Comparative pathoadaptation of Mycobacterium canettii and Mycobacterium tuberculosis: Insights from assays on phagosome acidification, cytosolic access, and transcriptomics

Autor(es)

Araujo, Camila do Nascimento ; Silva, Felipe ; Zimpel, Cristina Kraemer ; Silva-Pereira, Taiana Taina ; Soler-Camargo, Naila Cristina ; de Melo, Filipe Menegatti ; de Araujo, Marcelo Valdemir ; Guimaraes, Ana Marcia de Sa

• Tipo de documento: Artigo Científico
• Fonte: Microbes and Infection; v. 27, n. 4, p. 11-pg., 2025-05-01.

Resumo

Genetic and molecular differences between Mycobacterium tuberculosis (Mtb) and its ancestral counterpart, Mycobacterium canettii (Mcan), remain poorly known. Our study aimed to compare their modulation of phagosome acidification and cytosolic access in macrophages, and their in vitro transcriptomes. Using spectrofluorometry, we tracked pH changes in mycobacteria-containing vacuoles in THP-1 macrophages. A single-cell FRET protocol evaluated cytosolic access of mycobacteria in these cells. Similar to Mtb, Mcan inhibits phagosome acidification and accesses the cytosol. Transcriptomic and genetic analyses reveal mutations in two-component systems (PhoPR, SenX3-RegX3, and DevRS/DosRS) and in specific genes (e.g., lactate dehydrogenase and espACD) driving variations in gene expression between pathogens. Moreover, Mcan upregulates genes of iron and molybdopterin metabolism compared to Mtb, suggesting a role for metals in the evolution of tuberculous mycobacteria. The upregulation of the termination factor Rho in Mtb also suggests differences in antisense transcription and/or gene expression regulation. In conclusion, phagosome modulation and cytosolic access in macrophages are ancestral traits predating the emergence of the MTBC and not exclusive to Mtb's strict pathogenic lifestyle. Additionally, gene expression regulation likely shaped the phenotypic differences between Mcan and Mtb, contributing to the evolutionary transition from an environmental Mcan-like ancestor to the MTBC's host-adapted lifestyle. (AU)

• Processo FAPESP: 17/04617-3 - Adaptação de Mycobacterium tuberculosis e Mycobacterium bovis a hospedeiros: uma análise genômica e transcricional
• Beneficiário: Cristina Kraemer Zimpel
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/21847-8 - Estudo comparativo da resposta imune do macrófago humano infectado com diferentes espécies do Complexo Mycobacterium tuberculosis
• Beneficiário: Felipe Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 16/26108-0 - Biologia sistêmica e comparativa do complexo Mycobacterium tuberculosis: efeitos da variabilidade genética no fenótipo bacteriano
• Beneficiário: Ana Marcia de Sá Guimarães
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores