Klebsiella pneumoniae remodels its Kdo2-lipid A in a TLR4-dependent manner to adapt to the macrophage intracellular environment
Bartholomew, T. L.; sa=Pessoa, J.; Lancaster, R.; Zhang, N.; Wojtania-O'Farrell, K.; Hancock, S. J.; Mills, G.; Kissenpfennig, A.; Bengoechea, J.
Show abstract
Pathogen adaptations to the intracellular macrophage environment remain poorly understood. We performed a high-resolution structural analysis of the lipid A purified from intracellular Klebsiella pneumoniae (KP). In both mouse and human macrophages, KP produces hexa- and hepta-acylated lipid A species modified with palmitate and 2-hydroxylated. LpxL1, PagP, and LpxO enzymes govern the intracellular lipid A in a PhoPQ-dependent manner triggered by the acidic pH of the KP-containing vacuole (KCV). Absence of LpxO and PagP lipid A modifications impairs intracellular survival and heightens NF-{kappa}B and IRF3-mediated inflammation, though KCV maturation remains unaffected. Instead, these modifications fortify the bacterial membrane. Absence of TLR4-TRAM-TRIF signalling increases KCV pH, impairing the production of the intracellular lipid A. KP intracellular survival is reduced in tlr4-/- macrophages, highlighting the critical role of this signalling pathway in KP immune evasion and how the pathogen has evolved to rely on innate immune system cues for virulence.
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