Biology subjects

Mhlanga, M.

Publications and source records attributed to Mhlanga, M..

6 recordsLinked to original sources

bioRxiv2025

Using social network analysis and non-invasive antibody detection to explore pathogen exposure in wildlife communities

Understanding the dynamics of infectious diseases in ecosystems shared with wildlife is a priority for preventing future threats to human, animal health and conservation. However, the collection of ecological and epidemiological data on wild populations has relied on invasive and costly methods which limited the capacity of investigation. Recent technological developments have changed this trend. In Hwange national park and its surrounding area in Zimbabwe, we combined camera trap-based ecological monitoring over a period of 12 months, covering 14 water holes with a fecal-based antibody survey in 16 large herbivore species. A survey involving 52,829 pictures as well as 629 faecal samples collected every 15 days, has shown Through the modelling of multispecies contact networks, the risk of infection exposure at species-level is predicted. Coupled with foot-and-mouth disease virus (FMDV) antibody information, the role of each species in the dynamics of infectious diseases is explored. This study highlights how community networks can provide valuable insights into the functional epidemiological role of wildlife populations. Rather than establishing transmission routes, our aim is to propose a scalable and non-invasive surveillance framework that identifies priority species and areas for epidemiological monitoring in complex ecological systems. Significance StatementMonitoring disease circulation in wildlife is often hindered by the difficulty of collecting epidemiological data. We propose a novel non-invasive approach that combines species interaction networks derived from camera-trap data with non-invasive antibody detection to explore the exposure patterns of large herbivore communities to foot-and-mouth disease virus (FMDV). By linking the position of species in contact networks with their immunological status, we demonstrate the potential of using ecological centrality as a proxy for identifying key hosts in transmission or indicator species for pathogen circulation. Beyond FMDV, this framework can be adapted to other pathogens for which non-invasive immunological assays are currently being developed, making it broadly relevant for wildlife disease surveillance in remote or protected areas.

ecology↗

bioRxiv2023

Multi-omic profiling of pathogen-stimulated primary immune cells

We performed long-read transcriptome and proteome profiling of pathogen-stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors to discover new transcript and protein isoforms expressed during immune responses to diverse pathogens. Long-read transcriptome profiling reveals novel sequences and isoform switching induced upon pathogen stimulation, including transcripts that are difficult to detect using traditional short-read sequencing. Widespread loss of intron retention occurs as a common result of all pathogen stimulations. We highlight novel transcripts of NFKB1 and CASP1 that may indicate novel immunological mechanisms. RNA expression differences did not result in differences in the amounts of secreted proteins. Clustering analysis of secreted proteins revealed a correlation between chemokine (receptor) expression on the RNA and protein levels in C. albicans- and Poly(I:C)-stimulated PBMCs. Isoform aware long-read sequencing of pathogen-stimulated immune cells highlights the potential of these methods to identify novel transcripts, revealing a more complex transcriptome landscape than previously appreciated.

immunology↗

bioRxiv2022

Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls

C-C chemokine receptor 5 (CCR5) is the main HIV co-receptor affecting susceptibility and disease course. Quantitative trait loci (QTL) mapping analysis was performed to assess genetic variants associated with CCR5 expression on circulating immune cells in 209 PLHIV using ART and 304 healthy controls, all of Western European ancestry. The proportions of CCR5 positive cells and CCR5 mean fluorescence intensity (MFI) were assessed by flow cytometry in monocytes and CD4+ and CD8+ T cell subsets using flow cytometry. We identified the rs60939770, which is an intergenic variant in cis-region to CCR5 gene not in linkage disequilibrium with CCR5d32, related to the proportion of CCR5+ memory T regulatory cells, both in PLHIV and healthy controls. Two genome-wide significant loci, in linkage equilibrium with CCR5d32, were found to be associated with CCR5 MFI of multiple subsets of mostly differentiated memory T cells in both groups. The expression of nearby chemokines receptors (CCR1, CCR2, CCR3, CCRL2), existing in the same the same topologically associating domain, were also influenced by these genetic variants. Furthermore, we show the genetic variants which modulate CCR5 surface expression affect the production of other inflammatory mediators, including monocyte- and lymphocyte-derived cytokines as well as CCL4 and IL-8. Our data indicate that the genetic regulation of CCR5 expression is cell-specific and affects the production of various inflammatory mediators. Author SummaryCCR5 plays a important role in the acquisition of HIV and it is associated to immune activation in people living with HIV (PLHIV). Using samples of cohorts composed of healthy individuals and PLHIV, we sought to map genomic regions that influence CCR5 expression on monocytes and subsets of CD4+ and CD8+ cells. We identified distinct genetic variants that are associated with CCR5 cell proportions or mean fluorescence intensity in subpopulations of T cells with memory functions in both healthy and PLHIV. The genetic variants also influenced the expression of other nearby chemokine receptors and the production of inflammatory mediators. Thus, we demonstrated that the genetic regulation of CCR5 expression is cell-type specific and may impact HIV susceptibility and disease progression.

