Biology subjects

Naidoo, K.

Publications and source records attributed to Naidoo, K..

7 recordsLinked to original sources

bioRxiv2026

The extracellular matrix regulates tissue mechanics to enable cyclic lymph node remodelling and sustained immunity

Tissue shape and function are defined by the mechanical interactions of cellular and extracellular components. Lymph nodes cyclically remodel in response to immune challenges whilst preserving essential tissue architecture, comprised of a stromal fibroblastic reticular cell (FRC) network and extracellular matrix (ECM) it ensheaths. We experimentally quantified the contribution of ECM to the viscoelastic properties of the FRC network to parameterise an in silico model exploring factors affecting the FRC network's adaptation to lymph node expansion. The balance between tissue pressure, FRC contractility, and ECM stiffness permit robust tissue remodelling, while maintaining physiological geometries. Local perturbation of ECM stiffness or FRC contractility disrupts force distribution and impacts FRC proliferation and tissue expansion. Spatially dispersed perturbations exert higher impact on tissue remodelling than equivalent localised perturbations, with effects propagating across the network. The lymph node provides a system for studying the integration of cellular and extracellular mechanics during dramatic tissue remodelling.

biophysics↗

bioRxiv2026

Zebrafish knockout models of atxn1a, atxn1b, and atxn1l reveal distinct and shared phenotypic and transcriptomic alterations

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disorder caused by polyglutamine expansion in ATXN1, yet the normal physiological roles of ATXN1 and its paralog ATXN1L remain incompletely understood. To define these roles, we generated the first zebrafish knockouts (KOs) of the three ataxin-1 family genes, atxn1a, atxn1b, and atxn1l, using CRISPR/Cas9. These mutants reveal distinct and shared developmental, behavioral, and transcriptomic alterations. All KOs showed reduced early survival and mild larval growth deficits, indicating essential developmental functions. Behavioral assays revealed distinct paralog-specific effects: atxn1a KO larvae exhibited a unique light-dependent locomotor deficit, whereas atxn1b and atxn1l KOs displayed global hypoactivity. Adult behavioral assessment revealed a gradient of phenotypic severity: atxn1a KOs displayed the earliest and most pronounced alterations in vertical tank exploration and the greatest impairment in swim-tunnel performance, followed by atxn1b and then atxn1l mutants. To define molecular mechanisms underlying these phenotypes, we performed RNA-seq at 5 days post-fertilization and identified unique and shared differentially expressed genes across the three KO lines. Shared transcriptomic signatures highlighted suppression of leukotriene-biosynthetic pathways and diminished innate-immune pathways; suggesting that ATXN1-family genes influence neuroimmune signaling during early development. Weighted gene co-expression network analysis identified distinct KO-associated gene modules, including a phototransduction-enriched module strongly correlated with atxn1a KO status, offering a mechanistic link to its light-dependent locomotor phenotype. Together, these findings establish a comprehensive assessment of zebrafish models that reveal both shared core functions and specialized roles of ATXN1-family genes in development, neuroimmune regulation, sensorimotor behavior, and retinal signaling.

neuroscience↗

bioRxiv2025

Inflammatory Biomarkers of Asymptomatic and Symptomatic Tuberculosis

A large proportion of individuals with tuberculosis (TB) are asymptomatic. The biological and inflammatory underpinnings of asymptomatic TB are unknown and may differ from symptomatic TB. We characterised blood transcriptomic and proteomic profiles in South African community screening vs. health facility-based triage cohorts. Asymptomatic TB shared core transcriptomic and proteomic features with symptomatic TB, including upregulation of innate, interferon and inflammatory pathways and downregulation of T and B cell pathways. Integration of transcriptomic and proteomic data from asymptomatic TB individuals identified two distinct sub-clusters characterized by higher or lower bacterial burden, blood IFN-{gamma} responses, BMI, and chest radiographic abnormalities, suggesting different disease severity. We identified a new blood transcriptomic signature of asymptomatic TB. However, diagnostic performance of transcriptomic and proteomic markers was weaker for asymptomatic TB than symptomatic TB, suggesting that policy development for community-based, asymptomatic TB screening should not adopt biomarkers developed for symptomatic TB triage without further optimization.

immunology↗

bioRxiv2025

Immune Profiling the Axilla with Fine Needle Aspiration is Feasible to Risk-Stratify Breast Cancer

