Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence

Gisby, Jack; Buang, Norzawani; Papadaki, Artemis; Clarke, Candice; Malik, Talat H.; Medjeral-Thomas, Nicholas; Pinheiro, Damiola; Mortimer, Paige M; Lewis, Shanice; Sandhu, Eleanor; McAdoo, Stephen P; Prendecki, Maria; Willicombe, Michelle; Pickering, Matthew C.; Botto, Marina; Thomas, David; Peters, James E.

doi:10.1038/s41467-022-35454-4

Cited by 21 publications

(17 citation statements)

References 101 publications

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“…While our data highlights a new role for LRRC15 in promoting SARS-CoV-2 spike binding, limiting infection, and regulating collagen expression, it is currently unclear how LRRC15 contributes to human COVID-19 disease. Notably, while this manuscript was under revision, a preprint authored by Gisby and colleagues investigated serum from control and COVID-19 infected end stage kidney disease patients, and found that out of the entire serum proteome, depletion of circulating LRRC15 is the strongest predictor of COVID-19 clinical outcome [ 51 ]. Integrating these data, it is possible that fibroblast-expressed LRRC15, or potentially cell free LRRC15 deposits in the airways, could trap viral particles for subsequent clearance by the innate immune system, while at the same time enhancing cellular antiviral tone and suppressing fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

et al. 2023

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Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was a TLR-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 spike binding where they form a cell surface complex. LRRC15 mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe Coronavirus Disease 2019 (COVID-19) infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection in trans. Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection.

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Section: Discussionmentioning

confidence: 99%

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

et al. 2023

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“…The exosomes of mild COVID‐19 cases showed that the chloride intracellular channel protein 1 (CLIC1), CD9, CD36, CD47, FYN‐binding protein 1 (FYB, also known as adhesion and degranulation promoting adaptor protein, ADAP), and synaptosomal‐associated protein 23 (SNAP23) were associated with the antigen presentation and caused T‐cell activation. Platelet factor 4 (PF4) and Pro‐Platelet Basic Protein (PPBP) are chemoattractants that activate neutrophils and monocytes, respectively, and they explain the prolonged prothrombotic events following COVID‐19 128,129 …”

Section: Exosomes and Sars‐cov‐2mentioning

confidence: 99%

“…Platelet factor 4 (PF4) and Pro-Platelet Basic Protein (PPBP) are chemoattractants that activate neutrophils and monocytes, respectively, and they explain the prolonged prothrombotic events following COVID-19. 128,129 Furthermore, complement factors, clotting system components, inflammation stimulators, and promoters of the IL-6 pro-inflammatory signaling were abundant in the exosomes of individuals with severe illness. 130,131 The C1R (complement component 1 subcomponent r), which is known to start complement activation, plays a significant role in acute and chronic inflammation, endothelial cell disturbance, clot formation, and intravascular coagulation in the severe COVID-19 patients.…”

Section: Exosomes and Covid-19-related Coagulation Disordersmentioning

confidence: 99%

Intrinsic factors behind long‐COVID: I. Prevalence of the extracellular vesicles

El-Maradny

Rubio‐Casillas

Uversky

et al. 2023

J of Cellular Biochemistry

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It can be argued that the severity of COVID-19 has decreased in many countries. This could be a result of the broad coverage of the population by vaccination campaigns, which often reached an almost compulsory status in many places. Furthermore, significant roles were played by the multiple mutations in the body of the virus, which led to the emergence of several new SARS-CoV-2 variants with enhanced infectivity but dramatically reduced pathogenicity. However, the challenges associated with the development of various side effects and their persistence for long periods exceeding 20 months as a result of the SARS-CoV-2 infection, or taking available vaccines against it, are spreading horizontally and vertically in number and repercussions. For example, the World Health Organization announced that there are more than 17 million registered cases of long-COVID (also known as post-COVID syndrome) in the European Union countries alone. Furthermore, by using the PubMed search engine, one can find that more than 10 000 articles have been published focusing exclusively on long-COVID. In light of these enormous and ever-increasing numbers of cases and published articles, most of which are descriptive of the various long-COVID symptoms, the need to know the reasons behind this phenomenon raises several important questions. Is long-COVID caused by the continued presence of the virus or one/several of its components in the recovering individual body for long periods of time, which urges the body to respond in a way that leads to long-COVID development? Or are there some latent and limited reasons related to the recovering patients themselves? Or is it a sum of both? Many observations support a positive answer to the first question, whereas others back the second question but typically without releasing a fundamental reason/signal behind it. Whatever the answer is, it seems that the real reasons behind this widespread phenomenon remain unclear. This report opens a series of articles, in which we will try to shed light on the underlying causes that could be behind the long-COVID phenomenon.

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“…In this context, blood proteomics shows a great potentiality, since this biofluid can be collected in a less invasive way and reflects the changes of the whole organism [ 7 , 8 , 9 ]. It has been shown by supervised learning that the plasma proteome is a highly informative indicator of the clinical severity of COVID-19 patients, superior to other sources and techniques such as the transcriptome of the peripheral blood mononuclear cells (PBMCs) [ 10 ]. Therefore, in these two years of pandemic, blood collected from patients infected with SARS-CoV-2 has been widely studied with mass spectrometer (MS)-based proteomics techniques in order to investigate COVID-19 disease more deeply.…”

Section: Introductionmentioning

confidence: 99%

Plasma Proteomic Variables Related to COVID-19 Severity: An Untargeted nLC-MS/MS Investigation

Pagani

Chinello

Risca

et al. 2023

IJMS

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection leads to a wide range of clinical manifestations and determines the need for personalized and precision medicine. To better understand the biological determinants of this heterogeneity, we explored the plasma proteome of 43 COVID-19 patients with different outcomes by an untargeted liquid chromatography-mass spectrometry approach. The comparison between asymptomatic or pauci-symptomatic subjects (MILDs), and hospitalised patients in need of oxygen support therapy (SEVEREs) highlighted 29 proteins emerged as differentially expressed: 12 overexpressed in MILDs and 17 in SEVEREs. Moreover, a supervised analysis based on a decision-tree recognised three proteins (Fetuin-A, Ig lambda-2chain-C-region, Vitronectin) that are able to robustly discriminate between the two classes independently from the infection stage. In silico functional annotation of the 29 deregulated proteins pinpointed several functions possibly related to the severity; no pathway was associated exclusively to MILDs, while several only to SEVEREs, and some associated to both MILDs and SEVEREs; SARS-CoV-2 signalling pathway was significantly enriched by proteins up-expressed in SEVEREs (SAA1/2, CRP, HP, LRG1) and in MILDs (GSN, HRG). In conclusion, our analysis could provide key information for ‘proteomically’ defining possible upstream mechanisms and mediators triggering or limiting the domino effect of the immune-related response and characterizing severe exacerbations.

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Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence

Cited by 21 publications

References 101 publications

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

Intrinsic factors behind long‐COVID: I. Prevalence of the extracellular vesicles

Plasma Proteomic Variables Related to COVID-19 Severity: An Untargeted nLC-MS/MS Investigation

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