Biology subjects

Kaleebu, P.

Publications and source records attributed to Kaleebu, P..

8 recordsLinked to original sources

bioRxiv2024

Early regional lymph node activation drives influenza vaccine responses in an ancestrally diverse cohort

Early in vivo dynamics of human immune-cell activation across regionally activated lymphoid tissue sites upon immunisation are poorly characterised in ancestrally diverse individuals. Here, we profiled draining and non-draining axillary lymph nodes (dLNs and ndLNs) by ultrasound-guided fine-needle aspiration (FNA) in 13 Black and Asian ancestry individuals, before and 3-7 days after vaccination with adjuvanted influenza vaccine. Draining but not ndLNs rapidly increased in size post-vaccination, by day 3, with distinct cellular dynamics determined through single cell multiomics. Dissecting LN cellular diversity into 42 lymphoid and non-lymphoid cell states, post-vaccination cell abundance changes were observed across all LNs, but dLNs were specifically characterised by CD4+ T follicular helper (CD4+ Tfh) cell expansion. Gene expression analysis revealed a dLN post-vaccination hub of multicellular activity defined by CD4+ Tfh signalling, cross-compartmental activation, translation, and enhanced antigen-presentation capacity. Thus, robust responses to intramuscular immunisation transcending ancestral inter-individual variation are elicited through temporal, anatomical and cellular lymphatic co-ordination with implications for vaccine design in ancestrally diverse populations. SummaryIn this study of ancestrally diverse young adults, the temporarily co-ordinated response to an adjuvanted influenza vaccine at lymph nodes local to (draining) and distal from (non-draining) the injection site, reveals early regulation of cellular kinetics and anatomical hierarchy of the innate and adaptive immune responses.

immunology↗

bioRxiv2023

Ticks; a reservoir for virus emergence at the human-livestock interface in Uganda

BackgroundUganda is one of the most biodiverse regions on the planet and a hotspot for virus emergence. In particular, the warm-humid lowlands favour tick population growth with the associated risk of tick-borne disease. The prevalent tick species Rhipicephalus appendiculatus, R. evertsi evertsi and Amblyomma variegatum harbour a diverse range of viruses, from harmless to highly pathogenic. Notably, the orthonairoviruses cause human outbreaks of Crimean-Congo haemorrhagic fever (CCHF) regularly within the cattle corridor of Uganda, a region spanning from the south-west to the north-east of the country. MethodsIn the ArboViral Infection (AVI) study, the first to explore the virome of ticks in Uganda using next generation sequencing (NGS), we collected ticks from three geographically diverse areas and subjected these to target-enrichment (TE) NGS. Viral genomes were detected by de novo assembly, mapping and BLASTn. ResultsWe analyzed a total of 2,754 ticks collected from 31 livestock farms in the districts of Arua, Nakaseke and Lyantonde. These were combined into 219 pools by site of collection and tick species, including R. appendiculatus, R. evertsi evertsi, A. variegatum and Hyalomma rufipes. We detected partial or near-complete viral genomes in 163 tick pools; 110 (67%) of which were from Arua, 39 (24%) from Nakaseke and 12 (7%) from Lyantonde districts. 2 pools (2%) were from Arua/Lyantonde. These included 22 species of virus, representing 15 genera and 9 families, including the Nairoviridae, Retroviridae, Orthomyxoviridae, Chuviridae, Rhabdoviridae, Phenuiviridae, Parvoviridae, Poxviridae and Flaviviridae. There were 8 viral species known to be pathogens of humans or animals and 5 highly divergent genomes detected, representing novel virus species. A high abundance of orthonairoviruses was notable, including CCHFV, Dugbe virus and a novel Orthonairovirus species that we have named Macira virus. InterpretationTicks in Uganda are an important reservoir of diverse virus species, many of which remain uncharacterised and of unknown pathogenic potential. Author SummaryTicks are parasitic arachnids that may transmit a spectrum of viral diseases to humans and animals. Uganda is a hotspot for such tick-borne diseases. In this study, we sequenced ticks collected from three geographically diverse regions of Uganda using a semi-agnostic next- generation sequencing method in order to detect viruses from all known virus families. We collected and analyzed 2,754 ticks from 31 farms across the country. Within these ticks, we detected 22 species of virus from 15 genera and 9 viral families, including 8 animal or human pathogens and 5 new novel virus species. Notably, orthonairoviruses, including the highly pathogenic Crimean-Congo haemorrhagic fever virus, were highly prevalent in the ticks. The researchers suggest that ticks in Uganda serve as an important reservoir for diverse viruses, many of which have significant pathogenic potential. This information will inform public health efforts to prevent and control tick-borne diseases in Uganda and other similar regions.

microbiology↗

bioRxiv2022

Impaired HIV-specific T-cell responses in HIV and S. mansoni coinfected Ugandans.

