Biology subjects

Karlsson, C. A. Q.

Publications and source records attributed to Karlsson, C. A. Q..

5 recordsLinked to original sources

bioRxiv2026

Temporal changes in platelet activation and organ dysfunction during invasive Streptococcus pyogenes infection

A key feature of sepsis is immune dysregulation caused when a local infection progresses to systemic disease. Innate immune cells, including platelets, can both contribute to immune defense but also to collateral organ damage. In this study, we characterized the molecular, cellular, and proteome responses at distinct stages of invasive Streptococcus pyogenes infection in a mouse model, from a local infection to dissemination and systemic inflammation. Invasion of bacteria to the bloodstream was associated with escalating cytokine levels, platelet activation, and an early leukocytosis that progressed to leukopenia. Multiparameter mapping of organ function using plasma biomarkers, histopathological changes, and proteome reorganization revealed distinct temporal patterns of organ dysfunction. Platelets were mobilized to the local skin infection at early stages of inflammation but also accumulated in the liver at later stages, coinciding with sepsis-induced organ damage. We demonstrated that S. pyogenes bound to the GPIb receptor on platelets in vitro, suggesting that bacteria may bind to platelets in the bloodstream. Treatment of infected mice with antibiotics diminished the bacterial load, reduced sepsis-induced organ damage, and partially reverted the disease-associated proteome rearrangement in the plasma and liver. Treatment of infected mice with pharmacological blockade of platelet activation with ticagrelor neither exacerbated disease nor significantly protected against sepsis-induced organ damage. However, at the proteome level, ticagrelor significantly reverted sepsis-induced platelet activation and stress responses in the liver. We conclude that platelets contribute to liver dysfunction in sepsis and may represent a target for adjunct therapy in combination with antibiotics.

microbiology↗

bioRxiv2024

Inferring the composition of the blood plasma proteome by a human proteome distribution atlas

The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent different organs and cells contribute to the plasma proteome composition, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in human plasma in health and disease. First, we constructed an extensive human proteome atlas from 18 vascularized organs and the most abundant cell types in blood. Second, the atlas was interfaced with previous RNA/protein atlases to objectively define proteome wide protein-organ associations to enable both the inference of origin and the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in three separate patient cohorts with infection, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.

systems biology↗

bioRxiv2022

A pharmacoproteomic landscape of organotypic intervention responses in gram-negative sepsis

Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remains unclear. This knowledge gap has resulted in ineffective development of sepsis-specific biomarkers and therapies, and suboptimal treatment regimens to prevent or reverse organ damage. Here, we used pharmacoproteomics to score treatment effects in a murine Escherichia coli sepsis model based on changes in the organ, cell, and plasma proteome landscapes. A combination of pathophysiological read-outs and time-resolved proteome maps of organs and blood enabled us to define time-dependent and organotypic proteotypes of dysfunction and damage upon administration of several combinations of the broad-spectrum beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct response patterns were identified, defined as intervention-specific reversions, non-reversions, and specific intervention-induced effects, which depended on the underlying proteotype and varied significantly across organs. In the later stages of the disease, Gcc enhanced some positive treatment effects of Mem with superior reduction of the inflammatory response in the kidneys and partial restoration of sepsis-induced metabolic dysfunction. Unexpectedly, Mem introduced sepsis-independent perturbations in the mitochondrial proteome that were to some degree counteracted by Gcc. In summary, this study provides a pharmacoproteomic resource describing the time-resolved septic organ failure landscape across organs and blood, coupled to a novel scoring strategy that captures unintended secondary drug effects as an important criterion to consider when assessing therapeutic efficacy. Such information is critical for quantitative, objective, and organotypic assessment of benefits and unintended effects of candidate treatments in relationship to dosing, timing, and potential synergistic combinations in murine sepsis models.

systems biology↗

bioRxiv2021

Vascular proteome responses precede organ dysfunction in sepsis

Vascular dysfunction and organ failure are two distinct, albeit highly interconnected clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular crosstalk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of S. aureus sepsis by combining in vivo labeling of the endothelial proteome, data-independent acquisition (DIA) mass spectrometry, and an integrative computational pipeline. The data reveal, with unprecedented depth and throughput, that a septic insult evokes organ-specific proteome responses that are highly compartmentalized, synchronously coordinated, and significantly correlated with the progression of the disease. Vascular proteome changes were found to precede bacterial invasion and leukocyte infiltration into the organs, as well as to precede changes in various well-established cellular and biochemical correlates of systemic coagulopathy and tissue dysfunction. Importantly, our data suggests a potential role for the vascular proteome as a determinant of the susceptibility of the organs to undergo failure during sepsis.

immunology↗

bioRxiv2017

Streptococcus pyogenes infection and the human proteome with a special focus on the IgG-cleaving enzyme IdeS

Infectious diseases are characterized by a complex interplay between host and pathogen, but how these interactions impact the host proteome is unclear. Here we applied a novel mass spectrometry based proteomics strategy to investigate how the human proteome is transiently modified by the pathogen Streptococcus pyogenes, with a particular focus on bacterial cleavage of IgG in vivo. In invasive diseases, S. pyogenes evokes a massive host response in blood, whereas superficial diseases are characterized by a local leakage of several blood plasma proteins at the site of infection including IgG. S. pyogenes produces IdeS, a protease cleaving IgG in the lower hinge region and we find highly effective IdeS-cleavage of IgG in samples from local IgG poor microenvironments. The results show that IdeS contributes to the adaptation of S. pyogenes to its normal ecological niches. Additionally, the work identifies novel clinical opportunities for in vivo pathogen detection.

microbiology↗