Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.
Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.
Acute Kidney Injury (AKI) is strongly associated with adverse outcome and mortality independently of the cause of renal damage [1][2][3] . The mechanisms determining the deleterious systemic effects of AKI are poorly understood and specific interventions, including optimization of renal replacement therapy, had a marginal effect on AKI-associated mortality in clinical trials [4][5][6][7][8] . The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and stress conditions, mainly synthesized from lactate in the proximal tubule [9][10][11][12] , rendering this organ a major systemic lactate disposal 13 . Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remains unknown. Here we demonstrate that glucose production and lactate clearance are impaired during human AKI using renal arteriovenous catheterization in patients. Using single cell transcriptomics in mice and RNA sequencing in human biopsies, we show that glycolytic and gluconeogenetic pathways are modified during AKI in the proximal tubule specifically, explaining the metabolic alterations. We further demonstrate that impaired renal gluconeogenesis and lactate clearance during AKI are major determinants of systemic glucose and lactate levels in critically ill patients. Most importantly, altered glucose metabolism in AKI emerged as a major determinant of AKIassociated mortality. Thiamine supplementation restored renal glucose metabolism and substantially reduced AKI-associated mortality in intensive care patients. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism in stress conditions, delineates general mechanisms explaining AKI-associated mortality and introduces a potential therapeutic intervention for a highly prevalent clinical condition with limited therapeutic options.To study the impact of AKI on renal glucose and lactate metabolism, we performed renal vein catheterization in patients undergoing cardiac surgery with cardiopulmonary bypass and experiencing (n=18) or not (n=87) post-operative AKI (Supplementary Table 1). We found a switch from net renal lactate uptake to net renal lactate release in patients experiencing AKI (-0.01±0.03 mmol/min to 0.02±0.02 mmol/min, p<0.001). Moreover, AKI patients showed a decrease in the renal net glucose release (0.06±0.07 mmol/min to 0.01±0.04 mmol/min, p=0.016) compared to the control group (Fig. 1 a,b). This suggested a simultaneous reduction of gluconeogenesis and activation of glycolysis in the kidney in response to AKI. Glycosuria was unlikely to be involved since all patients had arterial glucose levels below the glycosuria threshold (5.4 ± 0.94 mmol/L). To further characterize this process, we compared kidney allograft biopsies obtained during transplantation shortly (49±16 minutes) after
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.