A5056347452- Malaria Research and Control
- Cellular Mechanics and Interactions
- Advanced Fluorescence Microscopy Techniques
- T-cell and B-cell Immunology
- Receptor Mechanisms and Signaling
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Mosquito-borne diseases and control
- Research on Leishmaniasis Studies
- Erythrocyte Function and Pathophysiology
- Immunotherapy and Immune Responses
- Cell Adhesion Molecules Research
- Lipid Membrane Structure and Behavior
- Complement system in diseases
- Cellular transport and secretion
- Phagocytosis and Immune Regulation
- Drug Transport and Resistance Mechanisms
- Trypanosoma species research and implications
- Invertebrate Immune Response Mechanisms
- Autophagy in Disease and Therapy
- Neurobiology and Insect Physiology Research
- Advanced Biosensing Techniques and Applications
- Glycosylation and Glycoproteins Research
- Immune cells in cancer
- Venomous Animal Envenomation and Studies
National Institute of Allergy and Infectious Diseases
2014-2025
National Institutes of Health
2014-2024
Immungenetics (Germany)
2020
National Institute of Diabetes and Digestive and Kidney Diseases
2002-2019
University of Massachusetts Lowell
2012
Combat Capabilities Development Command Soldier Center
2012
National Cancer Institute
2004
Center for Cancer Research
2004
University of Virginia
2000
The invasion of erythrocytes by Plasmodium merozoites requires specific interactions between host receptors and parasite ligands. Parasite proteins that bind erythrocyte during are localized in apical organelles called micronemes rhoptries. regulated secretion microneme rhoptry to the merozoite surface enable receptor binding is a critical step process. sequence these events external signals trigger release not known. We have used time-lapse video microscopy study changes intracellular...
Intracellular neutral lipid storage droplets are essential organelles of eukaryotic cells, yet little is known about the proteins at their surfaces or amino acid sequences that target to these droplets. The mammalian Perilipin, ADRP, and TIP47 share extensive sequence similarity, suggesting a common function. However, while Perilipin ADRP localize exclusively droplets, an association with intracellular has been controversial. We now show GFP-tagged co-localizes isolated have also detected...
Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in the control of blood-stage malaria. Antibody-dependent functions may include neutralization parasite–host interactions, complement activation, and activation Fc receptor functions. A role antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells protection from malaria has not been established. Here we show that IgG isolated adults living a malaria-endemic region activated...
B cell responses to membrane-presented antigens appear be strongly favored over soluble in vivo suggesting that vaccines mimic may highly efficacious. We recently demonstrated human membrane-associated but not vitro depended on the expression and activity of plasma membrane mechanosensitive ion channel, Piezo1. Here, we provide evidence efficacy current papillomavirus virus-like particle (HPV VLP) due part their inherent ability Piezo1-dependent presentation cells. compared HPV-specific HPV...
Merozoites of the protozoan parasite responsible for most virulent form malaria, Plasmodium falciparum, invade erythrocytes. Invasion involves discharge rhoptries, specialized secretory organelles. Once intracellular, parasites induce increased nutrient uptake by generating new permeability pathways (NPP) including a surface anion channel (PSAC). RhopH1/Clag3, one member three-protein RhopH complex, is important PSAC/NPP activity. However, roles other members complex in establishment are...
Significance We have shown in this study that the malaria parasite can rapidly evolve to adapt for loss of an “essential” kinase, Pf CDPK1. CDPK1 could not be disrupted wild-type parasite. However, we were able disrupt transgenic parasites adapted reduced kinase activity mutant Strategic disruption highlights importance understanding compensatory mechanisms, especially targets belonging multigene families. Our unequivocally demonstrates is critical mosquito infections and its leads defective...
Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected the basis of their ability bind, gather, and present antigen T follicular helper (Tfh) cells. Here, we show that human GC have intrinsically higher-affinity thresholds for both cell receptor (BCR) signaling gathering as compared with naïve these functions mediated distinct cellular structures pathways ultimately lead affinity- Tfh...
The demand for a vaccine coronavirus disease 2019 (COVID-19) highlighted gaps in our understanding of the requirements B cell responses to antigens, particularly membrane-presented as occurs vivo. We found that human antigens required function Piezo1, plasma membrane mechanosensitive cation channel. Simply making contact with glass probe induced calcium (Ca2+) fluxes cells were blocked by Piezo1 inhibitor GsMTx4. When placed on surfaces, tension increased, which stimulated Ca2+ influx and...
