bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.10.12.511145

Alterations in platelet proteome signature and impaired platelet integrin αIIbβ3 activation in patients with COVID-19

Goudswaard, L. J.·Williams, C. M.·Khalil, J.·Burley, K. L.·Hamilton, F.·Arnold, D.·Milne, A.·Lewis, P. A.·Heesom, K. J.·Mundell, S. J.·Davidson, A. D.·Poole, A. W.·Hers, I.
View original source ↗Export metadata ↓

Abstract

BackgroundPatients with coronavirus disease-19 (COVID-19) are at increased risk of thrombosis, which is associated with altered platelet function and coagulopathy, contributing to excess mortality. ObjectivesWe aimed to characterise the mechanism of altered platelet function in COVID-19 patients. MethodsThe platelet proteome, platelet functional responses and platelet-neutrophil aggregates were compared between patients hospitalised with COVID-19 and healthy control subjects using Tandem Mass Tag (TMT) proteomic analysis, Western blotting and flow cytometry. ResultsCOVID-19 patients showed a different profile of platelet protein expression (858 altered out of 5773 quantified). Levels of COVID-19 plasma markers were enhanced in COVID-19 platelets. Gene ontology (GO) pathway analysis demonstrated that levels of granule secretory proteins were raised, whereas some platelet activation proteins, such as the thrombopoietin receptor and PKC, were lowered. Basally, COVID-19 platelets showed enhanced phosphatidylserine (PS) exposure, with unaltered integrin IIb{beta}3 activation and P-selectin expression. Agonist-stimulated integrin IIb{beta}3 activation and PS exposure, but not P-selectin expression, were significantly decreased in COVID-19 patients. COVID-19 patients had high levels of platelet-neutrophil aggregates, even under basal conditions, compared to controls. This interaction was disrupted by blocking P-selectin, demonstrating that platelet P-selectin is critical for the interaction. ConclusionsOverall, our data suggests the presence of two platelet populations in patients with COVID-19: one with circulating platelets with an altered proteome and reduced functional responses and another with P-selectin expressing neutrophil-associated platelets. Platelet driven thromboinflammation may therefore be one of the key factors enhancing the risk of thrombosis in COVID-19 patients. Essentials- COVID-19 patient platelet function and platelet proteins were compared with healthy controls - Proteomic analysis of platelets indicated that COVID-19 decreased platelet activation proteins - Agonist induced PS exposure and integrin IIb{beta}3 activation were impaired in COVID-19 - COVID-19 led to maximal levels of P-selectin dependent platelet-neutrophil aggregates

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Goudswaard, L. J., Williams, C. M., Khalil, J., Burley, K. L., Hamilton, F., Arnold, D., Milne, A., Lewis, P. A., Heesom, K. J., Mundell, S. J., Davidson, A. D., Poole, A. W., Hers, I.. 2022-10-12. Alterations in platelet proteome signature and impaired platelet integrin αIIbβ3 activation in patients with COVID-19. https://doi.org/10.1101/2022.10.12.511145

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity

The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.

cell biology↗
bioRxiv2026

Nucleosome Core Allostery Governs Chromatin Recognition and Cell Fate

Nucleosomes regulate chromatin folding, accessibility, and factor recruitment. Current models primarily attribute these functions to histone tail modifications, while the core is largely viewed as a structural scaffold. Yet subtle changes within the nucleosome core can produce profound functional consequences, and the mechanisms underlying these effects remain unclear. Here, we describe nucleosome core allostery as a fundamental principle of chromatin regulation that amplifies the impact of minimal nucleosome variations. Leveraging natural differences between H2A.Z variants, we show that the nucleosome core encodes distinct conformational dynamics that propagate allosterically, thereby controlling nucleosome accessibility and recognition by chromatin factors. As a result, a single buried amino acid substitution alone is sufficient to reprogram nucleosome dynamics and bias cell identity. Our findings establish the nucleosome core as an allosteric regulatory module and provide a generalizable framework for how subtle variation within nucleosomes is amplified into diverse biological outcomes in development and disease.

cell biology↗
bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