Intracellular persister: A stealth agent recalcitrant to antibiotics

Abstract

The bulk of bacteria transiently evading appropriate antibiotic regimes and recovered from non-resolutive infections are commonly refer to as persisters. In this mini-review, we discuss how antibiotic persisters stem from the interplay between the pathogen and the cellular defenses mechanisms and its underlying heterogeneity.

Keywords: antibiotic; heterogeneity; infection; persisters; virulence.

Figure 1

(A) Formation of an intravacuolar persister. Quickly after uptake, the phagocytic vacuole maturates along the endo-lysosomal pathway. Within the phagosome various stressors contribute to the pathogen clearance. Both the alteration of the bacterial physiology (depicted in red) and the bacterial adaptative responses, to counter the macrophage-derived stress (“defensive mode” depicted in blue), favor (large blue and red arrows) the formation of a specialized subpopulation of survivors with high recalcitrance to antibiotics termed intracellular persisters (depicted in black). (B) The intravacuolar persisters undermine the host defense. In addition to their defensive mode, intracellular Salmonella and Legionella persisters can execute an offensive virulence program that translocated effectors via a type 3 or type 4 secretion system, respectively. Contrary to the Salmonella virulence factor SteE produced both by the persisters and the coexisting antibiotic susceptible individuals, the Legionella intracellular persisters specifically produced SidC and MavC. The figure depicts the mode of action those 3 effectors, the modes of action of which are detailed in the main text. Pattern Recognition Receptors (PRR) recognize molecules frequently found in pathogen and trigger pro-inflammatory response enhancing the bactericidal activities. Persisters may tackle immune recognition by modifying their peptidoglycan. PCV, persister containing vacuole; SCV, Salmonella containing vacuole; Ub, ubiquitination; P, phosphorylation. (C) Persisters formation stems from heterogeneity in biological processes. The underlying mechanisms remain largely unexplored. For L. pneumophila: alternative activation of the quorum sensing (blue and yellow bacteria) and intravacuolar heterogenous differentiation of the proliferative subset (green and orange bacteria). For M. tuberculosis: phagosome to phagosome pH variations depicted by different colors. For E. coli LF82: unknown. Persisters formation may result from heterogeneous stress exposure or response. For S. enterica: Alternative macrophage polarization (proinflammatory in red, anti-inflammatory in blue) possibly associated to distinct phagosomal features (pH and nutrients). For S. aureus: alternative oxidative stress pressure generating distinct persisters (i.e., with distinct dormancy’s depth depicted by the bacterial shape). QS, quorum sensing; RB, respiratory burst; Nu, nutrient limitation; OS, oxidative stress (strength depicted with a white triangle); MAP, metabolically active persisters; NMAP, non-metabolically active persisters; filled bacterium, antibiotic susceptible bacterium; hatched bacterium, antibiotic persister; dashed bacteria, dead individual;?, unknown mechanism. 1, uptake; 2 persister formation or intracellular proliferation of antibiotic susceptible bacteria; 3, antibiotic treatment; 4, Persister survival.