MODULATION OF THE BIOLOGICAL-ACTIVITIES OF MENINGOCOCCAL ENDOTOXINS BY ASSOCIATION WITH OUTER-MEMBRANE PROTEINS IS NOT INEVITABLY LINKED TOTOXICITY

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.