Pilot Projects help the COBRE expand our Center’s research footprint and support the careers of talented investigators. Pilots can be funded from the COBRE grant or directly from Institutional sources. As shown below these pilot projects study critical mechanisms in order to provide a better understanding of deadly pathogens and how to mitigate their impact on human health.
Abebe Fola, PhD
Assistant Professor, Pathology and Lab Med, Biology and Medicine, Brown University
Relevance: The emergence of Plasmodium falciparum parasites resistant to artemisinin threatens to reverse global progress in malaria control and increases the risk of severe disease among vulnerable African populations as well as non-immune U.S. travelers and military personnel. This project investigates the origin and rapid spread of a newly emerging resistance mutation, K13 P441L, recently detected across multiple countries in East and South Africa. By defining how this mutation emerges and spreads, this research provides the critical data needed to guide surveillance and containment strategies that prevent widespread treatment failure and protect global health.
Summary: Plasmodium falciparum remains the most lethal human malaria parasite and a major global health threat, accounting for over 90% of malaria-related deaths worldwide and disproportionately affecting children under five and pregnant women. While artemisinin-based combination therapies (ACTs) are the cornerstone of treatment, the emergence of Kelch13 (K13) mutations conferring artemisinin partial resistance (ART-R) threatens global malaria control. Each year, approximately 2,000 imported malaria cases are reported in the United States, disproportionately affecting travelers and military personnel; the vast majority are U.S. citizens. In these groups, no prior immunity exists; infection with resistant parasites increases the risk of treatment failure, progression to severe disease, and costly hospitalization. Of particular concern is the K13 P441L mutation, which has recently emerged across six geographically distant countries in East and Southern Africa (Ethiopia, Tanzania, Namibia, Uganda, Rwanda, and Zambia). Unlike other localized African mutations, P441L mirrors the rapid expansion of dominant resistant lineages in Southeast Asia, suggesting a unique fitness advantage or intrinsic evolutionary differences.
This project utilizes advanced genomic epidemiology to investigate the origins, spread, and population genomics of K13 P441L. Leveraging a unique collection of over 150 P441L mutant isolates and 150 paired wild-type controls, the research aims to characterize the evolutionary trajectory of this threat. Aim 1A employs Illumina and Oxford Nanopore whole-genome sequencing (WGS) to define extended haplotypes flanking the K13 P441L locus. These data are used to determine if the mutation arose from a single founder or multiple independent emergencies and to assess population connectivity and gene flow through identity-by-descent (IBD) and principal component analyses (PCA). Aim 1B assesses genome-wide variants that co-evolve with K13 P441L using linkage disequilibrium and selection analyses. The study evaluates co-occurring resistance haplotypes in established genes (pfcrt, pfmdr1, pfdhfr, pfdhps) and novel loci using integrated haplotype scores (iHS) and extended haplotype homozygosity (EHH). By understanding how this mutation is evolving and spreading, this research provides a critical framework for regional containment and surveillance strategies, directly advancing the mission to mitigate emerging drug resistance.
Sarah Jensen
Research Scientist II, Pediatrics, Women & Infants Hospital of Rhode Island
Relevance: The proposed research seeks to identify how maternal gut health and inflammation during pregnancy influence the developing fetal brain, potentially leading to long-term cognitive delays in children living in low-resource settings. By identifying specific maternal “enteric phenotypes” and their link to offspring brain activity at 24 months, this study will provide the foundational evidence needed to develop targeted prenatal interventions that protect neurodevelopment. Ultimately, this work aims to reduce global health disparities by ensuring that children in high-pathogen environments reach their full developmental and cognitive potential.