Alpha(L)beta(2) integrin (LFA-1) has an important role in the formation of T cell and NK cytotoxic immunological synapses target killing. Binding LFA-1 to ICAM on cells promotes not only adhesion but also polarization cytolytic granules cells. In this study, we tested whether LFA-1-dependent responses are regulated by distribution mobility at surface We show that depolymerization F-actin NK-sensitive abrogated conjugate granule primary Degranulation, which is controlled LFA-1, was impaired....
A scaffolding protein clusters B cell receptors to enable the rapid, high-titer antibody responses of memory cells.
Drug development efforts have focused mostly on the asexual blood stages of malaria parasite Plasmodium falciparum Except for primaquine, which has its own limitations, there are no available drugs that target transmission to mosquitoes. Therefore, is a need validate new proteins can be targeted blocking transmission. P. calcium-dependent protein kinases (PfCDPKs) play critical roles at various life cycle and, importantly, absent in human host. These features mark them as attractive drug...
Abstract Activation of CD4+ T cells to proliferate drives toward aerobic glycolysis for energy production while using mitochondria primarily macromolecular synthesis. In addition, the activated increase reactive oxygen species, providing an important second messenger intracellular signaling pathways. To better understand critical changes in that accompany prolonged cell activation, we carried out extensive analysis mitochondrial remodeling a combination conventional strategies and novel...
Atypical memory B cell antigens must be membrane associated to force exclusion of inhibitory receptors from the immune synapse.
Artemisinin and its semisynthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into later reactivate a dormant persister state. Here, we provide evidence the mitochondria of dihydroartemisinin (DHA)-exposed persisters dramatically altered enlarged relative to young, actively replicating ring forms. Restructured mitochondrial-nuclear associations an...
Abstract Recent work by our laboratory and others indicates that co-display of multiple antigens on protein-based nanoparticles may be key to induce cross-reactive antibodies provide broad protection against disease. To reach the ultimate goal a universal vaccine for seasonal influenza, mosaic influenza nanoparticle (FluMos-v1) was developed clinical trial (NCT04896086). FluMos-v1 is unique in it designed four recently circulating haemagglutinin (HA) strains; however, current analysis...
B-cell activation is initiated by the binding of antigen to receptor (BCR). Here we used dSTORM superresolution imaging characterize nanoscale spatial organization immunoglobulin M (IgM) and IgG BCRs on surfaces resting antigen--activated human peripheral blood B-cells. We provide insights into both fundamental process antigen-driven BCR clustering differences in IgM that may contribute characteristic responses naive memory B-cells antigen. evidence although reside highly heterogeneous...
Abstract Apart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show members of sand fly yellow salivary proteins induce in vitro chemotaxis mouse, canine and human transwell migration EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment vivo using flow cytometry two-photon intravital microscopy Lysozyme-M-eGFP transgenic...
Chloroquine resistance in Plasmodium falciparum malaria resultsfrom mutations PfCRT, a member of unique family transporters presentin apicomplexan parasites and Dictyostelium discoideum. Mechanismsthat have been proposed to explain chloroquine are difficult toevaluate within parasites. Here we report on the targeted expressionof wild-type mutant forms PfCRT acidic vesicles D.discoideum. We show that has minimal effect theaccumulation by D. discoideum, whereas PfCRTcarrying key charge-loss...
Imaging analyses and computer simulations suggest that a GPCR its G protein associate only in the presence of ligand.
Abstract B cell activation is regulated through the interplay of BCR with inhibitory coreceptor FcγRIIB and activating CD19. Recent studies suggest that Ag-driven microclusters are efficiently converted to a signaling active state on colocalization CD19 microclusters. Using total internal reflection fluorescence microscopy–based, high-resolution, high-speed live-cell molecule imaging approaches, we show when co-ligated BCR, can inhibit by blocking within immunological synapse. Remarkably,...
Migratory cells, like mammalian leukocytes and Dictyostelium, utilize G protein coupled receptor (GPCR) signaling to regulate MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase, actin polymerization, which collectively direct chemotaxis. Upon ligand binding, GPCRs are phosphorylated at cytoplasmic residues, uncoupling pathways, but activating others. Still, connections between GPCR phosphorylation chemotaxis unclear. In developing secreted cAMP serves as a chemoattractant, with extracellular...