Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in
antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG
infection after neonatal vaccination (
BCG-vaccine). Distinct M. bovis
BCG-vaccine derived clinical strains were recovered from the patient's lungs and brain. Methods: BCG strains were phenotypically (growth,
antibiotic susceptibility,
lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell
infection models were used to assess apoptosis,
necrosis,
cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level
rifampin resistance; the latter displayed
clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively.
Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and
Mycolic acid components in BCG-lung, compared to parent
BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher
cytokine release,
necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG
infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.