Biology subjects

McNamara, C.

Publications and source records attributed to McNamara, C..

3 recordsLinked to original sources

bioRxiv2024

Distinct Type 1 Immune Networks Underlie the Severity of Restrictive Lung Disease after COVID-19

The variable etiology of persistent breathlessness after COVID-19 have confounded efforts to decipher the immunopathology of lung sequelae. Here, we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed by their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+ CD8+ T-cell perturbations in mild-to-moderate lung disease, but attenuated T-cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators, and autoantibodies distinguished each restrictive phenotype, and differed from those of patients without significant lung involvement. These differences were reflected in divergent T-cell-based type 1 networks according to severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.

immunology↗

bioRxiv2023

Hierarchical encoding of reward and effort across the cortex and basal ganglia during cost-benefit decision making

Adaptive value-guided decision-making requires weighing up the costs and benefits of pursuing an available opportunity. Though neurons across frontal cortical-basal ganglia circuits have been repeatedly shown to represent decision-related parameters, it is unclear whether and how this information is coordinated. To address this question, we performed large-scale single unit recordings simultaneously across 5 medial/orbital frontal and basal ganglia regions as rats decided whether to pursue varying reward payoffs available at different effort costs. We found that single neurons encoding combinations of the canonical decision variables (reward, effort and choice) were represented within all recorded brain regions. Co-active cell assemblies - ensembles of neurons that repeatedly co-activated within short time windows (<25ms) within and across structures - were able to provide representations of the same decision variables through the synchronisation of individual neurons with different coding properties. Together, these findings demonstrate a hierarchical encoding structure for cost-benefit computations, where individual neurons with diverse encoding properties are coordinated into larger, low-dimensional spaces within and across brain regions that can signal decision parameters on the millisecond timescale.

neuroscience↗

bioRxiv2021

Wolbachia strain wAu differs in cellular perturbation and virus inhibition profiles from previously characterised Wolbachia strains

Some strains of the inherited bacterium Wolbachia have been shown to be effective at reducing the transmission of dengue and other positive-sense RNA viruses by Aedes aegypti in both laboratory and field settings and are being deployed for dengue control. The degree of virus inhibition varies between Wolbachia strains; density and tissue tropism can contribute to these differences but there are also indications that this is not the only factor involved: for example, strains wAu and wAlbA are maintained at similar densities but only wAu produces strong dengue inhibition. We previously reported perturbations in lipid transport dynamics, including sequestration of cholesterol in lipid droplets, with strains wMel / wMelPop in Ae. aegypti. Here we show that strain wAu does not produce the same cholesterol sequestration phenotype despite displaying strong virus inhibition and moreover, in contrast to wMel, wAu antiviral activity was not rescued by cyclodextrin treatment. To further investigate the cellular basis underlying these differences, proteomic analysis of midguts was carried out on Ae. aegypti lines and revealed that wAu-carrying midguts showed a distinct proteome when compared to Wolbachia-free, wMel- or wAlbA-carrying midguts, in particular with respect to lipid transport and metabolism. The data suggest a possible role for perturbed RNA processing pathways in wAu virus inhibition. Together these results indicate that wAu shows unique features in its inhibition of arboviruses compared to previously characterized Wolbachia strains. Author SummaryWolbachia endosymbionts can block transmission of dengue virus by Aedes aegypti mosquitoes, and Wolbachia release programs for dengue control are now being undertaken in several countries. Understanding the mechanisms of Wolbachia-mediated antiviral activity is important for maximizing the efficacy of this control approach. Using functional and proteomic analyses, this study indicates that different strains of Wolbachia perturb cellular functions in diverse ways and display different antiviral profiles. These differences raise the possibility that Wolbachia strain switching could be used to counteract viral escape mutations, should they arise and threaten the efficacy of dengue control programmes.

microbiology↗