Lasunskaia, E. | Search bioRxiv

bioRxiv2025

CD39 REGULATES P2RX7-MEDIATED LUNG NECROTIC LESIONS IN SEVERE EXPERIMENTAL TUBERCULOSIS

Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in developing severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in TB progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We proposed that by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/656614v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dc7320org.highwire.dtl.DTLVardef@a4202org.highwire.dtl.DTLVardef@173bb62org.highwire.dtl.DTLVardef@1132f0f_HPS_FORMAT_FIGEXP M_FIG C_FIG BriefIn tuberculosis, necrotic granuloma-like structures release extracellular ATP (eATP), which triggers P2RX7-mediated immune cell death. CD39 degrades eATP, preventing P2RX7 activation and promoting macrophage survival, thereby limiting inflammation, tissue damage, and bacterial dissemination.

immunology↗

bioRxiv2024

Phylogenomic and genomic analysis reveals unique and shared genetic signatures of Mycobacterium kansasii complex species

Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii (stricto sensu), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defense systems and show that the MKC species harbors unique and shared genomic signatures. High frequency of presence of prophages and different types of defense systems was observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the 20th century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasiis increased virulence and drug resistance. RepositoriesBioProject PRJNA1048499. Impact statementMycobacterium kansasii complex (MKC) is a group of closely related non-tuberculous mycobacteria species, recognized as a significant source of human infection. Species belonging to the MKC may present a broad spectrum of virulence, antimicrobial resistance and pathogenicity and there is a lack of knowledge about their genomic content related to these broad phenotypes. We have provided whole genomic sequencing DNA for 342 MKC isolates and, together with public data, investigated the MKC pangenome, mobilome, resistome, virulome and defense systems and show unique and shared genetic signatures within MKC species. Furthermore, with phylogenomic and bayesian population analysis, we inferred the distribution and emergence of the Mycobacterium kansasii species lineages and sub-lineages. This study has considerably expanded the MKC available data, by providing genomic sequences of isolates from countries and global regions with unknown or poorly MKC data until now. Data summaryNGS data generated in the study are available in the NCBI Sequence Read Archive (SRA) repository under the accession number PRJNA1048499 and the accession numbers for all data sets used are provided in Supplementary Table 1.

evolutionary biology↗