TABLE 1.

DS-M.tb and DR-M.tb interactions with the host at different stages of the infection.

Lung environments	DS-M.tb	DR-M.tb
Initial M.tb–host interactions ALF (e.g., hydrolases, surfactant proteins, etc.)	• Decrease of ManLAM and TDM in the cell envelope surface: increased P-L fusion in phagocytes (better control of M.tb intracellular growth). • Differential M.tb infection outcome in ATs after ALF exposure: H-ALF vs. L-ALF (based on ALF composition and functionality: host component). • Increased neutrophil’s capacity to eliminate ALF-exposed M.tb (increased P-L fusion and higher levels of TNF and IL-8, but reduced oxidative burst).	• Thicker cell envelope. • Presumably altered levels of fatty acids, TDM, TMM, glycerophospholipids, GLs, PDIM, PGL. • Presumably altered protein composition. • Presumably altered ALF-driven cell envelope modifications.
Initial stages of infection Macrophages, Neutrophils, ATs	• PAMPs in the M.tb cell envelope recognized by macrophages, DCs and other immune cells through different receptors. • Mannose-containing molecules in the cell envelope promote recognition and survival inside phagocytic cells. Host defense and immunomodulatory roles. • Efflux pumps correlated with development of drug resistance. • ManLAM, TDM, and PDIM levels associated with arrest of phagosomal acidification. • Virulence and pathogenesis correlated with the strain’s ability to invade ATs (protective intracellular niche).	• Increased expression of efflux pumps. • Reprogramming of host macrophage metabolism (bypassing the IL-1R1 pathway and inducing INF-β). • Remodeling of host transcriptional profiling through epigenetic manipulation. • Altered cytokine/chemokine production in macrophages. • Strains with low PDIM levels associated with low virulence. • Increased adhesion and invasion of ATs: successful dissemination. • Altered levels of CD3, CD4, NKT, CD4/CD8 ratio, TNF levels in serum: immune dysfunction.
Latent M.tb infection Granuloma	• Preference toward metabolic pathways using free fatty acids. • Dynamic remodeling of M.tb cell proteome and lipid metabolic networks. • Altered exporter function. • DS-M.tb becomes phenotypically drug-resistant (cell wall thickening). • Overexpression of efflux pumps.	• Transient drug-tolerance and permanent drug-resistance associated with trehalose-catalytic shift. • Similar phenotype as DS-M.tb in the granuloma environment.
Reactivation/active TB disease	• Increased production of mycolic acids, PDIM, SL-1, and PATs. • Biofilm formation in cavities (extracellular matrix of free mycolic acids).	• Currently unknown, although expected to have similarities to the interactions specifically described for DS-M.tb strains at this stage of the infection. It is at this stage when DR-M.tb is in cavities supposedly exposed to multiple drugs during DR-TB treatment and thus, DR-M.tb could also become resistant to these drugs (Sharma et al., 2020).

DS-M.tb, drug-susceptible Mycobacterium tuberculosis; DR-M.tb, drug-resistant Mycobacterium tuberculosis; ALF, alveolar lining fluid; TDM, trehalose dimycolate; ATs, alveolar epithelial cells; H-ALF, high-ALF; L-ALF, low-ALF; TMM, trehalose monomycolate; GLs, glycolipids; PDIM, phthiocerol dimycocerosate; PGL, phenolic glycolipids; PAMPs, pathogen-associated molecular patterns; DCs, dendritic cells.