Severe malaria (SM) places a disproportionate burden of nriortality and death on the children of Sub-Saharan Africa. Death, as a result of SM, is not a direct consequence of parasite load but is associated with excessive inflammatory response(s) in the brain and lungs of SM patients. Parasite-derived activators of the innate immune response, together with inflammatory monocytes, have been implicated in mediating this tissue damage. However, the activation pathways responsible for localized inflammation and compromising the blood brain barrier (BBB) remain to be determined. We propose elucidating the mechanism(s) by: 1. Defining the transcriptional profiles at the sites of damage in tissues from pediatric SM. We propose assembling a transcriptional """"""""road map"""""""" of the expression profiles at the sites of tissue damage in the brain and lungs of pediatric SM patients. The expression patterns will be validated by immuno-histological analysis of a broader bank of archived tissues from SM patients. 2. Do hemozoin-loaded peripheral blood monocytes demonstrate the capacity to mediate or exacerbate tissue damage? We will perform trancriptional and functional typing of hemozoin-loaded, peripheral blood monocytes from SM patients to determine whether or not their inflammatory activities correlate with the tissue-damaging pathways elucidated in Specific Aim #1. 3. Can these potentially damaging cells be re-programed by appropriate anti-inflammatory drugs or immunemodulators? We propose in vitro screening of a panel of anti-inflammatory compounds against patients' hemozoin-loaded monocytes to identify compounds capable of defusing the activation cascades that lead to tissue damage and death in SM. The goals of this project are designed to generate a mechanistic understanding of the pathology of disease in the SM patient cohort that is the subject of the parent ICEMR grant.

Public Health Relevance

90% of the deaths caused by severe malaria occur in children in Sub-Saharan Africa. Death, most frequently, is the result of an inappropriate level of inflammation in the microvasculature of the brain or the lungs of the SM patient. This project proposes determination of the role of parasite pigment-loaded monocytes in mediating or exacerbating this pathology, and the identification of chemotherapeutic approaches to de-activate the damaging cellular response. the identification of chemotherapeutic approaches to de-activate the damaging cellular response

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI089683-05
Application #
8691681
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
DUNS #
City
East Lansing
State
MI
Country
United States
Zip Code
Buchwald, Andrea G; Coalson, Jenna E; Cohee, Lauren M et al. (2017) Insecticide-treated net effectiveness at preventing Plasmodium falciparum infection varies by age and season. Malar J 16:32
Mohanty, Sanjib; Benjamin, Laura A; Majhi, Megharay et al. (2017) Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain. mSphere 2:
Gupta-Wright, Ankur; Tembo, Dumizulu; Jambo, Kondwani C et al. (2017) Functional Analysis of Phagocyte Activity in Whole Blood from HIV/Tuberculosis-Infected Individuals Using a Novel Flow Cytometry-Based Assay. Front Immunol 8:1222
Coalson, Jenna E; Walldorf, Jenny A; Cohee, Lauren M et al. (2016) High prevalence of Plasmodium falciparum gametocyte infections in school-age children using molecular detection: patterns and predictors of risk from a cross-sectional study in southern Malawi. Malar J 15:527
Buchwald, Andrea G; Walldorf, Jenny A; Cohee, Lauren M et al. (2016) Bed net use among school-aged children after a universal bed net campaign in Malawi. Malar J 15:127
Mzilahowa, Themba; Chiumia, Martin; Mbewe, Rex B et al. (2016) Increasing insecticide resistance in Anopheles funestus and Anopheles arabiensis in Malawi, 2011-2015. Malar J 15:563
Mathanga, Don P; Tembo, Atupele Kapito; Mzilahowa, Themba et al. (2016) Patterns and determinants of malaria risk in urban and peri-urban areas of Blantyre, Malawi. Malar J 15:590
Sisya, Tamika J; Kamn'gona, Raphael M; Vareta, Jimmy A et al. (2015) Subtle changes in Plasmodium falciparum infection complexity following enhanced intervention in Malawi. Acta Trop 142:108-14
Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda et al. (2015) Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network. Am J Trop Med Hyg 93:57-68
Moss, William J; Dorsey, Grant; Mueller, Ivo et al. (2015) Malaria Epidemiology and Control Within the International Centers of Excellence for Malaria Research. Am J Trop Med Hyg 93:5-15

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