A5022991460- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Animal Virus Infections Studies
- Long-Term Effects of COVID-19
- Escherichia coli research studies
- Viral gastroenteritis research and epidemiology
- Salmonella and Campylobacter epidemiology
- Immunotherapy and Immune Responses
- vaccines and immunoinformatics approaches
- SARS-CoV-2 detection and testing
- interferon and immune responses
- Brucella: diagnosis, epidemiology, treatment
- Virus-based gene therapy research
- Vibrio bacteria research studies
- Bacteriophages and microbial interactions
- Burkholderia infections and melioidosis
- Mechanical Circulatory Support Devices
- Phagocytosis and Immune Regulation
- Transgenic Plants and Applications
- Viral Infectious Diseases and Gene Expression in Insects
- COVID-19 Impact on Reproduction
- Transplantation: Methods and Outcomes
- Monoclonal and Polyclonal Antibodies Research
- Vaccine Coverage and Hesitancy
- Virology and Viral Diseases
Leiden University Medical Center
2020-2025
National Institutes of Health
2013-2023
National Institute of Allergy and Infectious Diseases
2013-2023
Leiden University
2021
Loyola University Medical Center
2021
Purdue University West Lafayette
2010-2013
Development of effective preventative interventions against SARS-CoV-2, the etiologic agent COVID-19 is urgently needed. The viral surface spike (S) protein SARS-CoV-2 a key target for prophylactic measures as it critical replication cycle and primary neutralizing antibodies. We evaluated design elements previously shown other coronavirus S protein-based vaccines to be successful, e.g., prefusion-stabilizing substitutions heterologous signal peptides, selection S-based vaccine candidate. In...
Abstract The rapid development of a SARS-CoV-2 vaccine is global priority. Here, we develop two capsid-like particle (CLP)-based vaccines displaying the receptor-binding domain (RBD) spike protein. RBD antigens are displayed on AP205 CLPs through split-protein Tag/Catcher, ensuring unidirectional and high-density display RBD. Both soluble recombinant bind ACE2 receptor with nanomolar affinity. Mice vaccinated or CLP-displayed RBD, formulated in Squalene-Water-Emulsion. RBD-CLP induce higher...
The intracellular pathogenic bacterium Brucella generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of host cell secretory pathway. rBCV biogenesis requires expression Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that modulate membrane trafficking along endocytic and pathways. To date, only few T4SS substrates have been identified, whose molecular functions remain unknown. Here, we used an in silico screen...
Safe and effective coronavirus disease–19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve magnitude durability of immunity protective efficacy. We assessed one- two-dose Ad26.COV2.S candidate in adult aged nonhuman primates (NHPs). A regimen induced higher peak binding neutralizing antibody responses compared with a single dose. In one-dose regimens, were stable for at least...
Understanding the mechanisms and impact of booster vaccinations are essential in design delivery vaccination programs. Here we show that a three dose regimen synthetic peptide vaccine elicits an accruing CD8+ T cell response against one SARS-CoV-2 Spike epitope. We see protection lethal infection K18-hACE2 transgenic mouse model absence neutralizing antibodies, but two approaches insufficient to confer protection. The third single epitope results superior generation effector-memory cells...
The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these activities during SARS-CoV-2 infection, we introduced mutations that disrupt binding to ubiquitin or ISG15. We identified several strongly reduced DUB activity PLpro, without affecting In contrast, abrogated also hampered processing when into virus...
Previously we have shown that a single dose of recombinant adenovirus serotype 26 (Ad26) vaccine expressing prefusion stabilized SARS-CoV-2 spike antigen (Ad26.COV2.S) is immunogenic and provides protection in Syrian hamster non-human primate infection models. Here, investigated the immunogenicity, protective efficacy, potential for vaccine-associated enhanced respiratory disease (VAERD) mediated by Ad26.COV2.S moderate challenge model, using currently most prevalent G614 variant. Vaccine...
Salmonella enterica serovar Typhimurium invade non-phagocytic cells by injecting bacterial effector proteins to exploit the host actin cytoskeleton network. SipC is such a known nucleate actin, bundle F-actin, and translocate type III effectors. The molecular mechanism of how bundles F-actin domains responsible for these activities are not well characterized. We successfully separated through series genetic deletion/insertions in SipC. found that C terminus (amino acids 200–409) bundled...
Vaccines pave the way out of SARS-CoV-2 pandemic. Besides mRNA and adenoviral vector vaccines, effective protein-based vaccines are needed for immunization against current emerging variants. We have developed a virus-like particle (VLP)-based vaccine using baculovirus-insect cell expression system, robust production platform known its scalability, low cost, safety. Baculoviruses were constructed encoding spike proteins: full-length S, stabilized secreted or S1 domain. Since subunit S only...
Mitochondrial antiviral signaling protein (MAVS) is a crucial adaptor in the sensing of positive-sense RNA viruses and subsequent induction innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (Mpro), which responsible for proteolytic cleavage largest part viral replicase polyproteins pp1a pp1ab. Additionally, it can cleave cellular substrates, such as factors, dampen Here, we show that MAVS cleaved cells...
Abstract The spike protein (S) of SARS-CoV-2 induces neutralizing antibodies and is the key component current COVID-19 vaccines. most efficacious vaccines are genetically-encoded spikes with a double proline substitution in hinge region to stabilize S prefusion conformation (S-2P). A subunit vaccine can be valuable addition mRNA viral vector-based but requires high stability spike. In addition, further stabilization might improve immunogenicity. To test this, five proteins were designed...
In order to detect and respond invading pathogens, mammals have evolved a battery of pattern recognition receptors. Among these, RIG-I-like receptors (RLR) are cytosolic RNA sensors that play an essential role in the innate immune response against viruses, including coronaviruses. return, coronaviruses acquired diverse strategies impair RLR-mediated responses enable productive infection. Viral evasion mechanisms been well studied for highly pathogenic human (HCoVs), often, these activities...
A Yersinia pestis-human protein interaction network is reported here to improve our understanding of its pathogenesis. Up 204 interactions between 66 Y. pestis bait proteins and 109 human were identified by yeast two-hybrid assay then combined with 23 previously published construct a protein-protein network. Topological analysis the revealed that targeted significantly enriched in are central Analysis this showed signaling pathways important for host immune responses preferentially pestis,...
Abstract Development of effective preventative interventions against SARS-CoV-2, the etiologic agent COVID-19 is urgently needed. The viral surface spike (S) protein SARS-CoV-2 a key target for prophylactic measures as it critical replication cycle and primary neutralizing antibodies. We evaluated design elements previously shown other coronavirus S protein-based vaccines to be successful, e.g. prefusion-stabilizing substitutions heterologous signal peptides, selection S-based vaccine...
Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of contribution each components to viral clearance remains unclear. Here, we studied timing in relation 122 immune parameters 102 hospitalised patients with moderate severe COVID-19 a longitudinal design. Delayed was associated more disease higher levels SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers...
The delivery of effector proteins by Salmonella across the host cell membrane requires a subset effectors secreted type III secretion system (TTSS) known as translocators. SipC and SipB are translocator that inserted into membranes presumably form channel translocates cell. molecular events how these translocators insert remain unknown. We have previously shown C-terminal amino acid region (321-409) is required for translocation cells. In this study, we demonstrate ability to SipC-SipB...
Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as deubiquitinating enzyme (DUB). In this study, using Middle East respiratory syndrome virus (MERS-CoV) PLpro modified in which the DUB selectively inactivated, we show an important MERS-CoV interferon antagonist virulence factor. Although DUB-negative rMERS-CoVMA replicates robustly lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause...
ObjectivesThe aim of this study was to assess safety and immunogenicity a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine.MethodsCOVID-19 naive adults aged 18-30 years were recruited from previous on primary vaccination regimens that compared 20 μg ID vaccinations 100 IM as series. Participants previously immunized randomly assigned (1:1) receive dose (20 μg) or standard-of-care intramuscular (IM) (50 vaccine, six months after completing their...
Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which required mount an adequate serologic response. Therefore, we aim investigate the antibody response SARS-CoV-2 in liver transplant (LT) recipients after COVID-19.Prospective multicentre case-control study, analysing antibodies against nucleocapsid protein, spike (S) protein of and their neutralising activity LT confirmed infection (COVID-19-LT) compared immunocompetent patients (COVID-19-immunocompetent)...
Summary Actin nucleation is the rate‐limiting step in actin assembly and regulated by actin‐binding proteins signal transduction molecules. Salmonella enterica serovar Typhimurium exploits dynamics reorganizing host cytoskeleton to facilitate its own uptake. SipC a protein that nucleates filament formation vitro . The molecular mechanism which not known. We show here 199–409 forms multimers promote nucleation. found wild‐type dimers while #1, mutant, less efficient dimer multimer formation....
Article23 August 2021Open Access Source DataTransparent process A Brucella effector modulates the Arf6-Rab8a GTPase cascade to promote intravacuolar replication Elizabeth Borghesan Paul G. Allen School for Global Health, Washington State University, Pullman, WA, USA These authors contributed equally this work. Search more papers by author Erin P Smith orcid.org/0000-0003-4822-476X Sebenzile Myeni Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Institutes...
SARS-CoV-2 is the third zoonotic coronavirus to cause a major outbreak in humans recent years, and many more SARS-like coronaviruses with pandemic potential are circulating several animal species. Vaccines inducing T cell immunity against broadly conserved viral antigens may protect hospitalization death caused by outbreaks of such viruses. We report design preclinical testing 2 cell-based pan-sarbecovirus vaccines, based on regions within proteins sarbecovirus isolates human other carrier...
Abstract Safe and effective coronavirus disease (COVID)-19 vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve magnitude durability of immunity protective efficacy. We assessed one- two-dose Ad26.COV2.S candidate in adult aged non-human primates (NHP). A regimen induced higher peak binding neutralizing antibody responses compared a single dose. In one-dose were stable for at least 14 weeks,...
Brucella abortus, the intracellular causative agent of brucellosis, relies on type IV secretion system (T4SS) effector-mediated modulation host cell functions to establish a replicative niche, Brucella-containing vacuole (BCV). exploits host's endocytic, secretory, and autophagic pathways modulate nature function its from an endocytic BCV (eBCV) endoplasmic reticulum (ER)-derived (rBCV) egress (aBCV). A role for ER-associated degradation pathway (ERAD) in B. abortus cycle was recently...