Biology subjects

Love, A. C.

Publications and source records attributed to Love, A. C..

6 recordsLinked to original sources

bioRxiv2026

A phytocannabinoid-sensitive phosphorylation switch converts endocannabinoids into alternative lipid GPCR activators

Abstract: Endocannabinoids (eCBs) like anandamide and 2-arachidonoylglycerol are endogenous lipid ligands for CB1 and CB2 G protein-coupled receptors (GPCRs). Here, we show that phosphorylation of biologically important anandamide generates naturally occurring anandamide phosphate (AEAp), which switches GPCR ligand specificity to lysophosphatidic acid (LPA) receptors (LPARs) and the primate-specific bile acid sensory receptor MRGPRX4. The kinase responsible for anandamide phosphorylation was identified asdiacylglycerol kinase (DGK) theta (DGKq or DGKQ) using activity-guided brain fractionation, inhibitor profiling, recombinant reconstitution, and DGK isozyme screening. DGKQ showed noncanonical biphasic lipid kinetics and was inhibited by phytocannabinoids, most notably tetrahydrocannabinolic acid. Thus, eCBs are not only cannabinoid receptor ligands but also enzymatically adaptable lipid signals activating LPARs and MRGPRX4, thus linking metabolism of the distinct lipid LPA with Cannabis pharmacology.

biochemistry↗

bioRxiv2025

Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes

The marine bacterial flavoenzymes Clz9 and Tcz9 can process cannabigerolic acid (CBGA) to the minor cannabinoid, cannabichromenic acid (CBCA), however, the mechanistic details of this extrinsic transformation are still obscure. Here, we report a thorough analysis of CBCA-formation by Clz9 and Tcz9 through high-resolution crystallographic characterization, biochemical analysis, and spectroscopic interrogation. Our work reveals that Clz9 and Tcz9 use different biochemical mechanisms from Cannabis cyclases and each other in their production of CBCA. Collection of a high-resolution substrate-bound structure, the first for any cannabinoid cyclase, provides key insights into how active site architecture affects substrate binding and stereoselectivity. Engineering approaches improve the stereoselectivity of CBCA formation by Clz9 and Tcz9, providing access to (R) and (S)-CBCA. Collectively, our work advances understanding of enzymatic cannabinoid formation and cements Clz9 and Tcz9 as two unique members of the BBE-like enzyme family with encouraging potential for biocatalytic cannabinoid production applications.

biochemistry↗

bioRxiv2024

Diet driven differences in host tolerance are linked to shifts in global gene expression in a common avian host-pathogen system

As humans alter the landscape, wildlife have become increasingly dependent on anthropogenic resources, altering interactions between individuals and subsequently disease transmission dynamics. Further, nutritional quantity and quality greatly impact an individual hosts immune capacity and ability to mitigate damage caused by infectious disease. Thus, understanding the impact of dietary nutrition on immune function is critical for predicting disease severity and transmission as human activity both facilitates the dispersal of pathogens and alters dietary options for wildlife. Here, we use transcriptomics to explore the previously unstudied molecular mechanisms underpinning diet-driven differences in pathogen tolerance using a widespread avian bacterial pathogen, Mycoplasma gallisepticum (MG). MG is an ideal model for understanding the dietary drivers of disease as the human supplementation that wild birds commonly rely on, bird feeders, are also an important source for MG transmission. Significant diet-driven differences in the expression of many genes encoding immune response and translational machinery proteins are seen both in the absence of MG and during the recovery period. Prior to infection, protein-fed birds are more transcriptionally primed for infection than lipid-fed birds which translates to greater tolerance in protein-fed birds during the recovery period. Given the significant importance of human supplemented food in wildlife disease systems, the molecular mechanisms by which interactions between diet and infection emerge provide insight into the ecological and immunological consequences of human behavior and wildlife disease.

ecology↗

bioRxiv2024

A high lipid diet leads to greater pathology and lower tolerance during infection

