Infection and Immunity, September 1998, p. 4215-4221, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
(IL-1
) but Augments the Lethality of
Escherichia coli by an IL-1- and Tumor Necrosis
Factor-Independent Mechanism
Surgical Infectious Disease Laboratory, University of Virginia, Charlottesville, Virginia1; Department of Surgery, University of Alabama, Birmingham, Alabama2; and Department of Surgery, University of South Florida, Tampa, Florida3
Received 30 December 1997/Returned for modification 5 March 1998/Accepted 22 May 1998
Many pathogenic Escherichia coli produce the toxin
alpha-hemolysin (Hly), and lipopolysaccharide (LPS), interleukin-1
(IL-1), and tumor necrosis factor (TNF) have all been recognized as
important effector molecules during infections by gram-negative
organisms. Despite the characterization of many in vitro effects of
hemolysin, no direct relationship has been established between
hemolysin, LPS, proinflammatory cytokine production, and E. coli-induced mortality. Previously, we have shown in vivo that
hemolysin elicits a distinct IL-1
spike by 4 h into a lethal
hemolytic E. coli infection. Using three transformed
E. coli strains, WAF108, WAF270, and WAH540 (which produce
no Hly [Hlynull], acylated Hly
[Hlyactive], or nonacylated Hly
[Hlyinactive], respectively), we sought to determine
the specific roles of hemolysin acylation, LPS, IL-1, and TNF in
mediating the lethality of E. coli infection in mice.
WAF270 was 100% lethal in BALB/c, C3H/HeJ, and C57BL/6 mice; in mice
pretreated with antibody to the type 1 IL-1 receptor; in type 1 IL-1
receptor-deficient mice; and in dual (type 1 IL-1 receptor-type 1 TNF
receptor)-deficient mice at doses which were nonlethal (0%) with both
WAF108 and WAH540. At lethal doses, WAF270 killed by 6 ± 2.3 h while WAF108 and WAH540 killed at 36 ± 9.4 and 36 ± 13.8 h, respectively. These differences in mortality were not due
to IL-1 or TNF release, and the enhanced expression of LPS, which
corresponded to Hly expression, was not likely the primary factor
causing mortality. We demonstrate that bacterial fatty acid acylation
of hemolysin is required in order for it to elicit IL-1 release by
monocytes and to confer its virulence on E. coli.
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