The inability to acquire fully protective immunity against Plasmodium is a chief obstacle to malaria control. High levels of inflammatory cytokines can inhibit memory T cell development in model systems. Notably, all Plasmodia species have been found to encode an ortholog of the upstream inflammatory cytokine, macrophage migration inhibitory factor (MIF). Plasmodium MIF (PMIF) upregulates inflammatory responses during infection, leading to enhanced activation-induced T cell apoptosis and fewer antigen- experienced CD4 T cells that become memory cells. This finding suggests that Plasmodia actively interfere with the generation of malaria-specific memory CD4 T cells to enable parasite persistence and transmission. To better understand ineffective immunity to malaria and to provide a foundation for better vaccines, we will determine the specific role of PMIF in the anti-malarial immune response in three Specific Aims, as follow:
Aim 1. Define the Molecular Basis for the Pro-inflammatory Activation of the Immune Response by Plasmodium-encoded MIF (PMIF). We hypothesize that PMIF increases inflammatory responses by activating the host MIF receptor. We will define shared and unique signaling properties of PMIF versus host MIF and examine the role of the conserved N-terminal region, which mediates binding to the MIF receptor. We will investigate the action of PMIF on Toll-like and NOD-like receptor activation pathways, and we will validate our observations in mice infected with a P. berghei ANKA strain lacking its mif gene.
Aim 2. Define the Cellular and Molecular Basis for the Suppression of the Anti-malarial Adaptive Immune Response by PMIF. We hypothesize that a strong pro-inflammatory environment during malaria infection favors the generation of terminal effector CD4 T cells at the expense of protective, memory precursor CD4 T cells. We will elucidate the cytokine and signaling pathways responsible for this response, examine the role of T follicular helper cells (TFH) and their ability to provide help to B and to T cells, and analyze T cell exhaustion.
Aim 3. Evaluate the Therapeutic Potential of PMIF Neutralization in Malaria. We will explore the impact of neutralization of PMIF in mouse models of blood-stage and sporozoite infection. Our approach will include immunization with PMIF by a novel self-amplifying RNA vaccine and a pharmacologic strategy based on our discovery of a selective, small molecule inhibitor of PMIF. These studies will provide insight into how Plasmodia direct the host inflammatory response to interfere with protective immunity and suggest new strategies for therapeutic immunomodulation and vaccine development. Conclusions from this work may be generalized to other parasite pathogens, such as Leishmania, Ancyclostoma, and Brugia, which produce their own closely homologous MIF proteins.

Public Health Relevance

Our knowledge of the immune response to malaria, which is the second leading cause of infectious disease death in the world, is inadequate and hinders the development of an effective vaccine. It recently has been discovered that all malaria parasites produce a mimic of the human immunoregulatory protein, MIF, which acts to suppress the development of a protective immune response. Investigation of the mechanism of action of the MIF ortholog produced by malaria parasites together with evaluation of novel inhibitors of this protein may accelerate the development of better therapies and vaccine strategies. This research also may open the way to new therapeutic approaches against infections caused by Leishmania, hookworm, and filaria, which also produce MIF-like proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI110452-01
Application #
8664206
Study Section
Immunity and Host Defense (IHD)
Program Officer
Wali, Tonu M
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Sparkes, Amanda; De Baetselier, Patrick; Brys, Lea et al. (2018) Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. FASEB J 32:3411-3422
Sparkes, Amanda; De Baetselier, Patrick; Roelants, Kim et al. (2017) The non-mammalian MIF superfamily. Immunobiology 222:473-482
Stijlemans, BenoƮt; Brys, Lea; Korf, Hannelie et al. (2016) MIF-Mediated Hemodilution Promotes Pathogenic Anemia in Experimental African Trypanosomosis. PLoS Pathog 12:e1005862
Holowka, Thomas; Castilho, Tiago M; Garcia, Alvaro Baeza et al. (2016) Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. FASEB J 30:2249-65
Pantouris, Georgios; Rajasekaran, Deepa; Garcia, Alvaro Baeza et al. (2014) Crystallographic and receptor binding characterization of Plasmodium falciparum macrophage migration inhibitory factor complexed to two potent inhibitors. J Med Chem 57:8652-6
Dahlgren, Markus K; Garcia, Alvaro Baeza; Hare, Alissa A et al. (2012) Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor. J Med Chem 55:10148-59
Sun, Tiffany; Holowka, Thomas; Song, Yan et al. (2012) A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria. Proc Natl Acad Sci U S A 109:E2117-26
Hare, Alissa A; Leng, Lin; Gandavadi, Sunilkumar et al. (2010) Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF). Bioorg Med Chem Lett 20:5811-4