Acute infection with malaria is often accompanied by the symptoms of a systemic cytokine storm. These symptoms result from a systemic inflammatory response via the activation of phagocytes. The overall goal of our ongoing project is to define the mechanisms of innate immune activation and regulation that account for the clinical symptoms and complications of malaria. This grant is a renewal of R01 AI079293. This RO1 has been highly productive having resulted in 40 publications including 16 peer-reviewed manuscripts of original work in the latest funding period (9 of these directly related to the grant, an additional 5 papers were supported by grant-related infrastructure in Brazil). Over the last decade, we have defined what we believe to be the principal ?malaria toxins? and their cognate receptors: parasite AT-rich DNA, immune complexes, hemozoin, free heme, and GPI anchors. We found that these ligands drive Toll-like receptors (TLRs 2, 3, 4, 9), NOD-like receptors (NLRP3, NLRP12), absent in melanoma 2 (AIM2), and the cGAS-STING pathway. Our work led to recognition that a cytosolic DNA binding protein Cnbp, regulates IL12b and IFNg and, under certain conditions, type I interferons. We have described the phenomena of innate immune memory in malaria, which is one part of an epigenetic process that may both protect the human host or, under certain conditions, might result in severe malaria (especially if accompanied by bacterial infection). More recently, we have identified several lncRNAs in malaria-stimulated phagocytes, many of which might regulate clinical disease. Thus, we have accomplished most of what we set out to do 5 years ago. In this renewal, we plan to focus on identifying the most basic methods by which the innate immune system is regulated in malaria by combining cell culture studies, in vitro mouse work with the analysis of patient samples. There are three Aims. The major hypothesis of the grant is that the innate immune response is highly regulated via epigenetic modifications of chromatin as well as at the transcriptional level. This regulation involves the interaction of lymphoid cells with phagocytes, resulting in innate immune training and a variety of epigenetic changes. The epigenetic changes involve the modification of chromatin, alterations of chromatin accessibility (Aim 1). In addition, inflammatory signals during malaria result in the generation of long non-coding RNAs including LUCAT-1 and LIMIT, whose roles we will explore in detail in vitro, in a LUCAT-1 KO mouse and in human clinical samples (Aim 2). Finally, we will define the role of a transcriptional regulator known as Cnbp, a nucleic acid binding protein that we initially thought to be a DNA sensor. Cnbp has proven to be involved in regulating IL12beta transcription and expression via its interaction with c-Rel and the IL12 promoter (Aim 3). In all of the Aims described briefly above, we will analyze leukocytes from febrile patients with malaria (both P. vivax and P falciparum) from our site in Porto Velho, Brazil. This grant is an ambitious project built upon the successful completion of two previously ambitious grants. Over the next funding cycle, we hope to contribute significantly more to our knowledge of innate immunity in malaria.

Public Health Relevance

Malaria is caused by Plasmodium, a parasite that is spread by mosquitoes, and the disease is often characterized by a high fever and other flu-like symptoms. The disease affects all organs of the body and can cause a heightened immune response that can lead to death; the World Health Organization reported that in 2017 there were ~435,000 deaths due to malaria. To better treat and prevent malaria, the goal of this proposal is to understand how the body?s immune system detects Plasmodium and identify the genes and pathways responsible for responding to and eliminating this parasite.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Pesce, John T
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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Costa, Pedro A C; Figueiredo, Maria M; Diniz, Suelen Q et al. (2018) Plasmodium vivax Infection Impairs Regulatory T-Cell Suppressive Function During Acute Malaria. J Infect Dis 218:1314-1323
Hirako, Isabella Cristina; Assis, Patrícia Aparecida; Hojo-Souza, Natália Satchiko et al. (2018) Daily Rhythms of TNF? Expression and Food Intake Regulate Synchrony of Plasmodium Stages with the Host Circadian Cycle. Cell Host Microbe 23:796-808.e6
Elling, Roland; Robinson, Elektra K; Shapleigh, Barbara et al. (2018) Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2. Cell Rep 25:1511-1524.e6
Gallego-Marin, Carolina; Schrum, Jacob E; Andrade, Warrison A et al. (2018) Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria. J Immunol 200:768-774
Galvão-Filho, Bruno; de Castro, Júlia Teixeira; Figueiredo, Maria Marta et al. (2018) The emergence of pathogenic TNF/iNOS producing dendritic cells (Tip-DCs) in a malaria model of acute respiratory distress syndrome (ARDS) is dependent on CCR4. Mucosal Immunol :
Strangward, Patrick; Haley, Michael J; Albornoz, Manuel G et al. (2018) Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria. Proc Natl Acad Sci U S A 115:7404-7409
Carpenter, Susan; Fitzgerald, Katherine A (2018) Cytokines and Long Noncoding RNAs. Cold Spring Harb Perspect Biol 10:
Schrum, Jacob E; Crabtree, Juliet N; Dobbs, Katherine R et al. (2018) Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity. J Immunol 200:1243-1248
Chen, Yongzhi; Sharma, Shruti; Assis, Patricia A et al. (2018) CNBP controls IL-12 gene transcription and Th1 immunity. J Exp Med 215:3136-3150
Atianand, Maninjay K; Caffrey, Daniel R; Fitzgerald, Katherine A (2017) Immunobiology of Long Noncoding RNAs. Annu Rev Immunol 35:177-198

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