Summary
Environmental Enteric Dysfunction (EED) is a subclinical condition characterized by chronic intestinal inflammation, intestinal epithelial barrier breakdown, and reduced nutrient absorption. Highly prevalent in low-resource settings, EED has been consistently linked to postnatal growth failure and cognitive delays in children. While most research has focused on the postnatal period, emerging evidence suggests that maternal EED may have fetal programming effects leading to shortened gestation, reduced birth length, and impaired neural wiring. The proposed project seeks to address critical knowledge gaps concerning the maternal-to-fetal effects of EED on fetal growth and early neurodevelopmental outcomes. Leveraging a unique longitudinal pregnancy-child cohort from the ENAT trial in rural Ethiopia (n~230), we will investigate the pathways through which maternal enteric dysfunction influences offspring development at 24 months. The project will be accomplished through three specific aims: Aim 1: Define maternal EED phenotypes by using Latent Profile Analysis (LPA) to cluster EED biomarkers (MPO, NEO, AAT, REG1B) and quantitative enteropathogen burden during pregnancy. Aim 2: Determine the impact of maternal EED on postnatal neurodevelopment at 24 months, assessed utilizing the Bayley Scales of Infant Development (BSID-III) and objective resting-state EEG to measure spectral power (theta-to-alpha ratio). Aim 3: Utilize Structural Equation Modeling to examine whether impaired maternal iron homeostasis (Total Body Iron) and systemic inflammation (e.g. pro-inflammatory cytokines and C-reactive protein) serve as primary mechanistic mediators between prenatal enteric dysfunction and offspring outcomes.
This project bridges pathology, nutrition, and neuroscience. The foundational evidence generated will guide the development of target biomarker panels to identify high-risk pregnancies, ultimately informing interventions to mitigate the intergenerational cycle of EED and its effects on human capital. By defining the role of maternal intestinal barrier breakdown in offspring outcomes, this research supports the NIH mission to translate biological insights into clinical strategies that reduce the global burden of developmental and nutritional disorders
Sanghyun Lee, PhD
Assistant Professor, Molecular Microbiology and Immunology, Brown University
Human coronaviruses have repeatedly caused major epidemics and pandemics, underscoring the need for mechanism-based countermeasures and platforms that can rapidly evaluate entry inhibition across viral diversity. HCoV-OC43 is among the most frequently detected seasonal human coronaviruses, yet-unlike other human coronaviruses with defined protein receptors-OC43 has long lacked a defined proteinaceous entry receptor, limiting rational development and benchmarking of vaccines and therapeutics that target entry. Our unpublished preliminary studies identify BRO (Binding Receptor for OC43) as a cellular entry receptor that is necessary and sufficient for OC43 infection, establish a structural and mechanistic basis for spike recognition, demonstrate conserved receptor activity across mammals, and show that BRO-directed blockade can reduce infection in cell lines and primary ex vivo human bronchial epithelial cultures. Building on this foundation, this 1-year Pathogens COBRE pilot project will deliver a scalable, quantitative OC43 entry and intervention toolkit by pursuing two aims: (1) develop BRO-dependent rVSV-based OC43 entry surrogates spanning circulating spike diversity, including a ~10-spike replication-defective reporter panel and two prioritized replication-competent reporter surrogates, and (2) generate and validate BRO-targeting monoclonal antibodies as entry inhibitors, defining potency, mechanism, and breadth across the straindiverse reporter panel with confirmation in authentic OC43 and ex vivo airway culture where feasible. Successful completion will provide assay-ready viral surrogates, SOP-level neutralization readouts, and prioritized receptor-blocking mAbs-transferable resources that enable rapid screening of vaccines/sera/therapeutics and establish a clear runway toward subsequent independent RO1-level funding focused on receptor-guided coronavirus entry biology and host-directed interventions.
Christopher de Graffenried
Associate Professor, Molecular Microbiology and Immunology, Brown University
Trypanosoma cruzi causes severe cardiac and intestinal diseases that sicken millions and kill thousands of people each year. This proposal will use organoids, which are small groups of cells that organize into structures that have similar properties to human organs, to elucidate how the parasite selects host cells for infection and will test a range of FDA-approved drugs as potential treatments for T. cruzi. Our primary goal is to understand T. cruzi host cell tropism, to establish what makes the parasite cause the specific damage that it does in the host, with the long-term goal of using drugs that target host cell pathways to block T. cruzi infection, rather than specifically targeting the parasite. In Aim 1, we will determine if T. cruzi infects specific intestinal cell subtypes, has different rates of proliferation in different cells, and how it disrupts host cells in a three-dimensional system during the lytic phase. In Aim 2, we will test if a range of FDA-approved drugs that alter host cell pathways are able to block T. cruzi cell entry or proliferation. Drugs that target host cell may serve as novel antiparasitics that have a lower likelihood of developing resistance. Overall, this work will define which host cells T. cruzi prefers and what host pathways contribute to these preferences, which will contribute to understanding how the parasite infects and damages its hosts.
