Biology subjects

Fry, L.

Publications and source records attributed to Fry, L..

4 recordsLinked to original sources

bioRxiv2025

Guanylate-Binding Proteins Promote Host Defense Against Leishmania major by Balancing iNOS/Arg-1 in Myeloid Cells

Cutaneous leishmaniasis (CL) is a debilitating neglected tropical disease characterized by lesions that can range from self-healing to permanent disfigurations. A predominant Th1 response, which stimulates IFN-{gamma} production, is crucial for parasite control during self-healing CL. While IFN-{gamma} primarily activates macrophages to produce nitric oxide via inducible nitric oxide synthase (iNOS) leading to parasite control, IFN-{gamma} also activates other downstream pathways involved in cell autonomous immunity. One such pathway is the activation of guanylate binding proteins (GBPs), a class of interferon inducible GTPases. However, the role of GBPs during CL has been minimally explored. Utilizing RNA-Seq we found that Leishmania major infection leads to the upregulation of several GBPs in C57Bl/6 mice. In vitro studies using GBPChr3 knockout (KO), and C57Bl/6 control mice reveal that bone marrow-derived macrophages (BMDMs) from KO mice exhibit higher parasite burdens following IFN-{gamma} treatment, independent of GBP localization to the parasite. Single-cell RNA-Seq identifies macrophages as the primary expressers of GBPs during L. major infection in vivo. In vivo, GBPChr3 KO mice display increased disease severity and parasite load. GBPChr3 KO macrophages and monocytes show elevated ARG-1 and reduced iNOS expression, indicating a shift toward a parasite-permissive environment that supports parasite growth. These findings highlight a critical role for GBPs in immune-mediated control of CL.

immunology↗

bioRxiv2025

Dysregulated lymphatic remodeling promotes immunopathology during non-healing cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a vector borne disease that is endemic to tropical and sub-tropical regions of the world disproportionately affecting those of low socioeconomic status. The combined role of the parasite and the hosts immune response in determining disease severity has made it challenging to discover new anti-leishmanial treatments. Previous work from our lab has established that the dermal lymphatic network is necessary for wound resolution in a model of healing CL with Leishmania major parasites. In CL, lymphatic remodeling allows for accumulated fluid to drain from the lesional site, thereby reducing disease severity. In this report, we present a new mechanism of immunopathology during non-healing CL brought about by L. amazonensis infection. We show non-healing CL develops alongside an accumulation of cells and fluid in the skin, resulting in chronic inflammation. Lymphatic remodeling is attenuated during the chronic phase of L. amazonensis infection. Moreover, the percentage of proliferating lymphatic endothelial cells (LECs) decreases from 6 to 12 weeks post infection (wpi), leading to a decrease over time in lymphatic vessel (LV) density. To induce lymphangiogenesis, exogenous vascular endothelial growth factor-C (VEGF-C) was administered by adenoviral delivery. VEGF-C increased LV dilation leading to reduced lesion sizes without altering parasite burdens, arguing targeting the lymphatics can alleviate immunopathology. Taken together, these results show impaired lymphatic function contributes to non-healing disease due to L. amazonensis infection and the lymphatics can be targeted to decrease inflammation in the skin during infection.

immunology↗

bioRxiv2021

Investigating the Interplay Between Affective, Phonatory and Motoric Subsystems in Autism Spectrum Disorder Using a Multimodal Dialogue Agent

We explore the utility of an on-demand multimodal conversational platform in extracting speech and facial metrics in children with Autism Spectrum Disorder (ASD). We investigate the extent to which these metrics correlate with objective clinical measures, particularly as they pertain to the interplay be-tween the affective, phonatory and motoric subsystems. 22 participants diagnosed with ASD engaged with a virtual agent in conversational affect production tasks designed to elicit facial and vocal affect. We found significant correlations between vocal pitch and loudness extracted by our platform during these tasks and accuracy in recognition of facial and vocal affect, as-sessed via the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA-2) neuropsychological task. We also found significant correlations between jaw kinematic metrics extracted using our platform and motor speed of the dominant hand assessed via a standardised neuropsychological finger tapping task. These findings offer preliminary evidence for the usefulness of these audiovisual analytic metrics and could help us better model the interplay between different physiological subsystems in individuals with ASD.

neuroscience↗

bioRxiv2019

Re-annotation of the Theileria parva genome refines 53% of the proteome and uncovers essential components of N-glycosylation, a conserved pathway in many organisms

BackgroundThe apicomplexan parasite Theileria parva causes a livestock disease called East coast fever (ECF), with millions of animals are at risk in sub-Saharan East and Southern Africa, the geographic distribution of T. parva. Over a million bovines die each year of ECF, with a tremendous economic burden to pastoralists in endemic countries. Comprehensive, accurate parasite genome annotation can facilitate the discovery of novel chemotherapeutic targets for disease treatment, as well as elucidate the biology of the parasite. However, genome annotation remains a significant challenge because of limitations in the quality and quantity of the data being used to inform the location and function of protein-coding genes and, when RNA data are used, the underlying biological complexity of the processes involved in gene expression. Here, we apply our recently published RNAseq dataset derived from the schizont life-cycle stage of T. parva to update structural and functional gene annotations across the entire nuclear genome. ResultsThe re-annotation effort lead to evidence-supported updates in over half of all protein-coding sequence (CDS) predictions, including exon changes, gene merges and gene splitting, an increase in average CDS length of approximately 50 base pairs, and the identification of 128 new genes. Among the new genes identified were those involved in N-glycosylation, a process previously thought not to exist in this organism and a potentially new chemotherapeutic target pathway for treating ECF. Alternatively-spliced genes were identified, and antisense and multi-gene family transcription were extensively characterized. ConclusionsThe process of re-annotation led to novel insights into the organization and expression profiles of protein-coding sequences in this parasite, and uncovered a minimal N-glycosylation pathway that changes our current understanding of the evolution of this post-translation modification in apicomplexan parasites.

genomics↗