Biology subjects

Anthony, R. M.

Publications and source records attributed to Anthony, R. M..

3 recordsLinked to original sources

bioRxiv2023

The appearance of sugI mixed loci in three individuals during treatment for MDR-TB, supports the involvement of sugI in Mycobacterium tuberculosis d-cycloserine resistance in vivo.

To study the adaptation of multi-drug resistant Mycobacterium tuberculosis (MDR-TB) during treatment patients diagnosed with MDR-TB were recruited into an observational study. Clinical data and M. tuberculosis DNA at diagnosis and between seven days and two months of MDR-TB treatment were collected. The drugs prescribed were recorded. Interpretable WGS data from 118 isolates from 54 participants was obtained (11 in Belarus and 43 in Moldova) and screened for the presence of unfixed single nucleotide polymorphisms (mixed SNPs / loci). This study was performed shortly after the publication of the 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Existing drug supplies and procurement in one country after the switch to the all oral MDR-TB regimen in addition to patient factors, influenced the selection of and exposure to drugs. Confidently mixed SNPs were identified in samples from multiple participants in only five genes (gyrA, pncA, Rv1129c, Rv1148c, and sugI). All other genes with confidently mixed SNPs were identified in isolates from only a single individual. A significant proportion of the participants (52 of 54 participants) received d-cycloserine as part of their initial treatment, most participants who initially received d-cycloserine did not receive bedaquiline in their initial regimen (all at one site). Three different mixed SNPs were identified in sugI gene from a follow up isolate from three participants (P7A, P7T, and Q6stop). Mutations in sugI have previously been reported in spontaneous in vitro d-cycloserine resistant mutants. Alterations in the sugI gene may indicate a sub optimal d-cycloserine containing regimen and potentially be of clinical significance with respect to adaptation to d-cycloserine. Monitoring the accumulation of low frequency escape mutants may help identify regimens insufficiently powerful to block the accumulation of antimicrobial resistance mutants and identify drug(s) at risk of resistance selection.

microbiology↗

bioRxiv2023

Lung injury induces a polarized immune response by self antigen-specific Foxp3+ regulatory T cells

Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury. Acute injury resulted in the exclusive expansion of regulatory T cells (Tregs) that was dependent on self antigen recognition and IL-2. Conversely, conventional T cells of the same self antigen specificity remained unresponsive, even following Treg ablation. Thus, the self antigen-specific T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.

immunology↗

bioRxiv2019

Genetic profiling of Mycobacterium tuberculosis \"modern\" Beijing strains from Southwest Colombia

Beijing strains of Mycobacterium tuberculosis (lineage2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian pacific coast exhibited a multidrug resistant (MDR) phenotype, in contrast with the phenotype observed in Beijing isolates from other South-American countries. We wanted to evaluate the clonality and genetic background of the Beijing strains isolated in Colombia that belong mostly to the spoligo-international type (SIT) 190. Out of 37 Beijing stains characterized in an 8-years period, we identified five Beijing clones; 36 that belong to the SIT190 type and only one to SIT1. Two loci in VNTR typing: MIRU 39 and QUB11b exhibited the highest level of variation among these strains. Out of the 37 Beijing strains, only one was drug susceptible, 28 represented MDR-TB, four extensively drug resistant TB (XDR-TB) and four pre-XDR-TB. The mutations rpoB S531L and katG S315T1 were the most common among the MDR strains as reported elsewhere. Whole genome sequencing analysis allowed us to classify them as modern lineage Beijing strains, sharing up to 76 out of the 275 SNPs described in Beijing strains, as identified worldwide by Schurch et al; including 54 non-synonymous SNPs and 23 silent mutations. We were also able to confirm the presence of 8 specific SNPs that were so far only found in the Beijing strains from Colombia. The presence of modern Beijing strains, most of them representing MDR-TB, suggests a different origin of this M. tuberculosis lineage compared to other Beijing strains found in neighboring countries, such as Peru. The specific 8-SNP signature confirmed the identity of these Colombian Beijing MDR strains. This work may serve as a genetic baseline to study the evolution and spread of M. tuberculosis Beijing strains in Colombia, which play an important role in the control of MDR-TB.

microbiology↗