Ek. Quakyi et al., MODULATION OF THE BIOLOGICAL-ACTIVITIES OF MENINGOCOCCAL ENDOTOXINS BY ASSOCIATION WITH OUTER-MEMBRANE PROTEINS IS NOT INEVITABLY LINKED TOTOXICITY, Infection and immunity, 65(5), 1997, pp. 1972-1979
Meningococcal sepsis results partly from overproduction of host cytoki
nes after macrophages interact with endotoxin. To obtain less toxic an
d highly immunomodulatory meningococcal endotoxins for prophylactic pu
rposes,,ve investigated the relationship between endotoxicity and immu
nomodulatory activity of several endotoxin preparations from Neisseria
meningitidis group B. Using the D-galactosamine-sensitized mouse mode
l to determine endotoxin lethality, we found that the toxicity of puri
fied lipooligosaccharide (LOS) from M986, a group B disease strain, wa
s three to four times higher than those of purified LOSs from the nonc
apsulated strains M986-NCV-1 and OP-, the truncated-LOS mutant. The LO
Ss of outer membrane vesicles (OMVs) and detergent-treated OMVs (D-OMV
s) from the three strains were 2 to 3 and over 300 times less toxic th
an the purified LOSs, respectively. Intraperitoneal administration of
these preparations induced production of tumor necrosis factor alpha (
TNF-alpha) and interleukin 6 (IL-6) in serum 2 h after injections, How
ever, repeated doses of low- and high-toxicity preparations induced lo
wer amounts of TNF-alpha and IL-6, i.e., LOS tolerance, Injection of m
ice with low doses of LOS was as effective as injection with high dose
s in inducing tolerance. Peritoneal macrophages from tolerant mice pre
treated with either high- or low-toxicity LOS preparations produced on
ly a fraction of the amounts of TNF-alpha and IL-6 produced by control
groups in response to LOS ex vivo. Despite tolerance to LOS induced b
y pretreatment with reduced-toxicity preparations, killing of N. menin
gitidis M986 by macrophages from these animals was enhanced. Protectio
n,vas achieved when mice treated with LOS, and especially that of D-OM
Vs, were challenged with live N. meningitidis. The least toxic LOS, th
at in D-OMVs, was most effective in inducing hyporesponsiveness to end
otoxin in mice but protected them against challenge with N. meningitid
is. No inevitable link between toxicity. and host immune modulation an
d responses was shown. Our results show that LOS Is responsible for bo
th toxicity and immunomodulation, When LOS is tightly associated with
outer membrane proteins in D-OMV it reduces toxicity but enhances bene
ficial effects compared to results with its purified form, Thus, syste
matic and critical evaluation of D-OMVs as adjuvants or as portions of
group B meningococcal vaccines may help improve survival and outcome
in meningococcal sepsis.