Fishing communities surrounding Lake Victoria in Uganda show an HIV-1 prevalence of 28% and incidence rates of 5%. More than 50% of the fishermen on the shores of Lake Victoria are infected with S. mansoni. Fishermen are more likely to die of AIDS related illness than farmers in the Lake Victoria region. Using polychromatic flow cytometry and mesoscale discovery platform, HIV specific and non-specific responses were measured and compared within individuals when HIV and S. mansoni coinfected and after the S. mansoni was cleared. Sixty-two unique clusters of cells in the UMAP space were identified after stimulations with GAG PTE POOL-1 and GAG PTE POOL-2 independently. However, the frequency of only three clusters is significantly higher after S. mansoni clearance. In addition, S. mansoni infection is associated with higher IL-9 and IL-10 and lower IL-15 in HIV and S. mansoni coinfected individuals. IL-9 concentration at enrolment visit predicts CD4 decline. S. mansoni infection negatively affects HIV specific and non-specific immune responses in HIV and S. mansoni coinfected individuals.

immunology↗

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↗

bioRxiv2020

Expression of type I interferon-associated genes at antiretroviral therapy interruption predicts HIV virological rebound

Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without evidence of viral load rebound, the mechanisms under-pinning post-treatment control remain unclear. Twelve individuals who had received 12 months of ART from primary HIV infection and then undertook a TI were sampled at the time of stopping therapy. Using RNA-Seq we explored gene expression in CD4 T cells to look for evidence of a mechanism that might underpin virological rebound and lead to discovery of an associated biomarker. Using independent analysis tools, genes associated with the type I interferon response were strongly associated with a delayed time to viral rebound following TI. These are the first data we are aware of that link transcriptomic signatures associated with innate immunity with control following TI. While these results need to be confirmed in larger trials, they could help define a strategy for new therapies and identify new biomarkers for remission.

microbiology↗

bioRxiv2020

Alternate primers for whole-genome SARS-CoV-2 sequencing

As the world is struggling to control the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there is an urgency to develop effective control measures. Essential information is encoded in the virus genome sequence with accurate and complete SARS-CoV-2 sequences essential for tracking the movement and evolution of the virus and for guiding efforts to develop vaccines and antiviral drugs. While there is unprecedented SARS-CoV-2 sequencing efforts globally, approximately 19 to 43% of the genomes generated monthly are gapped, reducing their information content. The current study documents the genome gap frequencies and their positions in the currently available data and provides an alternative primer set and a sequencing scheme to help improve the quality and coverage of the genomes.

genomics↗

bioRxiv2020

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5x10-8). The most significantly associated variant (rs2433603, p=2.4x10-9) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0x10-8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

genetics↗

bioRxiv2017

Enrichment of the HIV reservoir in CD32+ CD4 T cells occurs early in blood and tissue

The Fc receptor CD32 has been proposed as a marker for CD4 T cells latently infected with HIV. We demonstrate that enrichment for HIV DNA in CD32+ CD4 T cells can be found early in infection in both tissue and blood. However, we find no evidence for a correlation between CD32 expression on CD4 T cells and either HIV DNA levels or time to rebound viraemia following treatment interruption. CD32+ CD4 T cells have a more differentiated memory phenotype, and high levels of expression of immune checkpoint receptors PD-1, Tim-3 and TIGIT as well as the activation marker, HLA DR. There was no difference in the phenotype or frequency of CD32 expressing cells prior to or after the initiation of antiretroviral therapy, or compared with healthy controls, suggesting that preferential infection or survival, rather than up-regulation, may be responsible for the observed enrichment of proviral HIV DNA in CD32+ CD4 T cells.

immunology↗