Biology subjects

Martinson, N.

Publications and source records attributed to Martinson, N..

6 recordsLinked to original sources

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↗

bioRxiv2024

Plasma proteome profiling for AKI biomarker candidates associated with first-line ART in people living with HIV in South Africa

With the highest global burden of HIV, South Africa initiates HIV treatment using first-line antiretroviral therapy (ART) regimens in newly diagnosed patients. Antiretroviral (ARV)-associated nephrotoxicity has been observed in -10% of South African patients newly receiving first-line ART, as well as in patients who have extensively received TDF-based ART regimens, and this can progress to acute kidney injury (AKI). To identify potential biomarkers that will improve the detection of ARV-associated nephrotoxicity, proteomic analysis was performed using the sequential window acquisition of all theoretical mass spectra (SWATH-MS) data acquisition method on the plasma of the case group (AKI) and the control group (non-AKI). Data are available via ProteomeXchange with identifier PXD054218. Evaluation of the results identified thirty-four proteins that showed a significant change in abundance, with three proteins showing increased abundance, while thirty-one proteins showed decreased abundance between the AKI and non-AKI groups. Machine learning was also used to evaluate the results and showed twenty ranked proteins that contributed to distinguishing between the AKI and non-AKI groups. The majority of the proteins of significant differential abundance and those ranked by the machine learning model participate in enriched biological processes that correspond to known pathophysiological and cellular mechanisms that contribute to AKI, suggesting that those proteins can serve as potential biomarkers to be further verified and validated for AKI diagnosis. Comparison of the plasma and previously generated urinary proteome profiles showed five proteins with significant differences in abundance that overlapped both proteomes providing evidence for the renal physiological dynamics of these proteins in renal injury and disease. Significance: Improving the detection of ARV-associated nephrotoxicity is challenging because current serum creatinine (srCr) based-equations used to estimate the glomerular filtration rate (eGFR) for assessing kidney function have been reported to overestimate the eGFR in the South African population and changes in srCr measurements also reflect a delayed response to the initial structural injury of the kidney. This hinders the timeous detection of ARV-associated nephrotoxicity which can lead to irreversible renal damage and can compromise the continuation of treatment in PLHIV, thus emphasising the need to introduce novel AKI biomarkers to mitigate ARV-associated nephrotoxicity in at risk PLHIV in South Africa. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/605118v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@18743eaorg.highwire.dtl.DTLVardef@17bba7borg.highwire.dtl.DTLVardef@101c78org.highwire.dtl.DTLVardef@1bd2b23_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentified thirty-four proteins with significant changes in abundance between study groups. C_LIO_LIMachine learning showed fourteen proteins associated with renal disease biology that differentiate the study groups. C_LIO_LIFirst study to analyse plasma proteome of this cohort of PLHIV in South Africa C_LIO_LIFive proteins overlap the plasma and urinary proteome profiles of the study groups. C_LI

biochemistry↗

bioRxiv2024

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to [~]103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/L. In PWOH and PWH with CD4 counts [≥]200 cells/L, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

microbiology↗

bioRxiv2022

Polymorphisms in HIV-1 nef are associated with plasma concentration of biomarkers of endothelial activation

Infection with HIV is associated with an increased risk of cardiovascular disease (CVD), which may be mediated by the effect of the viral proteins, Nef and Tat, on inflammation and endothelial activation. The viral genes coding for Nef and Tat contain numerous polymorphisms, which we hypothesised may be differentially associated with endothelial activation. Therefore, our aim was to assess the association of these polymorphisms with endothelial activation and inflammation in subjects infected with HIV-1. The HIV-1 nef and tat genes were sequenced from clinical isolates from 31 and 34 patients, respectively. Plasma concentration of biomarkers of endothelial activation (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF)), and biomarkers of inflammation (tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and interleukin-8 (IL-8)), were measured. Analysis of HIV-1 nef gene sequences identified five polymorphisms (V16I, H40Y, T50A,H, S169N and H188Q,S) that were each significantly (p<0.05) associated with ICAM-1 plasma concentration. An additive effect of these variants on plasma ICAM-1 concentration (p=0.004 for trend), was observed. No significant associations were seen between Tat amino acid residues and plasma concentration of markers of endothelial activation and inflammation. These are the first human in vivo data that support the hypothesis that nef gene polymorphisms impact endothelial function. ImportanceCardiovascular disease (CVD) is a leading cause of mortality in adults living with HIV, which may in part be due to endothelial activation and inflammation caused by the viral proteins, Nef and Tat. However, there is no data from humans supporting the CVD-associated Nef and Tat hypothesis, and assays for accurately measuring Nef and Tat plasma concentrations are not currently available. Therefore, we hypothesized that polymorphisms in the nef and tat genes of clinical viral isolates may be associated with host plasma markers of endothelial activation and inflammation. Our results show that this was the case, with five nef polymorphisms showing both individual and additive association with plasma concentration of ICAM-1. The HIV-1 Tat gene, however, showed no significant association with plasma concentrations of markers of endothelial activation and inflammation. This is the first human study to directly link Nef to endothelial activation and to provide a possible screening tool i.e., nef genotyping, for identifying individuals at high risk of endothelial-based diseases.

