A5084409415- Inflammasome and immune disorders
- Malaria Research and Control
- Mosquito-borne diseases and control
- Cell death mechanisms and regulation
- Phagocytosis and Immune Regulation
- Immune responses and vaccinations
- Immune Cell Function and Interaction
- Autoimmune and Inflammatory Disorders Research
- Invertebrate Immune Response Mechanisms
- Drug Transport and Resistance Mechanisms
- Parasites and Host Interactions
- Viral Infections and Vectors
- IL-33, ST2, and ILC Pathways
- Molecular Biology Techniques and Applications
- Cancer Research and Treatments
- Computational Drug Discovery Methods
- Atherosclerosis and Cardiovascular Diseases
- Microbial Metabolism and Applications
- Salmonella and Campylobacter epidemiology
- Toxoplasma gondii Research Studies
- Complement system in diseases
- Vector-borne infectious diseases
- Streptococcal Infections and Treatments
- Food Allergy and Anaphylaxis Research
- Bacterial biofilms and quorum sensing
Duke University
2023-2024
University of North Carolina at Chapel Hill
2023-2024
National Institutes of Health
2024
University of Washington
2014-2023
Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase granzyme proteases cleave linker regions of activate GSDMB, E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis gasdermin family. A gene duplication GSDMA common ancestor caecilian amphibians, reptiles, birds gave rise GSDMA–D...
18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites used and Plasmodium rRNA/rDNA nucleic acid tests (NATs) for time positivity. validated multiplex quantitative reverse transcription–polymerase chain reaction (qRT-PCR) rRNA, prospectively compared qRT-PCR three trials, modeled treatment effects different biomarker-defined parasite densities assess the impact on...
The invention of liver-humanized mouse models has made it possible to directly study the pre-erythrocytic stages Plasmodium falciparum. In contrast, current blood stage infection in vivo are extremely limited. Humanization stream is achievable by frequent injections human red cells (hRBCs) and currently only system with which malaria infections a small animal model. Infections have been primarily achieved direct injection P. falciparum-infected RBCs but as such, this modality does not model...
Plasmodium vivax is a malaria-causing pathogen that establishes dormant form in the liver (the hypnozoite), which can activate weeks, months, or years after primary infection to cause relapse, characterized by secondary blood-stage infection. These asymptomatic and undetectable latent infections present significant obstacle goal of global malaria eradication. We use human liver-chimeric mouse model (FRG huHep) study P. hypnozoite latency activation an vivo system. Functional hypnozoites...
Abstract Granulomas often form around pathogens that cause chronic infections. Here, we discover an innate granuloma model in mice with environmental bacterium called Chromobacterium violaceum . Granuloma formation not only successfully walls off, but also clears, the infection. The infected lesion can arise from a single replicates despite presence of neutrophil swarm. Bacterial replication ceases when macrophages organize infection and granuloma. This response is accomplished independently...
Inflammasomes are sensors that detect cytosolic microbial molecules or cellular damage, and in response they initiate a form of lytic regulated cell death called pyroptosis. signal via homotypic protein-protein interactions where CARD PYD domains crucial for recruiting downstream partners. Here, we screened these from NLR family proteins, found the domain NLRP6 NLRP12 could activate caspase-1 to induce cleavage IL-1β GSDMD. Inflammasome reconstitution verified full length formed inflammasomes
A malaria vaccine that prevents infection will be an important new tool in continued efforts of elimination, and such vaccines are under intense development for the major human parasite Plasmodium falciparum (Pf). Antibodies elicited by can block initial phases when sporozoites deposited into skin mosquito bite then target liver further development. However, there currently no standardized vivo preclinical models measure inhibitory activity antibody specificities against Pf sporozoite via...
Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase granzyme proteases cleave linker regions of activate GSDMB, E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis gasdermin family. A gene duplication GSDMA common ancestor caecilian amphibians, reptiles, birds gave rise GSDMA–D...
Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates also important surveillance control elimination efforts. A variety reported NAT assays have been described, yet no formal external quality assurance (EQA) program provides validation the use. Here, we report results EQA exercise assays. Among five centers conducting controlled human infection trials, all achieved 100% specificity demonstrated...
Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand repertoire prophylactic drugs against malaria. Here, we demonstrate both Bcl-2 inhibitors P53 agonists dramatically reduce LS burden in mouse model vitro vivo by altering activity key hepatocyte factors on...
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These include prophylactic drugs that eliminate liver stages consequently prevent clinical disease, decrease transmission, reduce propensity for resistance development. Currently, identification of these relies on in vitro P. falciparum stage assays or vivo causal prophylaxis using rodent malaria parasites; there is no method directly test activity candidate antimalarials against human...
Malaria infection caused by Plasmodium parasites continues to cause enormous morbidity and mortality in areas where it is endemic, there no licensed vaccine capable of inducing sterile protection. Hyperimmunization with attenuated whole sporozoites can induce protective immune responses targeting preerythrocytic antigens. Most animal models hyperimmunization rely on dissected from mosquito salivary glands injected without further purification. In BALB/c mice, repeated small doses P. yoelii...
Latent liver stages termed hypnozoites cause relapsing Plasmodium vivax malaria infection and represent a major obstacle in the goal of elimination. Hypnozoites are clinically undetectable, presently, there no biomarkers this persistent parasite reservoir human liver. Here, we have identified proteins associated with extracellular vesicles (EVs) secreted from vivo infections exclusively containing hypnozoites. We used P. vivax-infected liver-chimeric (huHEP) FRG KO mice treated...
A patient in Washington State harbored a fish tapeworm most likely acquired from eating raw salmon. Diphyllobothrium nihonkaiense was identified by cox1 sequence analysis. Although this is the first documented human D. infection United States, parasite may have been present earlier but misidentified as latum.
Plasmodium gametocytes are sexual stages transmitted to female Anopheles mosquitoes. While parasites can be differentiated microscopically on Giemsa-stained blood smears, molecular methods increasingly used because of their increased sensitivity. Molecular detection requires that discriminate between asexual and stage parasites. Commonly tested gametocyte-specific mRNAs pfs25 pfs230 detected by reverse transcription polymerase chain reaction (RT-PCR). However, these unspliced mRNA targets...
Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. When a fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility compared pyroptosis in defense an bacterial We previously engineered Salmonella enterica serovar Typhimurium persistently express flagellin, thereby activate NLRC4 during systemic infection mice. The resulting clears this flagellin-engineered strain. now show caspase-1 or...
Abstract Inflammasomes are sensors that detect cytosolic microbial molecules or cellular damage, and in response they initiate a form of lytic regulated cell death called pyroptosis. signal via homotypic protein-protein interactions where CARD PYD domains crucial for recruiting downstream partners. Here, we screened these from NLR family proteins, found the domain NLRP6 NLRP12 could activate caspase-1 to induce cleavage IL-1β GSDMD. Inflammasome reconstitution verified full length formed...
Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase granzyme proteases cleave linker regions of activate GSDMB, E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis gasdermin family. A gene duplication GSDMA common ancestor caecilian amphibians, reptiles birds gave rise GSDMA-D...
Whole Plasmodium sporozoites serve as both experimental tools and potentially deployable vaccines in the fight against malaria infection. Live infect hepatocytes induce a diverse repertoire of CD8(+) T cell responses, some which are capable killing Plasmodium-infected hepatocytes. Previous studies yoelii-immunized BALB/c mice showed that responses expanded with repeated parasite exposure, whereas other did not.Here, similar outcomes were observed using known berghei epitopes C57BL/6 mice....
Granulomas often form around pathogens that cause chronic infections. Here, we discover a novel granuloma model in mice.
Development of a subunit vaccine targeting liver-stage Plasmodium parasites requires the identification antigens capable inducing protective T cell responses. However, traditional methods antigen are incapable evaluating responses against large numbers proteins expressed by these parasites. This bottleneck has limited development vaccines and other complex intracellular pathogens. To address this bottleneck, we developing synthetic minigene technology for multi-antigen DNA vaccines. In an...
Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. When a fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility compared pyroptosis in defense an bacterial We previously engineered Salmonella enterica serovar Typhimurium persistently express flagellin, thereby activate NLRC4 during systemic infection mice. The resulting clears this flagellin-engineered strain. now show caspase-1 or...