Biology subjects

Adamson, J.

Publications and source records attributed to Adamson, J..

3 recordsLinked to original sources

bioRxiv2021

Mycobacterium tuberculosis senses host Interferon- gamma via the membrane protein MmpL10

Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens and remains a leading cause of death from infectious disease. Interferon-{gamma} (IFN-{gamma}) is a central regulator of the immune defense against Mtb. Several cytokines have been shown to increase virulence of other bacterial pathogens, leading us to investigate whether IFN-{gamma} has a direct effect on Mtb. We found that both recombinant and T-cell derived IFN-{gamma} rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was also observed in clinical strains, but not in the vaccine strain Bacillus Calmette-Guerin (BCG), and did not occur for other cytokines tested, including TNF-. IFN-{gamma} binds to the cell surface of intact Mtb, but not BCG, whilst TNF- binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-{gamma} binding and the OCR response was absent in a Mtb {Delta}mmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-{gamma} exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-{gamma} resulted in sterilization of bacilli treated with isoniazid (INH), indicating clearance of phenotypically resistant bacteria that persist in the presence of INH alone. Our data suggest a novel mechanism allowing Mtb to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies. One-Sentence SummaryIFN-{gamma} is a critical component of effective immune defense in human tuberculosis yet its causative agent, Mycobacterium tuberculosis it able to sense this cytokine and increase virulence and respiration in response.

microbiology↗

bioRxiv2019

N-acetyltransferase 2 genotypes amongst ulu Speaking South Africans and isoniazid / N-acetyl-isoniazid pharmacokinetics during ant-tuberculosis treatment

BackgroundDistribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics in Zulu black HIV-infected South Africans in Durban, South Africa. Methods: HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Culture-confirmed participants were genotyped for NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A and 803A>G using Life Technologies pre-validated Taqman assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetylisoniazid concentrations. ResultsAmongst the 120 patients, 63/120 (52.5%) were slow metabolisers (NAT2*5/*5), 43/120 (35.8%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (NAT2*4/*11, NAT2*11/12 and NAT2*12/12). NAT2 alleles in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C and *12M. NAT2*5 was the most frequent allele (70.4%) followed by NAT2*12 (27.9%). 34/40 had both PK results and NAT2 genotyping results. The median area under the concentration-time-curve to infinity (AUC0-{infty}) interquartile range (IQR) was 7.81 (5.87 - 16.83) g/ml/hr and maximum concentration (Cmax) 3.14 g/ml (2.42 - 4.36) g/mL. Individual polymorphisms were not equally distributed, with some represented in small numbers. Genotype did not correlate with phenotype, rapid genotype showing higher AUC0-{infty} than slow but not significant, p=0.43. ConclusionThere was high prevalence of slow followed by intermediate then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence INH metabolism, and warrants further investigation in this population.

genetics↗

bioRxiv2019

The CNS in the face of ART contains T cell origin HIV which can lead to drug resistance

HIV persists despite antiretroviral therapy (ART) in cellular reservoirs thought to occur in distinct anatomical compartments. Therapy failure may occur because of incomplete ART adherence and possibly viral replication at some reservoir sites. The CNS may serve as a reservoir site due to lowered ART penetration and virus production from long-lived tissue resident macrophages. Compelling evidence for the CNS as a reservoir is the existence of individuals where HIV is suppressed below limit of detection in blood but detectable in the cerebrospinal fluid (CSF), termed CSF Escape. Here, we asked whether HIV in CSF Escape individuals is derived from macrophages or persists due to lowered ART. We used cell surface markers on the HIV envelope to determine the cellular source of HIV. We verified detection using in vitro derived virus from infected macrophages and T cells and tested CSF from CSF Escape individuals. We observed host surface markers consistent with T cell origin. We also measured ART concentrations in the CSF and plasma. We found a dramatic decrease in CSF ART concentrations described previously, but no significant difference between CSF Escape versus fully suppressed individuals. To examine the effect of the observed CSF ART concentrations on HIV replication, we used long-term infection with ART in cell culture. CSF Escape ART levels led to either HIV suppression or evolution of drug resistance, but not replication of drug sensitive HIV. These observations argue that persistent CNS viremia despite ART can be T cell generated and may result in drug resistance and therapy failure.

microbiology↗