Abstract
Wnt5A signaling facilitates the killing of several bacterial pathogens, but not the non-pathogen E. coli DH5α. The basis of such pathogen vs. non-pathogen distinction is unclear. Accordingly, we analyzed the influence of Wnt5A signaling on pathogenic E. coli K1 in relation to non-pathogenic E. coli K12-MG1655 and E. coli DH5α eliminating interspecies variability from our study. Whereas cell internalized E. coli K1 disrupted cytoskeletal actin organization and multiplied during Wnt5A depletion, rWnt5A mediated activation revived cytoskeletal actin assembly facilitating K1 eradication. Cell internalized E. coli K12-MG1655 and E. coli DH5α, which did not perturb actin assembly appreciably, remained unaffected by rWnt5A treatment. Phagosomes prepared separately from Wnt5A conditioned medium treated K1 and K12-MG1655 infected macrophages revealed differences in the relative levels of actin and actin network promoting proteins, upholding that the Wnt5A-Actin axis operates differently for internalized pathogen and non-pathogen. Interestingly, exposure of rWnt5A treated K1 and K12-MG1655/DH5α infected macrophages to actin assembly inhibitors reversed the scenario, blocking killing of K1, yet promoting killing of both K12-MG1655 and DH5α. Taken together, our study illustrates that the state of activation of the Wnt5A/Actin axis in the context of the incumbent bacteria is crucial for directing host response to infection.
Highlights
Wnt5A belongs to a 19-member family of Wnt ligands, which are secreted glycoproteins originally discovered with reference to embryonic development
In order to compare the effect of Wnt5A signaling on bacterial pathogens and non-pathogens, we focused on E. coli K1 as a pathogen in relation to E. coli K12-MG1655 or E. coli DH5a as non-pathogen
Since phagosomes control the fate of internalized bacteria, we examined if the respective phagosome compositions associated with pathogenic (K1) and non-pathogenic (K12-MG1655) E. coli infections in Wnt5A activated macrophages feature the observed differences in actin assembly (Figure 2)
Summary
Wnt5A belongs to a 19-member family of Wnt ligands, which are secreted glycoproteins originally discovered with reference to embryonic development. Wnts interact with Frizzled (Fz) and ROR cell surface receptors. Wnt signaling is divided into two main categories – canonical (b-catenin dependent) and non-canonical (b-catenin independent) [6, 8]. While canonical Wnt signaling mostly acts through b-catenin mediated transactivation of specific genes, non-canonical Wnt signaling often acts independent of b-catenin during regulation of cell polarity and differentiation [9,10,11,12]. On account of sequence homology within the Wnt and Frizzled/ ROR family members, cross reactivity in Wnt-Frizzled/ROR interactions and crosstalk among the signaling intermediates of the canonical and non-canonical Wnt signaling pathways is quite frequent [7, 13, 14]
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