Cliff Oduor
Assistant Professor of Pathology and Laboratory Medicine (Research)
Epstein-Barr virus (EBV) is an oncogenic human pathogen that contributes to Burkitt lymphoma and multiple other malignancies affecting patients in the United States. This project will determine whether EBV-positive Burkitt lymphoma cells can be pharmacologically induced into a lytic state that increases vulnerability to ganciclovir-containing therapy. The long-term goal is to develop a biomarker-guided EBV-directed therapeutic strategy in which viral state, rather than EBV positivity alone, identifies tumors most likely to respond to HDAC inhibitor plus valganciclovir/ganciclovir-based treatment. Findings from this work may inform therapeutic approaches for EBV associated malignancies relevant to U.S. public health.
Thomas Lavoie
Assistant Professor, College of Pharmacy, University of Rhode Island
In the United States, the steady increase in antimicrobial resistance has coincided with the progression from clinically identified extended- spectrum b-lactamases (ESBLs) to serine carbapenemases and more recently, metallo–lactamase (MBL) projected by Gram-negative bacteria. The limited therapeutic options for infections caused by pathogens harboring these resistance mechanisms underscore the need for exploratory studies to identify alternative treatments. One promising option is the diazabicycloocta (DBO) -lactamase inhibitor durlobactam.
The objective of this pilot project is to characterize durlobactam pharmacodynamic activity exposure response relationships, and resistance emergence against MBL-producing Enterobacterales using an integrated pharmacodynamic bioanalytical, and genomic approach.
This project is directly aligned with the mission of the Translational Approaches to Pathogens of Human Significance COBRE, which addresses pathogens of global significance through a translational, multidisciplinary approach and makes essential use of the Pathogens Pharmacology Core for bioanalytical support. The expected outcomes will provide the preliminary data necessary for a subsequent R01 application to develop optimized durlobactam containing regimens for these difficult to-treat infections.
Dr. Thomas Bartnikas
Associate Professor, Pathology and Laboratory Medicine, Brown University
Iron deficiency (ID) is the most common nutritional disorder in the U.S. and the world. It can be caused by inadequate intake, blood loss, and infection/inflammation, the latter suppressing dietary iron (Fe) absorption and Fe release from body stores to minimize Fe availability to pathogens. ID causes anemia, impaired neurocognitive development and function, and compromised cardiovascular health. It also increases dietary absorption of manganese (Mn), an essential yet potentially metal. Notably, our collaborator recently reported that acute inflammation increases biliary Mn excretion and decreases tissue Mn levels. This is predicted to limit Mn availability to pathogens, although the effects of chronic inflammation and infection have yet to be explored. Furthermore, the impact of ID- and inflammation/infection-induced perturbations in Mn levels on neurocognitive function has yet to be examined in human populations, even though Mn is a potent neurotoxicant. We propose to use existing biospecimens with deeply characterized cohorts which provides both cost-efficient pathway to rigorous human evidence as well as responsible stewardship of research resources. We hypothesize that serum Mn levels will reflect a balance between stimulation of Mn absorption by ID and stimulation of Mn excretion by inflammation and will correlate with neurocognitive function. To test this hypothesis, we will measure metal levels in serum levels from those studies and incorporate these new measurements into the large existing database of human subject phenotypes collected by Drs. Kurtis and Friedman. This will empower us to address a considerable knowledge gap in the field of metal biology—what are the physiologic consequences of ID- and inflammation induced perturbations in Mn levels on human health? Finally, the proposed work represents a new direction for Dr. Bartnikas’ laboratory, as it incorporates a population science approach to metal homeostasis, a topic he has explored in the past using model organisms, and will broaden the translational impact of future grant applications.
Rhode Island Hospital
55 Claverick St.
Suite 101
Providence, RI 02906
This website is supported by the Pathogens COBRE funded by the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM156688. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CORES RI
CIHR
Pharmacology Core of URI
International Health Institute at Brown Medical School
Global Health Initiative