Despite the clear effect of food resources on wildlife disease dynamics, few studies have investigated how shifts in diet, specifically macronutrient content, shape vertebrate host responses to infection. While each individual macronutrient plays a vital role in physiological processes necessary for pathogen defense, it is often difficult to disentangle the role of an individual macronutrient on disease pathology. We explored the effects of dietary macronutrient composition on disease pathology and feeding behavior of canaries (Serinus canaria domestica) infected with Mycoplasma gallisepticum (MG). First, we provided canaries with isocaloric diets comprised of identical ingredients that varied in macronutrient content (high-protein or high-lipid) then MG- or sham-inoculated birds. We then offered both diets to canaries before and after MG- and sham-inoculation. In experiment one, high protein diet birds consumed more food than high lipid diet birds and experienced a more pronounced decrease in food intake after infection. High protein diet birds were more tolerant to MG infection, exhibiting reduced pathology when compared to high lipid diet birds, despite the two treatments having similar levels of MG-specific antibodies and MG loads. When birds had access to both diets, they consumed more of the high protein diet and experienced pathology for less time than lipid or protein restricted birds. These results highlight that macronutrient makeup of the diet can shape host tolerance and pathology and thus affect host-pathogen transmission dynamics. Summary StatementMacronutrient composition of the diet shapes tolerance in an avian host pathogen system. Birds that had greater access to protein exhibited reduced pathology despite similar pathogen loads when compared with birds with greater access to lipids.

ecology↗

bioRxiv2023

Male pathology regardless of behaviour drives transmission in an avian host-pathogen system

Host sex is an important source of heterogeneity in the severity of epidemics. Pinpointing the mechanisms causing this heterogeneity can be difficult because differences in behaviour among sexes (e.g. greater territorial aggression in males) can bias exposure risk, obfuscating the role of immune function, which can lead to differences in pathology, in driving differential susceptibility between sexes. Thus, sex-biased transmission driven by differences in immune function independent of behaviour is poorly understood, especially in non-mammalian systems. Here we examine the previously unexplored potential for male-biased pathology to affect transmission using an avian host-pathogen system. We employ a sex-dependent multistate transmission model parameterized with isolated, individual-based experimental exposures of domestic canaries and experimental transmission data of house finches. The experiment revealed that male birds have shorter incubation periods, longer recovery periods, higher pathogen burdens, and greater disease pathology, than females. Our model revealed that male-biased pathology led to epidemic size rapidly increasing with the proportion of male birds, with a nearly 16-fold increase in total epidemic size from an all-female to an all-male simulation. Our results demonstrate that female-biased resistance, independent of male behaviour, can drive sex-dependent transmission in wildlife, indicating that sex-based differences in immune function, not just differences in exposure risk, can shape epidemic dynamics.

ecology↗

bioRxiv2021

Longitudinal monitoring of individual infection progression in Drosophila melanogaster

The innate immune system is critical for host survival of infection. Infection models in organisms like Drosophila melanogaster are key for understanding evolution and dynamics of innate immunity. However, current toolsets for fly infection studies are limited in their throughput and their ability to generate longitudinal measurements of infection progression in single animals. Here we report a novel bioluminescent imaging strategy enabling non-invasive characterization of pathogen load over time. We demonstrate that photon flux from autobioluminescent reporter bacteria can be used to monitor relative pathogen loads in individual animals. Escherichia coli expressing the ilux operon were imaged in whole, living flies at relevant concentrations for immune study. Because animal sacrifice was not necessary to estimate pathogen load, stochastic responses to infection were characterized in individuals over time for the first time. The high temporal resolution of bioluminescence imaging also enabled visualization of the fine dynamics of microbial clearance on the hours time-scale. Overall, this non-invasive imaging strategy provides a simple and scalable platform to observe changes in pathogen load in vivo over time.

immunology↗