Biology subjects

Wilson, D. B.

Publications and source records attributed to Wilson, D. B..

4 recordsLinked to original sources

bioRxiv2023

The molecular reach of antibodies determines their SARS-CoV-2 neutralisation potency

Key functions of antibodies, such as viral neutralisation, depend on bivalent binding but the factors that influence it remain poorly characterised. Here, we develop and employ a new bivalent model to mechanistically analyse binding between >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. Our method reproduces the monovalent on/off-rates and enables measurements of the bivalent on-rate and the molecular reach: the maximum antigen separation that supports bivalent binding. We find large variations in these parameters across antibodies, including variations in reach (22-46 nm) that exceed the physical antibody size ([~]15 nm) due to the antigen size. The bivalent model integrates all parameters, including reach and antigen density, to predict an emergent binding potency for each antibody that matches their neutralisation potency. Indeed, antibodies with similar monovalent affinities to the same RBD-epitope but with different reaches display differences in emergent bivalent binding that match differences in their neutralisation potency. Together, our work highlights that antibodies within an isotype class binding the same antigen can display differences in molecular reach that can substantially modulate their emergent binding and functional properties. Lay SummaryAntibodies are soluble proteins that can neutralise pathogens by sticking to them. They contain two identical arms that allow them to simultaneously bind two identical antigen molecules on pathogen surfaces. Although we know that bivalent binding is important for neutralisation, we dont know how different antibodies achieve it. We developed a new model to analyse the mechanism of bivalent binding and used it to study over 45 antibodies from COVID-19 patients that bind the RBD antigen of SARS-CoV-2. Unexpectedly, we found that the molecular reach of an antibody, which is the maximum antigen separation that supports bivalent binding, varied widely between antibodies and exceeded their physical size. We show how antibody binding emerges from the interplay of multiple factors, including reach, and that this emergent binding predicts their neutralisation function. The ability to analyse and predict bivalent binding should improve our understanding and exploitation of antibodies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/556503v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1674563org.highwire.dtl.DTLVardef@fc7feborg.highwire.dtl.DTLVardef@1325847org.highwire.dtl.DTLVardef@41ad51_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Genetic diversity in facultatively sexual populations and its implications for the origins of self-incompatibility in algae and fungi

The evolutionary mechanism that drove the establishment of self-incompatibility in early sexual eukaryotes is still a debated topic. While a number of competing hypotheses have been proposed, many have not received detailed theoretical attention. In particular, the hypothesis that self-incompatibility increases the benefits of genetic recombination in sexual haploids has been comparatively understudied. In this paper we address this topic by mathematically deriving how the probability of mating with a genetically distinct individual changes as a function of the presence or absence of self-incompatible mating type classes. We find that although populations with mating types successfully engage in sexual reproduction less frequently than their self-compatible competitors, they can nevertheless engage in useful sex with genetically distinct partners more frequently. This conclusion holds when the number of sexual reproductive events per generation is low (i.e. in small populations with low rates of facultative sexual reproduction). Finally we demonstrate the potential for frequency-dependent selection in competitive dynamics between self-compatible and self-incompatible types. These analytic results provide a baseline for studying the sex advantage enhancer model for the evolutionary origin of mating types within each specific hypothesis for the evolution of recombination. PACS87.23.-n Ecology and evolution, 87.23.Kg Dynamics of evolution, 02.50.Ey Stochastic processes 2000 MSC37N25: Dynamical systems in biology, 60J70: Applications of diffusion theory (population genetics, absorption problems, etc.)

evolutionary biology↗

bioRxiv2020

The discriminatory power of the T cell receptor

T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as KD ~1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.

immunology↗

bioRxiv2020

T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands

T cells use their T cell receptors (TCRs) to discriminate between peptide MHC (pMHC) ligands that bind with different affinities but precisely how different remains controversial. This is partly because the affinities of physiologically relevant interactions are often too weak to measure. Here, we introduce a surface plasmon resonance protocol to measure ultra-low TCR/pMHC affinities (KD ~ 1000 M). Using naive, memory, and blasted human CD8+ T cells we find that their discrimination power is unexpectedly low, in that they require a large >100-fold decrease in affinity to abolish responses. Interestingly, the discrimination power reduces further when antigen is presented in isolation on artificial surfaces but can be partially restored by adding ligands to CD2 or LFA-1. We were able to fit the kinetic proof-reading model to our data, yielding the first estimates for both the time delay (2.8 s) and number of biochemical steps (2.67). The fractional number of steps suggest that one of the proof-reading steps is not easily reversible.

immunology↗