We will establish a core to support three Pilot Projects that add mechanistic insight to the correlates of protection that will be established in Project 1 and Project 2. In the major projects, existing clinical studies in diverse immunization and challenge models will be used to identify patterns of leukocyte function, antigenspecific response, cytokine secretion and gene expression that are associated with either protection from infection, or amelioration of pathology, in living human subjects. In parallel, three mechanistic Pilot Projects will explore the biology ofthe interaction between malaria parasites and host cells in vitro. In Pilot Project 1, we will determine the effect of Plasmodium falciparum sporozoites on human Kupffer cells, which are widely believed to be a crucial portal of entry used by the parasites to gain access to hepatocytes. In Pilot Project 2, we will analyze the interaction between human anti-malaria cytotoxic effector cells raised against genetically modified vaccine strains, and infected hepatocytes. To achieve this we will use an optimized method to obtain hepatocyte-like cells direct from stem cells, and thus derive cell cultures highly susceptible to infection with P. falciparum sporozoites. In Pilot Project 3 we will directly identify the CD8+ T cells that are engaging malaria-infected hepatocytes, selectively harvest that small minority of cells by laser-mediated ablation of other cells, and perform RNA profiling on these antigen-specific CD8+ cytotoxic T cells. This will generate a transcriptome analysis of those CTL that are specially activated by malaria vaccines. All three of these Pilot Projects will provide mechanistic insight into the interaction between human malaria parasites and the immune system, with emphasis on pre-erythrocytic stages.

Public Health Relevance

Taking the results of these Pilot Projects together with the two main Projects, we will develop a better understanding of the process of human malaria infection, the way malaria parasites avoid immune defenses,and how vaccines work. This will help in the design of next-generation experimental vaccines, leading towards the long-term goal of malaria eradication.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098055-04
Application #
8471166
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$522,887
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304
Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8
Gulshan, Kailash; Brubaker, Gregory; Conger, Heather et al. (2016) PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. Circ Res 119:827-38
Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis et al. (2016) Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo. Elife 5:
Iqbal, Asif J; Fisher, Edward A; Greaves, David R (2016) Inflammation-a Critical Appreciation of the Role of Myeloid Cells. Microbiol Spectr 4:
Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115
Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558

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