systems biology↗

bioRxiv2022

Blockage of Lamin-A/C loss diminishes the pro-inflammatory macrophage response

Mutations and defects in nuclear lamins can cause major pathologies in affected tissues. Recent studies have also established potential links between lamins, inflammation, and inflammatory diseases but the underlying molecular mechanisms are unknown. We now report that pro-inflammatory activation of macrophages reduces levels of Lamin-A/C to augment pro-inflammatory gene expression and cytokine secretion. We show that activation of bone-marrow derived macrophages (BMDMs) degrades Lamin-A/C, as preceded by its phosphorylation, which is mediated by Caspase-6 and CDK1, respectively. Inhibiting Lamin-A/C phosphorylation and degradation severely inhibits pro-inflammatory gene expression and cytokine secretion. Using LPS-activated Lamin-A/C Knock Out BMDMs, we confirmed that the activation of the IFN-{beta}-STAT pathway is amplified due to Lamin-A/C reduction, which ultimately augments the pro-inflammatory response. As Lamin-A/C is a previously unappreciated regulator of the pro-inflammatory macrophage response, our findings could provide novel opportunities to treat inflammatory diseases. In first proof-of-concept studies we show that macrophage pro-inflammation, as induced by Lipopolysaccharide or pathogenic E. coli, could be reduced by inhibiting Lamin-A/C phosphorylation and degradation. The inhibition of macrophage pro-inflammation could also be achieved by inhibiting members of the Lamin-A/C regulated IFN-{beta}-STAT pathway, i.e., phospho-STAT1 and phospho-STAT3. This newly found mechanism to suppress the pro-inflammatory response of macrophages will provoke a re-thinking of how inflammation can be addressed therapeutically.

cell biology↗

bioRxiv2017

Genome-wide identification and analysis of transcribed enhancers during macrophage polarization

Macrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M(IFN-{gamma}) and M(IL-4/IL-13) are well-known for their opposing pro- and anti-inflammatory roles. Enhancers have emerged as regulatory DNA elements crucial for transcriptional activation of gene expression. Using cap analysis of gene expression and epigenetic data, we identify on large-scale transcribed enhancers in mouse macrophages, their time kinetics and target protein-coding genes. We observe an increase in target gene expression, concomitant with increasing numbers of associated enhancers and find that genes associated to many enhancers show a shift towards stronger enrichment for macrophage-specific biological processes. We infer enhancers that drive transcriptional responses of genes upon M(IFN-{gamma}) and M(IL-4/IL-13) macrophage activation and demonstrate stimuli-specificity of regulatory associations. Finally, we show that enhancer regions are enriched for binding sites of inflammation-related transcription factors, suggesting a link between stimuli response and enhancer transcriptional control. Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage activation, and offers a detailed genome-wide catalogue to further elucidate enhancer regulation in macrophages.

bioinformatics↗

bioRxiv2017

The Human Cell Atlas

The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body, by undertaking a Human Cell Atlas Project as an international collaborative effort. The aim would be to define all human cell types in terms of distinctive molecular profiles (e.g., gene expression) and connect this information with classical cellular descriptions (e.g., location and morphology). A comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, as well as provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas.

cell biology↗