Whether breast cancer (BC) has metastasised to the regional axillary lymph nodes (ALN) is an important prognostic factor that directs the extent of axillary surgery. However, surgically clearing the axilla carries morbidity, so less invasive methods of risk-stratifying patients are needed. ALN fine needle aspiration (FNA) is currently used to detect BC metastases, but these samples also contain immune cells. Here we show that FNA acquires sufficient leukocytes for comprehensive immunophenotyping of reactive, patient-derived ALN. All CD4+ and CD8+ T cells subsets (naive, terminal effector, central and effector memory) and rarer (<2%) natural killer (NK) and plasmacytoid dendritic cell (pDCs) populations are represented. Importantly, the immune cell profile of one reactive ALN appears to reflect the immune status of the patients axilla. We show that FNA captures immune differences between patients with [≤]1 or [≥]2 metastatic ALN. Significantly increased numbers of naive CD4+ T cells, but significantly fewer terminal effector, central memory and effector memory subpopulations, were obtained from patients with [≥]2 metastatic ALN. Moreover, despite their sparse distribution pattern on whole-section immunohistochemistry (WSI), FNA revealed that CD56+ NK cell activation receptors were decreased in patients with [≥]2 metastatic ALN. Finally, FNA captured a significant decrease in pDCs in patients with [≥]2 metastatic ALN, despite their clustered distribution pattern on WSI. In summary, FNA is not only feasible for sampling leukocytes from reactive, patient-derived ALN, but also identifies immune cell profiles that reflect axillary tumour burden in BC. Thus, this technique could be used to risk-stratify BC patients in future.

cancer biology↗

bioRxiv2025

Topological Analysis of the Human Lymph Node Reticular Network Predicts Outcome in Breast Cancer

Axillary lymph nodes (ALN) initiate local immune responses in breast cancer (BC) but how and when ALN become dysfunctional, facilitating metastasis, is unclear. We use unbiased computational approaches to quantify features of ALN stromal architecture. We identify PDGFR{beta} as a robust, immunomarker for human fibroblastic reticular cells (FRC) and use it to quantify how FRC network topology changes during BC progression and after treatment. ALN (n = 331) from 179 BC patients and 23 benign reactive controls were assessed for FRC network metrics, including lacunarity and branchpoints, alongside de-identified clinico-pathological data. We find in node-negative, triple-negative BC, neoadjuvant treatment induced denser FRC networks which correlated with improved survival. Conversely, denser FRC networks in node-positive patients correlated with worsened survival, regardless of BC subtype or treatment. Further, increased FRC alignment within metastases improved survival. We show that FRC network topology predicts prognosis in BC, providing a new avenue for mechanistic, translational research.

pathology↗

bioRxiv2024

Basophils drive the resolution and promote wound healing in adult and aged mice

An active resolution is critical to control the duration of inflammation and limit its pathological consequences. Defects in resolution during wound healing allow the emergence of chronic wounds, a common complication in the elderly. Here, we show that basophils infiltrate the periphery of mouse skin wounds for at least three weeks, during both the inflammation and resolution phases of wound healing. Depletion of basophils induces an increased secretion of inflammatory molecules, accumulation and activation of pro-inflammatory leukocytes, and delays the wound healing response. Basophils particularly promote epidermal differentiation towards homeostasis in the wounds. Basophil-derived IL-4 and M-CSF drive partly their immunoregulatory and healing properties. Unexpectedly, aged mice basophils infiltrate more potently the wounds to promote inflammation resolution, showing a transcriptomic signature biased towards tissue remodeling. Thus, basophils are not pro-inflammatory but pro-resolution cells during an essential biological process such as skin wound healing. Unraveling basophil pro-resolution properties may reveal new strategies to fight chronic wounds in the elderly. SUMMARYThe resolution of inflammation is essential for homeostasis and becomes defective with age. Here we show basophil immunoregulatory properties promote resolution during skin wound healing, in both adult and aged mice.

immunology↗

bioRxiv2023

Altered glucose utilization and disrupted mitochondrial homeostasis in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy

BackgroundFor optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial homeostasis. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve antiviral immune responses. MethodsWhole blood was drawn from HIV uninfected female volunteers and women with chronic HIV infection on combination antiretroviral therapy. Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescent markers: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. ResultsDuring chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells (DCs) in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. ConclusionsSignificant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

immunology↗