biochemistry↗

bioRxiv2022

Bacterial Microbiome of Foreskin Tissue: Impact of Short-course PrEP and Host Inflammation

As part of the CHAPS randomized clinical trial, we sequenced a segment of the bacterial 16S rRNA gene from foreskin tissue of 144 adolescents from South Africa and Uganda collected during surgical penile circumcision after receipt of 1 to 2 doses of placebo, emtricitabine with tenofovir disoproxil fumarate, or emtricitabine with tenofovir alafenamide. We found a large proportion of Corynebacterium in addition to other anaerobic species. Cutibacterium acnes was more abundant among participants from South Africa than Uganda, though this made no difference in surgical recovery. We did not find a difference in bacterial populations by treatment received nor bacterial taxa that were differentially abundant between participants who received placebo versus active drug. Using RNAseq libraries from foreskin tissue of the same participants, we found negative correlations between the relative abundance of bacterial taxa and the expression of genes downstream of the innate response to bacteria and regulation of the inflammatory response. When participants were divided into clusters based on bacterial community composition, two main clusters emerged which were distinguished by high and low bacterial diversity. Random forest classification showed higher expression of NFATC3 and SELENOS and lower expression of STAP1 and NLRP6 in the higher diversity group compared to the lower. Our results show no difference in the tissue microbiome of the foreskin with short-course PrEP but that bacterial taxa were largely inversely correlated with gene expression, consistent with non-inflammatory colonization. Author SummaryWe investigated the bacterial community of the foreskin of the penis. Previous studies found increased inflammation with certain anaerobic bacteria from swabs taken under the foreskin, but we found that higher relative abundances of the bacteria were correlated with lower expression of inflammatory genes. We did not find different bacteria in participants who received medicine to prevent HIV. Understanding the relationship between bacteria and inflammation in the penis will help us to understand how interventions like penile circumcision reduce the risk of acquiring sexually transmitted infections such as HIV.

microbiology↗

bioRxiv2017

Detection of live mycobacteria with a solvatochromic trehalose probe for point-of-care tuberculosis diagnosis

AbstractTuberculosis (TB) is the leading cause of death from an infectious bacterial disease. Poor diagnostic tools to detect active disease plague TB control programs and affect patient care. Accurate detection of live Mycobacterium tuberculosis (Mtb), the causative agent of TB, will improve TB diagnosis and patient treatment. We report that live mycobacteria can be specifically detected with a fluorogenic trehalose analog. We designed a 4-N,N-dimethylamino-1,8- naphthalimide-trehalose (DMN-Tre) conjugate that undergoes >700-fold fluorescence increase when transitioned from aqueous to hydrophobic environments. This enhancement occurs upon metabolic conversion of DMN-Tre to trehalose monomycolate and incorporation into the outer membrane. DMN-Tre labeling enabled the rapid, no-wash visualization of mycobacterial and corynebacterial species without nonspecific labeling of Gram-positive or -negative bacteria. DMN-Tre labeling was selective for live mycobacteria and was reduced by treatment with TB drugs. Lastly, DMN-Tre labeled Mtb in TB-positive sputum samples suggesting this operationally simple method may be deployable for TB diagnosis.

microbiology↗