Mus musculus
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ABSTRACT:
PROVIDER: PRJNA291427 | ENA |
REPOSITORIES: ENA
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Project description:Chemo-attenuated sporozoite vaccines are considered promising for malaria prevention, but safety concerns persist regarding anti-malarial drugs targeting either liver or blood-stage parasites. In this study, we found that nitroquine (CI-679), used to eliminate malaria blood-stage parasites, effectively attenuated sporozoites by halting early liver-stage development. A single vaccination with CI-679-attenuated Plasmodium berghei (P. berghei) sporozoites provided significant protection to BLAB/c mice against sporozoites challenge. The differences in protective efficacy between two genetically distinct strains, BLAB/c and C57BL/6 mice, were primarily linked to the frequency of parasite-specific CD8+ tissue-resident memory (Trm) cells. Additionally, high IL-15 expression in monocytes was associated with the generation of CD8+ Trm cells in immunized mice. Our findings characterize a novel chemo-attenuated sporozoite vaccine that warrants further human testing, and provides mechanistic evidence supporting IL-15 as an adjuvant to enhance the efficacy of exo-erythrocytic stage vaccines.
2026-09-13 | GSE305696 | GEO
Project description:In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements likely depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory (Trm) T cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion or depletion, which may be harnessed to control liver infections or autoimmunity.
2016-10-02 | GSE71518 | GEO
Project description:Malaria, caused by Plasmodium parasites is responsible for the illness of millions of individuals each year. Plasmodium sporozoites inoculated by mosquitoes migrate to the liver and infect hepatocytes prior to release of merozoites that initiate symptomatic blood-stage malaria. Parasites are thought to be restricted to hepatocytes throughout this obligate liver-stage of replication and differentiation. In contrast to this notion, we found that a subset of hepatic dendritic CD11c+ cells co-expressing F4/80, CD103, CD207 and CSF1R, acquired a substantial parasite burden during the liver-stage of malaria, but only after initial hepatocyte infection. These CD11c+ cells found in the infected liver and liver-draining lymph nodes exhibited transcriptionally and phenotypically enhanced antigen-presentation functions; and primed protective CD8 T cell responses against Plasmodium liver-stage restricted antigens. Our findings uncover a novel aspect of Plasmodium biology as well as the fundamental mechanism by which CD8 T cell responses are primed against liver-stage malaria.
2019-02-05 | GSE126110 | GEO
Project description:Attenuated whole organism vaccines targeting the malaria liver stage reliably confer sterile immunity. These vaccines can completely protect female mice from infection, but protection in male mice remains unproven. We discovered that male BALB/cJ mice vaccinated with prime-and-trap, a whole organism-based vaccine strategy, exhibit poorer protection against Plasmodium yoelii sporozoite challenge than females. We investigated this sex difference, and identified vaccinated males have fewer hepatic memory CD8+ T cells than females when scaling for differences in liver biomass, and reduced acute inflammatory responses post-vaccination. Surgical hormone manipulation clarified that the presence of testicular hormones, not the absence of ovarian hormones, hindered protection in male mice. The presence of androgens did not affect memory CD8+ T cells quantity nor quality of, but inhibited protective cellular responses during sporozoite challenge. Thus, both males and females form functional memory responses following prime-and-trap vaccination, but androgens during sporozoite challenge impair protection in male mice.
2025-04-04 | GSE253755 | GEO
Project description:Tissue resident memory T cell populations play a critical role in host defense against respiratory viral infections by surveilling the respiratory tract and mounting rapid antiviral responses to their cognate antigens. While previous studies focused on lung resident memory T cells in the context of direct intranasal infection models, we utilize a natural respiratory virus transmission model to examine the transcriptional changes in antigen-specific nasal resident memory CD8 T cells during their initial response to infection. Here, we demonstrate that during respiratory virus transmission, nasal resident memory CD8 T cells adopt antiviral transcriptional programs denoted by expression of classical CD8 T cell activation and effector function genes, further supporting the development of upper respiratory tract targeting vaccination strategies.
