Moving Morehouse School of Medicine Translation Tx Research through MDTTs-Multidisciplinary Translational Teams.

Morehouse School of Medicine (SOM) works to achieve its vision of advancing health equity through conducting transformational, translation science (Tx). Tx describes our translational research continuum, symbolizing a method and scientific philosophy that intentionally promotes and supports convergence of interdisciplinary approaches and scientists to stimulate exponential advances for the health of diverse communities. Morehouse SOM actualizes Tx through multidisciplinary translational teams (MDTTs). We chronicle the identification of MDTTs by documenting formation, composition, functioning, successes, failures, and sustainability. Data and information were collected through key informant interviews, review of research documents, workshops, and community events. Our scan identified 16 teams that meet our Morehouse SOM definition of an MDTT. These team science workgroups cross basic science, clinical, and public health academic departments, and include community partners and student learners. We present four MDTTs, in various stages of progress, at Morehouse SOM and how they are advancing translational research.

Predicting Low-Level Childhood Lead Exposure in Metro Atlanta Using Ensemble Machine Learning of High-Resolution Raster Cells.

Low-level lead exposure in children is a major public health issue. Higher-resolution spatial targeting would significantly improve county and state-wide policies and programs for lead exposure prevention that generally intervene across large geographic areas. We use stack-ensemble machine learning, including an elastic net generalized linear model, gradient-boosted machine, and deep neural network, to predict the number of children with venous blood lead levels (BLLs) ≥2 to <5 µg/dL and ≥5 µg/dL in ~1 km2 raster cells in the metro Atlanta region using a sample of 92,792 children ≤5 years old screened between 2010 and 2018. Permutation-based predictor importance and partial dependence plots were used for interpretation. Maps of predicted vs. observed values were generated to compare model performance. According to the EPA Toxic Release Inventory for air-based toxic release facility density, the percentage of the population below the poverty threshold, crime, and road network density was positively associated with the number of children with low-level lead exposure, whereas the percentage of the white population was inversely associated. While predictions generally matched observed values, cells with high counts of lead exposure were underestimated. High-resolution geographic prediction of lead-exposed children using ensemble machine learning is a promising approach to enhance lead prevention efforts.

Increased Risk of Sub-Clinical Blood Lead Levels in the 20-County Metro Atlanta, Georgia Area-A Laboratory Surveillance-Based Study.

Lead (Pb) is a naturally occurring, highly toxic metal that has adverse effects on children across a range of exposure levels. Limited screening programs leave many children at risk for chronic low-level lead exposure and there is little understanding of what factors may be used to identify children at risk. We characterize the distribution of blood lead levels (BLLs) in children aged 0-72 months and their associations with sociodemographic and area-level variables. Data from the Georgia Department of Public Health's Healthy Homes for Lead Prevention Program surveillance database was used to describe the distribution of BLLs in children living in the metro Atlanta area from 2010 to 2018. Residential addresses were geocoded, and "Hotspot" analyses were performed to determine if BLLs were spatially clustered. Multilevel regression models were used to identify factors associated with clinical BBLs (≥5 µg/dL) and sub-clinical BLLs (2 to <5 µg/dL). From 2010 to 2018, geographically defined hotspots for both clinical and sub-clinical BLLs diffused from the city-central area of Atlanta into suburban areas. Multilevel regression analysis revealed non-Medicaid insurance, the proportion of renters in a given geographical area, and proportion of individuals with a GED/high school diploma as predictors that distinguish children with BLLs 2 to <5 µg/dL from those with lower (<2 µg/dL) or higher (≥5 µg/dL) BLLs. Over half of the study children had BLLs between 2 and 5 µg/dL, a range that does not currently trigger public health measures but that could result in adverse developmental outcomes if ignored.

Hematological Differences among Malaria Patients in Rural and Urban Ghana.

BACKGROUND: Scarce studies have addressed hematological differences of malaria in urban and rural regions. METHODS: Full or complete blood cell counts from 46 and 75 individuals (age range from < 1 to 92 years) with uncomplicated malaria infection living in urban (Accra) and rural (Dodowa) Ghana, respectively, were assessed. Sickle cell trait and patients were excluded from the study. RESULTS: Between overall groups, patients from Accra had significantly lower parasite count (p < 0.0001) and granulocyte number (p = 0.026). Children in Accra had a significantly lower parasitemia (p = 0.0013), hemoglobin (p = 0.0254), platelet count (p = 0.0148) and red blood cell levels (p = 0.0080) when compared with the children of Dodowa. In adults, mean cell hemoglobin (p = 0.0086) and parasite count (p < 0.0001) were significantly higher in Dodowa. CONCLUSION: These results indicate that children living in urban setting may experience a greater anemic effect to malaria as compared with those living in a rural setting.

Plasmodium-infected erythrocytes (pRBC) induce endothelial cell apoptosis via a heme-mediated signaling pathway.

