Biology subjects

Barber, M. F.

Publications and source records attributed to Barber, M. F..

7 recordsLinked to original sources

bioRxiv2026

Evolution of the proinflammatory receptor TREM-1 in mammals reveals signatures of pathogen-driven conflict

Animal immune cells express a range of surface receptors that promote the detection of diverse host and pathogen-derived molecules. The triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell surface receptors involved in the modulation of immune signaling cascades. Mammalian TREM-1 has emerged as a critical mediator of antibacterial immune defense and inflammatory disease, yet much remains unknown regarding its evolution and relevant molecular interactions. Here we applied a comparative phylogenetic approach to investigate patterns of divergence and natural selection among mammalian TREM-1 orthologs. We identify evidence of repeated positive selection acting within the extracellular ligand binding domain of TREM-1 among primates, rodents, and particularly bats. Structural simulations further suggest that genetic variation in TREM-1 impacts recognition of putative host and microbial ligands, with implications for downstream signaling functions. Together our findings identify patterns of rapid divergence in mammalian TREM-1, suggesting a history of evolutionary conflict in response to pathogen antagonism.

evolutionary biology↗

bioRxiv2026

De novo origin and evolution of an antimicrobial protein function

Antimicrobial peptides (AMPs) constitute key components of innate immunity across the tree of life. Canonical AMPs are typically translated as small proteins and secreted from host cells to act against microbes. However, cryptic AMP-like domains are also embedded within diverse proteins not classically associated with antimicrobial function. How such embedded AMPs first emerge and diversify remains unclear. Here we retrace the origin and evolution of the abundant mammalian protein lactoferrin and its embedded AMP, lactoferricin. By resurrecting extinct lactoferrin ancestors dating back to the earliest mammals, we identify a gradual enrichment of cationic and hydrophobic amino acids in the lactoferricin domain over time. These changes enabled ancient lactoferricin to first rupture bacterial membranes, an activity that was later enhanced in extant mammals conferring potent bactericidal activity against diverse bacteria. In addition, we find that recent natural selection within the lactoferricin domain has continued to modulate antimicrobial activity on recent evolutionary timescales. In particular, we pinpoint a single rapidly evolving site in lactoferricin among great apes that significantly enhances antimicrobial potency against major pathogenic bacteria. Together our study illustrates how novel immune protein functions can arise, evolve, and diversify to strengthen host defense against diverse microbial pathogens.

evolutionary biology↗

bioRxiv2026

Non-canonical stringent response signaling mediates antimicrobial fatty acid sensitivity in Staphylococcus aureus

Staphylococcus aureus is a leading cause of skin and soft tissue infections, yet colonization of healthy skin is limited by multiple defenses, including antimicrobial fatty acids (AFAs) produced by host cells and the resident microbiota. The mechanisms by which S. aureus overcomes these lipid-based defenses remain incompletely understood. Here, we show that mutations truncating the essential stringent response regulator Rel confer broad tolerance to both host-and microbially-derived AFAs in diverse S. aureus strains. Unlike classical stringent response activation, C-terminal Rel truncations do not induce typical (p)ppGpp-dependent transcriptional changes but instead enhance activity of the alternative sigma factor SigB and the staphylococcal accessory regulator SarA. This SigB-SarA regulatory cascade promotes transcriptional remodeling, including upregulation of pyrimidine biosynthesis genes, and coincides with alterations to cell envelope structure. Moreover, in the absence of SigB or SarA, tolerance can be restored through mutations in the serine/threonine phosphatase Stp1, highlighting additional pathways that modulate cell envelope-mediated resistance to AFAs. These findings identify a previously unrecognized consequence of Rel mutation in S. aureus; whereby small truncations may promote survival in AFA-rich host environments facilitating skin colonization and infection. ImportanceStaphylococcus aureus is a major cause of skin and soft tissue infections, and persistent skin colonization is a significant risk factor for infection. Antimicrobial fatty acids (AFAs), produced by microbes and host cells on human skin, normally limit S. aureus colonization. The mechanisms that allow this pathogen to overcome these lipid defenses are incompletely understood. We show that mutations truncating the essential stringent response regulator Rel enable S. aureus to tolerate both host-and microbially derived AFAs. These Rel variants, which have been identified in clinical isolates, alter cell envelope properties through the transcriptional regulator SarA rather than activating a classical stringent response. Our findings reveal a previously unrecognized adaptation that may facilitate S. aureus survival on the skin and promote infection.

microbiology↗

bioRxiv2024

Adaptation to skin mycobiota promotes antibiotic tolerance in Staphylococcus aureus

The microbiota can promote host health by inhibiting pathogen colonization, yet how host-resident fungi, or the mycobiota, contribute to this process remains unclear. The human skin mycobiota is uniquely stable compared to other body sites and dominated by yeasts of the genus Malassezia. We observe that colonization of human skin by Malassezia sympodialis significantly reduces subsequent colonization by the prominent bacterial pathogen Staphylococcus aureus. M. sympodialis secreted products possess potent bactericidal activity against S. aureus and are sufficient to impair S. aureus skin colonization. This bactericidal activity requires an acidic environment and is exacerbated by free fatty acids, demonstrating a unique synergy with host-derived epidermal defenses. Leveraging experimental evolution to pinpoint mechanisms of S. aureus adaptation in response to the skin mycobiota, we identified multiple mutations in the stringent response regulator Rel that promote survival against M. sympodialis. Similar Rel alleles have been reported in S. aureus clinical isolates, and natural Rel variants are sufficient for tolerance to M. sympodialis antagonism. Partial stringent response activation underlies tolerance to clinical antibiotics, with both laboratory-evolved and natural Rel variants conferring multidrug tolerance. These findings demonstrate the ability of the mycobiota to mediate pathogen colonization resistance, identify new mechanisms of bacterial adaptation in response to fungal antagonism, and reveal the potential for microbiota-driven evolution to shape pathogen antibiotic susceptibility. Highlights- M. sympodialis reduces colonization of human skin by S. aureus - Bactericidal activity of M. sympodialis is exacerbated by features of the skin niche - S. aureus Rel variants are sufficient for tolerance to Malassezia antagonism - Evolved tolerance to yeast antagonism coincides with S. aureus multidrug tolerance

microbiology↗

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↗

bioRxiv2019

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri. By swapping this membrane-binding motif between primate GBP orthologs, we find that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World monkeys. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.

microbiology↗

bioRxiv2018

Molecular basis for the evolution of species-specific hemoglobin capture by pathogenic Staphylococcus

Metals are a limiting resource for pathogenic bacteria and must be scavenged from host proteins. Hemoglobin provides the most abundant source of iron in the human body and is required by several pathogens to cause invasive disease. However, the consequences of hemoglobin evolution for bacterial nutrient acquisition remain unclear. Here we show that the - and {beta}-globin genes exhibit strikingly parallel signatures of adaptive evolution across simian primates. Rapidly evolving sites in hemoglobin correspond to binding interfaces of IsdB, a bacterial hemoglobin receptor encoded by pathogenic Staphylococcus aureus. Using an evolution-guided experimental approach, we demonstrate that divergence between primates and staphylococcal isolates governs hemoglobin recognition and bacterial growth. Reintroducing putative adaptive mutations in - or {beta}-globin proteins is sufficient to impair S. aureus binding, providing a mechanism for the evolution of disease resistance. These findings suggest that bacterial hemoprotein capture has driven repeated evolutionary conflicts with hemoglobin during primate descent.

microbiology↗