shares 44% amino acid sequence identity with its homology, NRP2. 3 , 4 , 24 …”

“…In recent years, NRP1 has also been shown to be expressed by various immune cells, such as macrophages, including alveolar, adipose tissue, bronchial, and vascular macrophages, dendritic cells, T-cells, particularly CD8 cells, regulatory T-cells, B-cells, and mast cells where it controls a multitude of functions, including development, migration, and recruitment, communication between different immune cells, as well as immune system regulation under normal physiological condition. 3 , 4 NRP1 has also been detected in bone cells like osteoclasts and osteoblasts where it has an important role in regulating bone remodeling, for instance osteo-protection through its binding with SEMA3A. 3 , 34 , 35 …”

“… 38 Their abundant expression on epithelia exposed to the external environment as well as their multifaceted functions are the possible reasons that make NRP1 an ideal entry factor for SARS-CoV-2 as well as a critical contributing factor for multisystem involvement of SARS-CoV-2 infection. 4 , 6 , 22 …”

“… 2 NRP1 can exist in two isoforms, namely, secretory and transmembrane isoforms. 3 , 4 The former, also known as truncated or soluble NRP1, circulates freely in the body fluid, whereas the latter isoform, transmembrane NRP1, is a highly conserved single-pass transmembrane protein that interacts with different ligands and has multifaceted functions, including mediating of varieties of physiological and pathological processes; as a result, it is commonly called NRP1. 1 , 3 , 4 …”