Blood最新文献

Malaria, caused by Plasmodium parasites, accounts for ~250 million cases and over 600,000 deaths annually. One leading cause of mortality and morbidity is cerebral malaria (CM). Platelets mediate CM pathogenesis, although the exact mechanisms remain largely unknown. We examined if the mechanistic target of rapamycin (mTOR) pathway in platelets contributes to malaria pathogenesis. Our results demonstrate activation of the mTOR pathway in platelets ex vivo after co-incubation with Plasmodium falciparum-infected red blood cells and in vivo in Plasmodium berghei ANKA (PbA)-infected mice. When mTOR was specifically deleted in platelets (mTORplt-/-), mice with experimental cerebral malaria (ECM) had significantly increased survival. Survival differences were independent of parasitemia and thrombocytopenia. PbA-infected mTORplt-/- mice demonstrated significantly reduced platelet deposition in the brain resulting in improved cerebral blood flow and reduced brain vascular permeability. Plasma heme levels, generated during malaria, correlated significantly with intracerebral platelet accumulation in the PbA-infected mTORplt+/+ mice, but not in PbA-infected mTORplt-/- mice. In vitro experiments demonstrated that heme activates platelet mTOR downstream of Immunoreceptor Tyrosine-based Activation Motif (ITAM) signaling, predominantly through C-type lectin-like receptor 2. Blockage of heme-induced platelet activation with cobalt protoporphyrin significantly reduced platelet mTOR activation and decreased ECM-associated mortality. In conclusion, our findings demonstrate that platelet mTOR amplifies platelet activation responses induced by heme and deletion of platelet mTOR reduces platelet deposition in the brain, which we propose impedes symptomatic disease progression and malaria-associated mortality.

Plasminogen activator inhibitor 1 (PAI-1) is an inhibitor of fibrinolysis, thereby promoting blood clot stabilization. PAI-1 contributes to thrombosis, diet-induced obesity, and age-associated diseases such as diabetes, cancer, and Alzheimer's disease. Circulating PAI-1 increases with age, contributing to the increased thrombotic risk in age-related diseases. In contrast, partial PAI-1 deficiency protects patients from cardiovascular morbidity and extends lifespan. Decreasing circulating PAI-1 levels has both experimental and therapeutic value. RNA gene therapy can regulate the levels of target proteins, including those not amenable to traditional small-molecule or antibody-based therapies. Here, we developed a therapeutic approach to induce long-lasting PAI-1 knockdown in vivo with siRNA-lipid nanoparticles (siPAI-1). One dose of siPAI-1 resulted in 90% knockdown of plasma PAI-1 and lasted 10 days post-administration with no overt toxicity. siPAI-1 decreased thrombus weight following complete ligation of the inferior vena cava (IVC) in young and aged mice, and increased survival in aged mice four days post-IVC ligation. Hepatic PAI-1 mRNA expression in diet-induced obese mice was >10-times higher than in healthy mice and was exponentially correlated with body weight. One dose of siPAI-1 in obese mice resulted in 70% knockdown of circulating PAI-1. Furthermore, siPAI-1 normalized the supraphysiologic concentration of PAI-1 in aged mice, and prolonged lifespan in a fast-aging mouse model. Thus, siRNA-mediated PAI-1 knockdown represents a long-term anti-thrombotic approach and effective strategy to limit pathologic impact of PAI-1 inaging and in age-related diseases.

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic cell transplantation. Currently, immunosuppressants are used for GvHD prophylaxis and treatment in the majority of transplant recipients. Due to their systemic, non-specific mode of action, this treatment regimen is frequently associated with severe toxic side effects, opportunistic infections as well as cancer relapse when treating haematologic malignancies. By using short-term ex vivo modulation of haematopoietic cell transplants with the anti-human CD4 antibody MAX.16H5, we have developed a novel immune tolerance-inducing strategy enabling potent GvHD prevention. Functional in vitro assays and transcriptome profiling data suggest impaired TCR signalling and a shift towards an IL-10-dependent regulatory phenotype as the primary mechanism of action of anti-human CD4 antibody treatment, leading to a significantly reduced activation and proliferation of CD4+ and CD8+ T cells. A one-time incubation of haematopoietic transplants with MAX.16H5 prolongs survival of NSG mice and reduces signs of GvHD manifestation as effectively as repeated application with clinically applied immunosuppressants - making it a safe and effective immunotherapy for GvHD prevention.

By integrating short-read WGS and RNA-seq data with long-read RNA sequencing, we dissect the complex genomic architecture of PAX5 intragenic tandem multiplication (PAX5-ITM), revealing that these complex rearrangements result in in-frame transcripts that likely encode proteins with altered domains.