Biology subjects

Kilpatrick, L. E.

Publications and source records attributed to Kilpatrick, L. E..

4 recordsLinked to original sources

bioRxiv2026

Homozygosity for rare or common hypomorphic IL23R variants confers a predisposition to tuberculosis in humans

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-{gamma} production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12R{beta}1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-{gamma} production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria. One sentence summaryHomozygous hypomorphic IL23R variants impair IL-23-dependent IFN-{gamma} production and underlie tuberculosis.

genetics↗

bioRxiv2025

Co-targeting MERTK and EGFR with a Bispecific Antibody Overcomes Drug Resistance Across Mutations in Exons 19, 20, and 21

Resistance of lung cancer to EGFR-specific tyrosine kinase inhibitors (TKIs), such as osimertinib, often arises from secondary mutations or the activation of bypass signaling pathways. We noted elevated levels of GAS6 and its receptor, MERTK, in patients acquiring resistance to osimertinib, hence hypothesized that the GAS6-MERTK axis can serve as a therapeutic target. GAS6 promoted cell survival and an anti-GAS6 antibody we generated delayed tumor relapses in a xenograft model. Likewise, MERTK ablation sensitized lung cancer cells to osimertinib due to a newly described EGFR-to-MERTK crosstalk. Hence, we developed Bis3, a bispecific antibody targeting both MERTK and EGFR and promoting their degradation. Bis3 plus TKIs cooperatively inhibited the growth of TKI-resistant lung cancer spheroids and markedly delayed relapses of patient-derived xenografts harboring the clinically challenging exon-20 mutations. These findings establish the GAS6-MERTK axis as a driver of drug resistance and provide a rationale for clinical development of Bis3.

cancer biology↗

bioRxiv2021

CXCL17 is an endogenous inhibitor of CXCR4 via a novel mechanism of action

CXCL17 is the most recently described chemokine. It is principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, as well as being highly upregulated during viral infections of the lung. However, the exact role of CXCL17 in health and disease is largely unknown, mainly due to a lack of known molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET) based assays, here we demonstrate that CXCL17 inhibits CXCR4-mediated signalling and ligand binding. Moreover, CXCL17 interacts with neuropillin-1, a VEGFR2 co-receptor. Additionally, we find CXCL17 only inhibits CXCR4 ligand binding in intact cells and demonstrate that this effect is mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. This indicates that CXCL17 inhibits CXCR4 by a unique mechanism of action that potentially requires the presence of a glycosaminoglycan containing accessory protein. Altogether, our results reveal that CXCL17 is an endogenous inhibitor of CXCR4 and represents an important discovery in our understanding of the (patho) physiological functions of CXCL17 and regulation of CXCR4 signalling.

pharmacology and toxicology↗

bioRxiv2019

Characterization of a Human Liver NIST Reference Material fit for Proteomics Applications

The National Institute of Standards and Technology (NIST) is creating new, economical, qualitative reference materials and data for proteomics comparisons, benchmarking and harmonization. Here we describe a large dataset from shotgun proteomic analysis of RM 8461 Human Liver for Proteomics, a reference material being developed. Consensus identifications using multiple search engines and sample preparations demonstrate a homogeneous and fit-for-purpose material that can be incorporated into automated or manual sample preparation workflows, with the resulting data used to directly assess complete sample-to-data workflows and provide harmonization and benchmarking between laboratories and techniques. Data are available via PRIDE with identifier PXD013608.

biochemistry↗