2026-07-23 | GSE329262 | GEO
Project description:Purpose: To characterize the tumor-specific TRM cells in LNs, skin, lung and liver in mice with melanoma-associated vitiligo (MAV). scRNAseq was performed to identify populations of CD8 T cells with TRM transcriptional characteristics. Methods: CD8+Thy1.1+ T cells were sorted from DLN, skin lung and liver of MAV mice and scRNA-sequenced Results: Heterogenouse CD8 memory populations with both circulatating and resident phenotypes were identified. Conclusions: Tumor-specific CD8 T cells form TRM responses in tumor-draining LNs.
2021-07-04 | GSE171161 | GEO
Project description:Purpose: To characterize the tumor-specific TRM cells in LNs, skin, lung and liver in mice with melanoma-associated vitiligo (MAV). Bulk RNA-seq was performed to identify populations of CD8 T cells with TRM transcriptional characteristics. Methods: CD8+THy1.1+ T cells were sorted from DLN, skin lung and liver of MAV mice and bulk RNA-sequenced Results: Heterogenouse CD8 memory populations with both circulatating and resident phenotypes were identified. Conclusions: Tumor-specific CD8 T cells form TRM responses in tumor-draining LNs.
2021-07-04 | GSE169237 | GEO
Project description:Increasing evidence suggests the liver as to be an effector against blood-stage malaria. Vaccination induces changes in the liver and survival of otherwise lethal blood-stage malaria of Plasmodium chabaudi which is associated with changes in the liver. Here, the time-course of expression of erythroid genes is investigated during infections with P. chabaudi in the liver of vaccination-protected and unprotected non-vaccinated mice.
2020-02-10 | GSE129133 | GEO
Project description:A major obstacle in deciphering the hepatic stage of the malaria parasite has been the challenges associated with culturing the infected hepatocytes through the entire liver stage cycle, including that of the dormant form known as hypnozoites. Primary hepatocytes lose their specialized functions in long-term in vitro culture. Hepatocyte infection represents the first step for clinically silent infection and development of malaria parasite Plasmodium in the liver. Thus this liver stage is an ideal target for development of novel antimalarial drugs and vaccine. However, drug discovery against Plasmodium liver stage is severely hampered by the poor understanding of host-cell and parasites interactions during the liver stage infection and development. In this study, we have performed tandem mass tags (TMT) labelling based quantitative proteomic analysis in simian primary hepatocytes cultured in three different systems of susceptibility to plasmodium infection. Our results represent the first documentation of potentially essential molecular markers including asialoglycoprotein receptor (ASGPR), apolipoproteins, squalene synthase and scavenger receptor B1 (SR-BI) required for productive infection and full development in relapsing Plasmodium species. The identification of these candidate proteins for constructive infection and development of Plasmodium in malaria paves the way to explore them as therapeutic targets.
2019-09-02 | PXD013310 | Pride
Project description:Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Yet, the underlying mechanisms driving the pathogenesis of malaria-associated hypoglycemia remain poorly understood. Here we report that labile heme, an alarmin generated as a byproduct of hemolysis during the blood stage of Plasmodium spp. infection, plays a central role in the development of malaria-associated hypoglycemia. Labile heme recapitulated the hypometabolic response to Plasmodium (chabaudi chabaudi; Pcc) infection in mice, including the development of anorexia, transcriptional repression of hepatic glucose production (HGP) and reduction of glycemia, energy expenditure (EE) as well as core body temperature. While this hypometabolic response is protective against immune-mediated liver damage and anemia, when sustained over time it can lead to hypoglycemia and compromise EE as well as thermoregulation. I response, asexual stages of Plasmodium spp. activate a transcriptional program that reduces virulence in favor of sexual commitment and presumably malaria transmission. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic defense strategy against Plasmodium infection.
2021-12-31 | E-MTAB-10939 | biostudies-arrayexpress