Key result
Fatal COVID-19 is linked to significantly upregulated pulmonary endothelial NRP1 expression despite minimal ACE2.
Why the study?
Because ACE2 expression is low in certain SARS-CoV-2-infected cell types, neuropilins (NRP1 and NRP2) were evaluated as potential alternative co-factors for viral entry.
Observational (n=33)
Yes
p-value: p=<7.5E-6
Supports neuropilin-mediated entry in ACE2-low cells during fatal COVID-19; hypothesis-generating and requires functional validation before clinical consideration.
Coronavirus disease 2019 (COVID-19) is associated with hyperinflammation, endothelialitis, hypoxemia, and hypercoagulation, contributing to thrombosis in acute severe and long COVID. While ACE2 is the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, its low expression in certain infected cell types suggests alternative co-receptors. Neuropilins (NRP1 and NRP2), widely expressed, have been proposed as co-factors for viral entry. We analyzed NRP1 and NRP2 expression in autopsy tissues from heart, lung, and hematolymphoid organs using immunohistochemistry ( n = 20) and compared findings with public single-cell RNA sequencing (scRNAseq) data. Selected cases were further examined by spatial multiplex immunofluorescence (CODEX). In vitro binding of NRP1/NRP2 to SARS-CoV-2 spike fragments S1 and S1′ was assessed by immunofluorescence microscopy. NRP1 was abundantly expressed in myocardial capillary endothelial cells (ECs) and macrophages in the heart and lung; NRP2 was found in alveolar macrophages and mast cells. scRNAseq re-analysis confirmed these in situ patterns. In vitro , NRP1 exclusively bound S1, while NRP2 bound both S1 and S1′. SARS-CoV-2 RNA was detected in neuropilin-positive, ACE2 / TMPRSS2 -negative vascular EC and mast cells. The detection of SARS-CoV-2 RNA in neuropilin-positive but ACE2 / TMPRSS2 -negative cell clusters supports that neuropilins are involved in systemic viral dissemination. NRP1 on vascular EC may contribute to angiogenesis, vascular damage, and microangiopathy, while NRP2 represents a potential immunomodulatory target to regulate macrophage activity, resolve inflammation, and potentially prevent the progression of pulmonary fibrosis and limit excessive mast cell activation in long COVID. IMPORTANCE The well-known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), exhibits low expression in key cell types implicated in coronavirus disease 2019 (COVID-19) pathology, such as endothelial cells and B cells, macrophages, and mast cells. In contrast, neuropilins, identified as co-receptors for SARS-CoV-2, are abundantly expressed in these cells under physiological conditions and may be involved in virus-host interactions. This study presents a detailed in situ analysis of Neuropilin 1 (NRP1) and Neuropilin 2 (NRP2) expression in fatal COVID-19 cases using immunohistochemistry and spatial multiplex immunofluorescence phenotyping, complemented by single cell RNA sequencing. Additionally, it demonstrates differential binding affinities of NRP1 and NRP2 to SARS-CoV-2 spike protein fragments S1 and S1′ in vitro , suggesting distinct roles for these neuropilins in viral recognition. This study highlights the impact of the unique furin cleavage site in SARS-CoV-2, which may contribute to increased pathogenicity through its interaction with NRP1.
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Dette et al. (2025) conducted an observational in Fatal COVID-19 (n=33). Fatal COVID-19 infection vs. Influenza and non-infectious deaths was evaluated on Expression of NRP1 transcripts in pulmonary vascular endothelial cells (p=<7.5E-6). Fatal COVID-19 infection is associated with abundant NRP1 and NRP2 expression in cells with minimal ACE2 expression, and significantly upregulated NRP1 transcripts in pulmonary vascular endothelial cells compared to noninfectious controls.
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