Biology subjects

Al-Zubieri, H.

Publications and source records attributed to Al-Zubieri, H..

2 recordsLinked to original sources

bioRxiv2021

Dynamic evolution of bacterial ligand recognition by formyl peptide receptors

The detection of invasive pathogens is critical for host immune defense. Cell surface receptors play a key role in the recognition of diverse microbe-associated molecules, triggering leukocyte recruitment, phagocytosis, release of antimicrobial factors, and cytokine production. The intense selective forces acting on innate immune receptor genes has led to their rapid diversification across plant and animal species. However, the impacts of this genetic variation on immune functions are often unclear. Formyl peptide receptors (FPRs) are a family of animal G-protein coupled receptors which are activated in response to a variety of ligands including formylated bacterial peptides, microbial virulence factors, and host-derived peptides. Here we investigate patterns of gene loss, sequence diversity, and ligand recognition among primate and carnivore FPRs. We observe that FPR1, which plays a critical role in innate immune defense in humans, has been lost in New World primates. Patterns of amino acid variation in FPR1 and FPR2 suggest a history of repeated positive selection acting on extracellular domains involved in ligand binding. To assess the consequences of FPR variation on bacterial ligand recognition, we measured interactions between primate FPRs and the FPR agonist Staphylococcus aureus enterotoxin B, as well as S. aureus FLIPr-like which functions as an FPR inhibitor. We find that comparatively few sequence differences between great ape FPRs are sufficient to modulate recognition of S. aureus ligands, further demonstrating how genetic variation can act to tune FPR activation in response to diverse microbial binding partners. Together this study reveals how rapid evolution of host immune receptors shapes the detection of diverse microbial molecules.

evolutionary biology↗

bioRxiv2020

Diversification of CD1 molecules shapes lipid antigen selectivity

Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

evolutionary biology↗