Biology subjects

Van der Veken, P.

Publications and source records attributed to Van der Veken, P..

3 recordsLinked to original sources

bioRxiv2026

Chemical tools to Detect and Inhibit IgA1 Proteases in Haemophilus influenzae

Non-encapsulated ("non-typeable") Haemophilus influenzae is a major cause of mucosal infections such as otitis media, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. Rising antibiotic resistance has increased interest in anti-virulence strategies that reduce pathogenicity without exerting selective pressure for resistance. A key virulence factor of H. influenzae is immunoglobulin A1 protease (IgA1P), a secreted serine protease that promotes colonization by cleaving human IgA1 at the hinge region and enabling immune evasion. Despite its therapeutic promise, progress has been limited by the lack of chemical tools to probe IgA1P activity in its native biological environment. Here, we report the first activity-based probes that enable direct detection of active IgA1Ps in complex samples and H. influenzae clinical isolates. Competitive activity-based screening using these probes identified novel IgA1P inhibitors, and structure-activity relationship guided optimization yielded a potent lead IgA1P inhibitor. This inhibitor preserves IgA1 at the bacterial surface, demonstrating effective inhibition of IgA1P activity in its native context and chemical disruption of an IgA1P-dependent immune-evasion mechanism. Together, these chemical tools establish a versatile platform for elucidating IgA1Ps role in H. influenzae colonization and virulence, and for validating IgA1Ps as diagnostic markers and antivirulence targets.

microbiology↗

bioRxiv2021

Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration

Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novel in vivo zebrafish and in vitro 3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/429622v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@d6d9e5org.highwire.dtl.DTLVardef@17b6790org.highwire.dtl.DTLVardef@cc581eorg.highwire.dtl.DTLVardef@1ad2129_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

Neuronal networks are surrounded by the extracellular matrix (ECM), which functions both as a scaffold and as a regulator of neuronal function. The ECM is in turn dynamically altered through the action of serine proteases, which break down its constituents. This pathway has been implicated in the regulation of synaptic plasticity and of intrinsic excitability. Here, we determined the effects of acutely inhibiting two important regulators of the ECM, Urokinase Plasminogen Activator and Neuropsin, selectively and potently with the inhibitor UAMC-01162. Spontaneous electrophysiological activity was recorded from in vitro primary rat cortical cultures using microelectrode arrays. While inhibition at a low dosage had no significant effect, at elevated concentrations network bursting dynamics and functional connectivity were drastically altered. These results indicate that the serine protease inhibition affects neuronal and synaptic properties, likely through their actions on the ECM. We propose that in the acute phase, a transient increase of excitatory synaptic efficacy is compensated for by a downregulation of single-cell excitability.

neuroscience↗