Genetic and immunologic determinants of BCG disease: from mechanism to prevention

Background Bacillus Calmette-Guérin (BCG) infection, a disseminated infection triggered in immunocompromised hosts by the administration of the attenuated BCG vaccine, is characterized by a pathogenic mechanism that involves the synergistic interaction between host immune deficiencies and strain-specific genetic mutations. Methods This review synthesizes published multi-omics and proteomics findings from the past decade, along with reported results from in vitro drug susceptibility assays and molecular diagnostics, to explore key pathogenic genes in BCG strains. We compare differences in pathogen characteristics, host immune responses, and clinical manifestations between BCG disease and tuberculosis (TB) disease caused by Mycobacterium tuberculosis (Mtb). Additionally, we summarize evidence on BCG drug susceptibility and the roles of resistance-related genes in drug resistance mechanisms. Results The study revealed the following findings: 1) The occurrence of BCG disease follows the "dual-hit model," where defects in the host interferon-gamma/interleukin-12 (IFN-γ/IL-12) signaling pathway (in 70% of cases) synergize with genetic mutations in BCG strains (such as pks12 and mma3), leading to immune evasion and disseminated infection; 2) Compared to Mtb, BCG strains exhibit reduced virulence due to the loss of the RD1 region, but strain heterogeneity leads to differences in cell wall lipid metabolism, which induces atypical systemic symptoms in immunocompromised hosts; 3) Some BCG strains display low-level resistance to isoniazid and rifampicin, with resistance linked to mma3 mutations (resulting in increased MIC for isoniazid) and inactivation of pncA (resulting in resistance to pyrazinamide); 4) Genetic modifications of strains (such as BCGΔBCG1419c vaccine), delayed vaccination, and individualized immune monitoring can effectively reduce the infection risk in immunocompromised hosts. T-cell receptor excision circles (TREC)/K-cell receptor excision circles (KREC) screening improves the identification rate of immunocompromised hosts. Conclusion BCG disease represents a typical case of host-pathogen interaction imbalance. Its prevention and control require an integrated approach combining molecular mechanisms and clinical practice improvements.