Helen Lenthall
A5076152705- SARS-CoV-2 and COVID-19 Research
- Immunodeficiency and Autoimmune Disorders
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Viral gastroenteritis research and epidemiology
- Immune Cell Function and Interaction
- Viral Infections and Immunology Research
- SARS-CoV-2 detection and testing
- CAR-T cell therapy research
- Chronic Lymphocytic Leukemia Research
- NF-κB Signaling Pathways
- Blood disorders and treatments
- CRISPR and Genetic Engineering
- vaccines and immunoinformatics approaches
- Cell Adhesion Molecules Research
- Whipple's Disease and Interleukins
- Bacteriophages and microbial interactions
- Cytokine Signaling Pathways and Interactions
- Animal Virus Infections Studies
- Pancreatic function and diabetes
- PI3K/AKT/mTOR signaling in cancer
- Biosensors and Analytical Detection
Garvan Institute of Medical Research
2018-2025
St Vincent's Clinic
2016-2025
UNSW Sydney
2016-2025
The Kinghorn Cancer Centre
2023
Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these defects, we studied large cohort patients with PIK3CD GOF and established novel mouse model using CRISPR/Cas9-mediated gene editing to introduce common pathogenic mutation Pik3cd. In both species, hyperactive...
Abstract Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing genomics surveillance, enabled all major SARS-CoV-2 circulating in Australia 2021. Our facilitated variant isolation, resolution fitness nasopharyngeal swabs ranking...
Abstract Emerging variants of concern (VOCs) are threatening to limit the effectiveness SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing strategies for their identification therefore urgently required. Here we demonstrate that can be isolated from peripheral blood mononuclear cells convalescent patients using receptor binding domains carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, epitope class 1,...
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse receptor-binding domains (RBDs) identify targeting of vulnerability. Antibodies broad reactivity clade B RBDs class 4 epitope, recurring IGHV/IGKV pairs, were readily elicited but...
Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) PIK3CD the PI3K p110δ catalytic subunit). While several studies have established how GOF leads immune dysregulation, less is known about LOF alter cellular function. By studying novel CRISPR/Cas9 mouse model and patients' cells, we...
The emergence of SARS-CoV-2 variants concern (VOCs) has greatly diminished the neutralizing activity previously FDA-approved monoclonal antibodies (mAbs), including that antibody cocktails and first-generation broadly such as S309 (Sotrovimab). In contrast, targeting cryptic conformational epitopes receptor binding domain (RBD) have demonstrated broad against emerging variants, but exert only moderate activity, which so far hindered clinical development. Here, we utilize in vitro display...
Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit phosphoinositide 3-kinase (PI3K), have highly penetrant secretion autoreactive IgM antibodies. In mice corresponding...
Antibodies against coronavirus spike protein potently protect infection and disease, but whether such protection can be extended to variant coronaviruses is unclear. This exemplified by a set of iconic well-characterized monoclonal antibodies developed after the 2003 SARS outbreak, including mAbs m396, CR3022, CR3014 80R, which neutralize SARS-CoV-1, not SARS-CoV-2. Here, we explore antibody engineering strategies change broaden their specificity, enabling nanomolar binding potent...
Abstract Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, Omicron (B.1.1.529) virus variant emerged, with significant genetic differences clinical effects from other concern (VOC). This a demonstrated higher number polymorphisms gene...
Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment many diseases. To monitor spatial temporal activity live setting, we generated Akt-FRET biosensor mouse that allows longitudinal assessment using intravital imaging conjunction with image stabilization optical window technology. We demonstrate sensitivity various cancer models verify its suitability to response drug targeting spheroid organotypic...
ABSTRACT Antibodies against coronavirus spike protein potently protect infection and disease, however it remains unclear if such protection can be extended to variant coronaviruses. This is exemplified by a set of iconic well-characterized monoclonal antibodies developed after the 2003 SARS outbreak including mAbs m396, CR3022, CR3014 80R, which neutralize SARS-CoV-1, but not SARS-CoV-2. Here we explore antibody maturation strategies change broaden their specificity, enabling potent binding...
SUMMARY Emerging variants of concern (VOCs) are threatening to limit the effectiveness SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing strategies for their identification therefore urgently required. Here we demonstrate that can be isolated from peripheral blood mononuclear cells (PBMCs) convalescent patients using receptor binding domains (RBDs) carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05,...
Abstract Activated PI3K Delta Syndrome (APDS) is a rare condition caused by heterozygous gain of function mutations in PIK3CD, which encodes the leukocyte-restricted p110δ catalytic subunit phosphoinositol 3-kinase (PI3K). activated downstream many T cell receptors and has been implicated control CD4+ helper differentiation, activation proliferation. APDS patients have increased activity that leads to several immune manifestations including lymphoproliferation, Th2-related pathologies...