SURVIVAL OF FIMH-EXPRESSING ENTEROBACTERIA IN MACROPHAGES RELIES ON GLYCOLIPID TRAFFIC

Strains of Escherichia coli persist within the human gut as normal com mensals, but are frequent pathogens and can cause recurrent infection( 1-3). Here we show that, in contrast to E. coli subjected to opsonic i nteractions stimulated by the host's immune response, E. coli that bin d to the macrophage surface exclusively through the bacterial lectin F imH can survive inside the cell following phagocytosis. This viability is largely due to the attenuation of intracellular free-radical relea se and of phagosome acidification during FimH-mediated internalization , both of which are triggered by antibody-mediated internalization. Th is different processing of non-opsonized bacteria is supported by morp hological evidence of tight-fitting phagosomes compared with looser, a ntibody-mediated phagosomes. We propose that non-opsonized FimH-expres sing E. coli co-opt internalization of lipid-rich microdomains followi ng binding to the FimH receptor, the glycosylphosphatidylinositol-link ed protein CD48, because (1) the sterol-binding agents filipin, nystat in and methyl beta-cyclodextrin specifically block FimH-mediated inter nalization; (2) CD48 and the protein caveolin both accumulate on macro phage membranes surrounding bacteria; and (3) antibodies against CD48 inhibit FimH-mediated internalization. Our findings bring the traditio nally extracellular E. coli into the realm of opportunistic intracellu lar parasitism and suggest how opportunistic infections with FimH-expr essing enterobacteria could occur in a setting deprived of opsonizing antibodies.