A5067419787- Malaria Research and Control
- Mosquito-borne diseases and control
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- HIV Research and Treatment
- Hepatitis B Virus Studies
- Research on Leishmaniasis Studies
- CRISPR and Genetic Engineering
- Receptor Mechanisms and Signaling
- Trypanosoma species research and implications
- Complement system in diseases
- Platelet Disorders and Treatments
- Glycosylation and Glycoproteins Research
- Hepatitis C virus research
- Liver Disease Diagnosis and Treatment
- Protein Structure and Dynamics
- HIV/AIDS drug development and treatment
- Aquaculture disease management and microbiota
- Autophagy in Disease and Therapy
- SARS-CoV-2 and COVID-19 Research
- Cell Adhesion Molecules Research
- Protein Kinase Regulation and GTPase Signaling
- Parasites and Host Interactions
- Monoclonal and Polyclonal Antibodies Research
- Parasitic Infections and Diagnostics
Infectious Disease Research Institute
2015-2024
University of Washington
2000-2024
Seattle University
2011-2023
Brotman Baty Institute
2020-2022
Center for Infectious Disease Research
2011-2022
California Institute for Regenerative Medicine
2020-2022
Harvard University
2008-2013
Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in host liver during initial stage infection. However, vivo malaria liver-stage (LS) studies humans are virtually impossible, and vitro models LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for study P. falciparum vivo: immunocompromised fumarylacetoacetate hydrolase-deficient (Fah-/-, Rag2-/-, Il2rg-/-, termed FRG...
The invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet precisely how target their cell and facilitate productive infection remains largely unknown. We found that the EphA2 receptor was critical for establishing permissive intracellular replication compartment, parasitophorous vacuole. Sporozoites productively infected hepatocytes with high expression, deletion protected mice from liver...
Plasmodium parasites infect the liver and replicate inside hepatocytes before they invade erythrocytes trigger clinical malaria. Analysis of host signaling pathways affected by liver-stage infection could provide critical insights into host–pathogen interactions reveal targets for intervention. Using protein lysate microarrays, we found that yoelii rodent malaria perturb hepatocyte regulatory involved in cell survival, proliferation, autophagy. Notably, prodeath p53 was substantially...
ABSTRACT Evidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel antibody (Ab) targets could be key improving formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods assess effects sporozoite-specific Abs infection in vivo remain underdeveloped. Here, we combined passive transfer...
Immunization with live-attenuated Plasmodium sporozoites completely protects against malaria infection. Genetic engineering offers a versatile platform to create sporozoite vaccine candidates. We previously generated genetically attenuated parasite (GAP) by deleting the P52 and P36 genes in NF54 wild-type (WT) strain of falciparum (Pf p52−/p36− GAP). Preclinical assessment GAP humanized mouse model indicated an early severe liver stage growth defect. However, human exposure >200 Pf...
Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium a significant health burden in humans, killing up to one million people annually. To succeed the mammalian after transmission by mosquitoes, must complete intracellular replication within hepatocytes then release new infectious forms into blood. Using yoelii rodent malaria parasites, we show some liver stage (LS)-infected...
The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with production reactive oxygen species, lipid peroxidation, and a form cell death called ferroptosis, plays critical role in stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces parasite In contrast, negative regulators this NOX1 TFR1, leads to an increase have shown previously increased levels P53 LS burden...
Abstract Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce health and economic burdens caused by malaria worldwide. N -myristoyltransferase (NMT) is an essential eukaryotic enzyme a validated drug target for combating malaria. However, previous Pv NMT inhibitors have failed due their low selectivity over human NMTs. Herein, we apply structure-guided hybridization approach combining chemical moieties previously reported develop next generation inhibitors....
Many bacterial pathogens translocate effector proteins into host cells to manipulate cell functions. Here, we used a protein microarray comprising virtually all human SRC homology 2 (SH2) and phosphotyrosine binding domains comprehensively quantitatively assess interactions between the early phase Chlamydia trachomatis translocated actin-recruiting phosphoprotein (Tarp), which is rapidly tyrosine phosphorylated upon entry. We discovered numerous novel SH2 phosphopeptides derived from Tarp....
Histology-directed imaging mass spectrometry (IMS) is a spatially targeted IMS acquisition method informed by expert annotation that provides rapid molecular characterization of select tissue structures. The annotations are usually determined on digital whole slide images histological stains where the staining preparation incompatible with optimal preparation, necessitating serial sections: one for annotation, IMS. Registration then used to align onto section. Herein, we report...
Kinases are key players in endothelial barrier regulation, yet their temporal function and regulatory phosphosignaling networks incompletely understood. We developed a novel methodology, Temporally REsolved KInase Network Generation (TREKING), which combines 28-kinase inhibitor screen with machine learning network reconstruction to build time-resolved, functional networks. demonstrated the utility of TREKING for identifying pathways mediating integrity after activation by thrombin or without...
Cerebral malaria (CM), a life-threatening complication of Plasmodium falciparum infection, is characterized by the sequestration infected erythrocytes in brain microvasculature. Our study investigated potential repurposing anti-cancer BCR-ABL drugs, also known to be effective against P. blood-stage parasites, for mitigating inflammation and blood-brain barrier breakdown CM. analysis demonstrated differential protective effects drugs on primary human microvascular endothelial cells (HBMEC)...
Abstract Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge specific regulators. Here we assess 34 host-targeted kinase inhibitors for capacity to eliminate yoelii -infected hepatocytes. Using pre-existing activity profiles each inhibitor, generate a predictive computational model that identifies kinases, which facilitate infection. We predict 47 including novel and previously described...
Receptor tyrosine kinases transmit and process extracellular cues by recruiting intracellular signaling proteins to sites of phosphorylation. Using protein microarrays comprising virtually every human SH2 PTB domain, we generated quantitative interaction maps for three well-studied receptors--EGFR, FGFR1 IGF1R--using phosphopeptides derived from residue on each receptor, regardless whether or not they are phosphorylated in vivo. We found that, general, peptides physiological phosphorylation...