A large toxin from pathogenic Escherichia coli strains that inhibits lymphocyte activation

The mechanisms by which bacteria resist cell-mediated immune responses to c ause chronic infections are largely unknown. We report the identification o f a large gene present in enteropathogenic strains of Escherichia coli (EPE C) that encodes a toxin that specifically inhibits lymphocyte proliferation and interleukin-2 (IL-2), IL-4 and gamma interferon production in response to a variety of stimuli. Lymphostatin, the product of this gene, is predic ted to be 366 kDa and shares significant homology with the catalytic domain s of the large clostridial cytotoxins. A mutant EPEC strain that has a disr uption in this gene lacks the ability to inhibit lymphokine production and lymphocyte proliferation, Enterohemorrhagic E. coli strains of serotype O15 7:H7 possess a similar gene located on a large plasmid. Loss of the plasmid is associated with loss of the ability to inhibit IL-2 expression while tr ansfer of the plasmid to a nonpathogenic strain of E. coli is associated wi th gain of this activity. Among 89 strains of E. coli and related bacteria tested, lifA sequences were detected exclusively in strains capable of atta ching and effacing activity. Lymphostatin represents a new class of large b acterial toxins that blocks lymphocyte activation.