Heme is cytotoxic to the plasmodium parasite, which converts it to an insoluble crystalline form called hemozoin (malaria pigment) in erythrocytes during replication. The increased serum levels of free heme cause tissue damage, activation of microvascular endothelial and glial cells, focal inflammation, activation of apoptotic pathways, and neuronal tissue damage. Several hypotheses have been proposed to explain how these causative factors exacerbate fatal malaria. However, none of them fully explain the detailed mechanisms leading to the high morbidity and mortality associated with malaria. We have previously reported that heme-induced brain microvascular endothelial cell (HBVEC) apoptosis is a major contributor to severe malaria pathogenesis. Here, we hypothesized that heme (at clinically relevant levels) induces inflammation and apoptosis in HBVEC, a process that is mediated by independent proinflammatory and proapoptotic signaling pathways. In this study, we determined the key signaling molecules associated with heme-mediated apoptosis in HBVEC in vitro using RT2 profiler polymerase chain reaction array technology and confirmed results using immunostaining techniques. While several expressed genes in HBVEC were altered upon heme stimulation, we determined that the apoptotic effects of heme were mediated through p73 (tumor protein p73). The results provide an opportunity to target heme-mediated apoptosis therapeutically in malaria-infected individuals.

Iron Supplementation Alters Heme and Heme Oxygenase 1 (HO-1) Levels In Pregnant Women in Ghana.

BACKGROUND: Iron supplementation is recommended for pregnant women to meet their iron requirement for a healthy pregnancy. The benefits and risks of universal iron supplementation during pregnancy in malaria endemic countries are currently being debated. As part of a broader study that focused on the effect of heme/HO-1 on pregnancy outcomes in malaria in pregnancy, we determined the association between iron supplementation and free heme levels in blood of pregnant women with and without malaria in Ghana. We hypothesized that pregnant women with malaria who took iron supplements will have higher levels of Heme/HO-1 than those who did not take iron supplements. METHODS: A total of 337 women were recruited for this study. Blood samples were collected for malaria diagnosis and heme/HO-1 measurement. Quantification of heme was done using a heme colorimetric assay kit and HO-1 levels were performed using Enzyme-Linked Immunosorbent Assay (ELISA) on plasma samples. RESULTS: Malaria positive iron supplemented women, in their third trimester, had significantly higher median levels of heme 59.3(43.1 - 60.4) than non-malaria iron supplemented women 35.7(33.0 - 62.2), p = 0.026. Also, malaria positive iron supplemented women had significant higher median levels of HO-16.2(IQR 4.9 - 8.1) than pregnant women who did not take iron supplements 2.9 (IQR 2.1 - 3.8), p = <0.001. CONCLUSION: Although iron supplementation may be highly beneficial and improve pregnancy outcomes for iron deficient or anemic mothers, it is also likely that iron supplementation for pregnant women who are not iron deficient may put this group of women at risk for adverse pregnancy outcomes. Findings from this study sheds light on the effect of iron supplementation on malaria derived heme in pregnancy, which may inform how iron supplementation is recommended for pregnant women who are not iron deficient.

Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.

Plasmodium falciparum infection can cause microvascular dysfunction, cerebral encephalopathy and death if untreated. We have previously shown that high concentrations of free heme, and C-X-C motif chemokine 10 (CXCL10) in sera of malaria patients induce apoptosis in microvascular endothelial and neuronal cells contributing to vascular dysfunction, blood-brain barrier (BBB) damage and mortality. Endothelial progenitor cells (EPC) are microvascular endothelial cell precursors partly responsible for repair and regeneration of damaged BBB endothelium. Studies have shown that EPC's are depleted in severe malaria patients, but the mechanisms mediating this phenomenon are unknown. Toll-like receptors recognize a wide variety of pathogen-associated molecular patterns generated by pathogens such as bacteria and parasites. We tested the hypothesis that EPC depletion during malaria pathogenesis is a function of heme-induced apoptosis mediated by CXCL10 induction and toll-like receptor (TLR) activation. Heme and CXCL10 concentrations in plasma obtained from malaria patients were elevated compared with non-malaria subjects. EPC numbers were significantly decreased in malaria patients (P < 0.02) and TLR4 expression was significantly elevated in vivo. These findings were confirmed in EPC precursors in vitro; where it was determined that heme-induced apoptosis and CXCL10 expression was TLR4-mediated. We conclude that increased serum heme mediates depletion of EPC during malaria pathogenesis.

CXCL10 gene promoter polymorphism -1447A>G correlates with plasma CXCL10 levels and is associated with male susceptibility to cerebral malaria.

The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter (-135G>A [rs56061981] and -1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the -1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51-5.85, p = 0.021). In addition, individuals with the -1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the -1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34-22.29, p = 0.018). Furthermore, -135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05-0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the -1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males.