Pseudomonas aeruginosa alginate promotes intracellular Mycobacterium tuberculosis and NTM growth by modulating innate immunity

The complex interplay between pulmonary dysbiosis and tuberculosis (TB) susceptibility, relapse, and treatment failure is increasingly recognized, yet specific mechanistic contributions of airway pathogens remain elusive. Pseudomonas aeruginosa, particularly its mucoid phenotype characterized by alginate overproduction, is frequently found in chronic lung diseases and TB-associated microbiomes. Understanding how this common co-pathogen influences host immunity and mycobacterial persistence is crucial, as current TB therapies do not directly address the impact of such microbial interactions on disease progression.

Researchers investigated the immunomodulatory effects of mucoid P. aeruginosa and its alginate on mycobacterial infection. They used human type II pneumocytes and monocyte-derived macrophages, exposing them to heat-killed mucoid P. aeruginosa or non-mucoid P. aeruginosa. Subsequently, cells were infected with Mycobacterium tuberculosis (M. tuberculosis) or Mycobacterium abscessus (M. abscessus). In parallel experiments, cells were treated with exogenous alginate in a dose- and time-dependent manner before mycobacterial infection. Primary endpoints included intracellular mycobacterial growth, assessed by colony-forming unit (CFU) assays, and mRNA expression of antimicrobial peptides (LL-37, hBD-2, hBD-3) and key pro- and anti-inflammatory cytokines, measured by qPCR.

Heat-killed mucoid P. aeruginosa significantly enhanced intracellular growth of both M. tuberculosis and M. abscessus in human type II pneumocytes and monocyte-derived macrophages, compared to the non-mucoid phenotype. Exogenous alginate alone reproduced these growth-promoting effects in a dose- and time-dependent manner, without directly stimulating mycobacterial proliferation in culture. Mechanistically, alginate treatment was associated with a reduced mRNA expression of critical antimicrobial peptides, including LL-37, hBD-2, and hBD-3, in M. tuberculosis-infected macrophages. Furthermore, alginate modulated the expression of key pro- and anti-inflammatory cytokines. > In pneumocytes, alginate induced a delayed inflammatory transcriptional response that proved insufficient to control intracellular mycobacterial growth, highlighting a critical immune evasion mechanism. These findings collectively identify alginate as a potent immunomodulatory factor that shifts innate immune responses to favor mycobacterial persistence.