Neuropilin-1 in the pathogenesis of preeclampsia, HIV-1, and SARS-CoV-2 infection: A review

Abstract

This review explores the role of transmembrane neuropilin-1 (NRP-1) in pregnancy, preeclampsia (PE), human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Since these conditions are assessed independently, this review attempts to predict their comorbid clinical manifestations. Dysregulation of NRP-1 contributes to the pathogenesis of PE by (a) impairing vascular endothelial growth factor (VEGF) signaling for adequate spiral artery remodeling and placentation, (b) inducing syncytiotrophoblast (ST) cell apoptosis and increasing ST-derived microparticle circulation and (c) by decreasing regulatory T cell activity predisposing maternal immune intolerance. Although NRP-1 is upregulated in SARS-CoV-2 placentae, its exploitation for SARS-CoV-2 internalization and increased infectivity may alter angiogenesis through the competitive inhibition of VEGF. The anti-inflammatory nature of NRP-1 may aid its upregulation in HIV-1 infection; however, the HIV-accessory protein, tat, reduces NRP-1 expression. Upregulated NRP-1 in macrophages and dendritic cells also demonstrated HIV-1 resistance/reduced infectivity. Notably, HIV-1-infected pregnant women receiving antiretroviral therapy (ART) to prevent vertical transmission may experience immune reconstitution, impaired decidualization, and elevated markers of endothelial injury. Since endothelial dysfunction and altered immune responses are central to PE, HIV-1 infection, ART usage and SARS-CoV-2 infection, it is plausible that an exacerbation of both features may prevail in the synergy of these events. Additionally, this review identifies microRNAs (miRNAs) mediating NRP-1 expression. MiR-320 and miR-141 are overexpressed in PE, while miR-206 and miR-124-3p showed increased expression in PE and HIV-1 infection. Additionally, miR-214 is overexpressed in PE, HIV-1 and SARS-CoV-2 infection, implicating treatment strategies to reduce these miRNAs to upregulate and normalize NRP-1 expression. However, inconsistencies in the data of the role and regulation of miRNAs in PE, HIV-1 and SARS-CoV-2 infections require clarification. This review provides a platform for early diagnosis and potential therapeutic intervention of PE, HIV-1, and SARS-CoV-2 infections independently and as comorbidities.

Keywords: HIV-1 infection; MicroRNAs; Neuropilin-1; Preeclampsia; SARS-CoV-2 infection.

Fig. 1

Neuropilin-1 structure, ligands, and biological effects. Adapted from (Chuckran et al., 2020). Abbreviations: C-end rule motif (CendR); CD4+ regulatory T cell (Treg); Coagulation factors, V/VIII domains (b1/b2); Complement C1r/C1s, uEGF bone morphogenetic protein 1 ( CUB or a1/a2); Hepatocyte growth factor (HGF); Interleukin-10 and -35 (IL-10 and IL-35); Meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu domain (c); Met/hepatocyte growth factor receptor (HGFR); Neuropilin-1 (NRP-1); Platelet-derived growth factor (PDGF); Platelet-derived growth factor receptor alpha (PDGFR-α); PSD-95/Dlg/ZO-1 homology domain (PDZ); Semaphorin (SEMA A, 3A and 4A); Serine/Glutamate/Alanine sequence (SEA); Severe acute respiratory coronavirus 2 (SARS-CoV-2); Vascular endothelial growth factor 165 (VEGF165); VEGF receptor 2 (VEGFR-2).

Fig. 2

Maternal endothelial dysfunction in preeclampsia. Adapted from (Naidoo et al., 2021). Abbreviations: Angiotensin II (Ang II); Endothelial nitric oxide synthase (eNOS); Endothelin-1 (ET-1); Hypoxia-inducible factor (HIF); Interleukin-1, 6, and 8 (IL-1, IL-6, and IL-8); Nitric oxide (NO); Prostaglandin (PGI2); Protein kinase C (PKC); Placental growth factor (PlGF); Reactive oxygen species (ROS); Soluble endoglin (sEng); Soluble fms-like tyrosine kinase-1 (sFlt-1); Syncytiotrophoblast microparticles STBM); Transforming growth factor-β (TGF-β); Tumor necrosis factor-α (TNF-α); Thromboxane A2 (TXA2); Vascular endothelial growth factor (VEGF); VEGF receptor (VEGFR).

Fig. 3

The role of NRP-1 in SARS-CoV-2 infection. Adapted from (Gudowska-Sawczuk and Mroczko, 2021;RayBiotech, 2021). Abbreviations: Coagulation factors, V/VIII domains (b1 and b2); Complement C1r/C1s, uEGF bone morphogenetic protein 1 (a1 and a2); Meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu domain (MAM); PSD-95/Dlg/ZO-1 homology domain (PDZ); Receptor binding domain (RBD); Serine/Glutamate/Alanine sequence (SEA); Severe acute respiratory coronavirus 2 (SARS-CoV-2); Spike protein subunit 1 and 2 (S1 and S2).

Fig. 4

Neuropilin-1 in PE, HIV-1 and SARS-CoV-2 infection. Abbreviations: Angiopoietin 2 (Ang2); Angiotensin-converting enzyme 2 (ACE 2); CD4+ regulatory T cell (Treg); Coronavirus disease 2019 (COVID-19); Dendritic cells (DCs); Extravillous trophoblast (EVT); Human immunodeficiency virus type 1 (HIV-1); Interferon gamma (IFN-γ); Matrix metalloproteinase (MMP); Neuropilin-1 (NRP-1); Nuclear factor kappa B (NF-κB); Phosphatidylinositol 3-kinase (PI3K); Phosphate group (P); Placental growth factor (PlGF); Preeclampsia (PE); Protein kinase B (Akt); Reactive oxygen species (ROS); Severe acute respiratory coronavirus 2 (SARS-CoV-2); Signal transducer and activator of transcription 3 (STAT3); Soluble endoglin (sEng); Soluble fms-like tyrosine kinase-1 (sFlt-1); Syncytiotrophoblast microparticles (STBM); Trans-activator of transcription protein in HIV-1 (tat); uterine natural killer (uNK); Vascular cell adhesion molecule 1 (VCAM-1); Vascular endothelial growth factor 165 (VEGF165); VEGF receptor 2 (VEGFR-2).

Fig. 5

The angiogenic and inflammatory status of identified microRNAs.