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Objective: Human cytomegalovirus (HCMV) is a widespread pathogen that correlates with various clinical complications, including atherosclerosis. HCMV is released into the circulation during primary infection and periodic viral reactivation, allowing virus-platelet interactions. Platelets are important in the onset and development of atherosclerosis, but the consequences of platelet-HCMV interactions are unclear., Approach and Results: We studied the effects of HCMV-platelet interactions in blood from healthy donors using the purified clinical HCMV isolate VR1814. We demonstrated that HCMV bound to a Toll-like receptor (TLR) 2-positive platelet subpopulation, which resulted in signal transduction, degranulation, and release of proinflammatory CD40L and interleukin-1β and proangiogenic vascular endothelial-derived growth factor. In mice, murine CMV activated wild-type but not TLR2-deficient platelets. However, supernatant from murine CMV-stimulated wild-type platelets also activated TLR2-deficient platelets, indicating that activated platelets generated soluble mediators that triggered further platelet activation, independent of TLR2 expression. Inhibitor studies, using ADP receptor antagonists and apyrase, revealed that ADP release is important to trigger secondary platelet activation in response to HCMV. HCMV-activated platelets rapidly bound to and activated neutrophils, supporting their adhesion and transmigration through endothelial monolayers. In an in vivo model, murine CMV induced systemic upregulation of platelet-leukocyte aggregates and plasma vascular endothelial-derived growth factor in mice and showed a tendency to enhance neutrophil extravasation in a TLR2-dependent fashion., Conclusions: HCMV is a well-adapted pathogen that does not induce immediate thrombotic events. However, HCMV-platelet interactions lead to proinflammatory and proangiogenic responses, which exacerbate tissue damage and contribute to atherogenesis. Therefore, platelets might contribute to the effects of HCMV in accelerating atherosclerosis.

Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs) both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35+/-2.3% of cells in arterioles (range, 0.08-12.51%). As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41+/-1.03, p = 0.034) and the number of leukocytes (19.1+/-12.7 per 20 high-power fields, p = 0.01). The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1) released from leukocytes was crucial for SMC migration. After heart allotransplantation, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts.

Sepsis is a serious, potentially fatal disease caused by the body's reaction to microbial invasions by bacteria, viruses, and fungi. Current research shows that the process of fighting sepsis passes through two phases. The first phase is a cytokine storm, and the second phase involves a cycle of pro-inflammatory and anti-inflammatory responses led by Regulatory CD4+ T-cells (CD4+ Tregs). Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials are yet to show any promising results, indicating the need for further research into the mechanisms behind Treg dysfunction. We used next-generation sequencing (NGS) analysis of five datasets comprising of bulk RNA-seq and single-cell RNA-seq data to explore our research question. Our results identified Acod1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells as well as various metabolic pathways regulated by IL4 and IL10. scRNA-seq analysis showed that Acod1 and FoxP3 were localised in the same Treg-like cells. Further evidence from our study further suggests a mutual positive regulation loop between Acod1 and FoxP3 in sepsis. Additionally, CD36 was identified as a downstream target of Acod1. CD36 is a known metabolite regulator in Tregs, where it functions as a transporter of long fatty chains (LCFA) and is regulated by IL4 and IL10. Taken together, our results indicate that the metabolic CD36/Acod1 axis could be responsible for the continuous activation of Treg in sepsis. Thus, targeting this axis could prove valuable in improving the sepsis prognosis. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) infection has been associated with accelerated transplant vasculopathy. In this study, we assessed the effects of acute rat CMV (RCMV) infection on vessel remodeling in transplant vasculopathy, focusing on allograft morphology, inflammation and contribution of adventitial cells to intimal hyperplasia. Methods: Infrarenal aorta was locally infected with RCMV and transplanted from female F344 rats to male Lewis rats. Graft samples were collected 2 and 8 weeks after transplantation and analyzed for intimal hyperplasia, collagen degradation and inflammation. Transplantation of aorta followed by transplantation of RCMV infected and labeled isogenic adventitia were performed to study migration of adventitial cells towards the intima. Results: Intimal hyperplasia was increased threefold in infected allografts. RCMV induced apoptosis in the media, expression of matrix metalloproteinase 2, and decreased collagen deposits. Macrophage infiltration was increased in the infected allografts and resulted in increased production of MCP-1. RCMV-infected macrophages were observed in the adventitia and intima. Cells derived from infected adventitia migrated towards the intima of the allograft. Conclusions: RCMV enhances infiltration of macrophages to the allografts, and thereby increases MCP-1 production and inflammation, followed by recruitment of adventitial cells to the intima and accelerated intimal hyperplasia. [ABSTRACT FROM AUTHOR]