Endotoxin released from different strains of Neisseria meningitidis were studied for their ability to induce procoagulant (tissue factor, TF), fibrinolytic (plasminogen activator, PA) and antifibrinolytic (plasminogen activator inhibitor 2, PAI-2) factors in human monocytes. Two meningococcal strains that liberate endotoxin (E+; 270+ and 840+) and 2 non-liberating (E-; 270- and 840-) strains were used. The endotoxin activity in culture filtrates of these strains was monitored with the Limulus amoebocyte lysate (LAL) test. There was a marked difference between E+ and E- strains in their ability to liberate endotoxin. Suspensions of whole bacteria of all 4 strains induced a significant (14-19-fold) increase in monocyte TF expression when present in concentrations > 10(5) CFU/ml. At lower concentrations (10(4) CFU/ml), E+ strains were clearly more potent stimulators of TF synthesis than E- strains. Culture filtrates of E+ strains were up to 10(4)-fold more potent in inducing TF synthesis than filtrates from E- strains. This marked difference in inducing potency between E+ and E- strains was also observed when monocyte PAI-2 synthesis was examined. The PA expression, on the other hand, was suppressed when monocytes were incubated in the presence of culture filtrates, especially filtrates from the E+ strains. The increased procoagulant and antifibrinolytic activity, together with reduced profibrinolytic activity of monocytes, was closely correlated to the amount of endotoxin measured in the culture filtrates. These changes may contribute substantially to the coagulopathic state seen during systemic meningococcal disease.
Endotoxin liberation was studied in a blinded material of 121 Neisseria meningitidis isolates; from nasopharynx of 58 carriers and from cerebrospinal fluid or blood of 63 cases with meningococcal disease. Endotoxin activity in culture filtrates was determined by a Limulus lysate test. Meningococci isolated from clinical cases were significantly more frequently endotoxin-liberating (E+) (84.1%) than in carriers (25.9%); p less than 0.001. Serogroupable carrier isolates had a significantly higher frequency of E+ meningococci (61.9%) than non-groupable ones (5.4%); p less than 0.002. Serogroup B case isolates, which generally had a larger amount of capsular polysaccharide than B meningococci from carriers, had a significantly higher proportion of E+ meningococci than group B from carriers; p = 0.007. All 7 serogroup C isolates were E+ (5 cases and 2 carriers). No correlation was found between endotoxin liberation and the serotype: subtype 15:P1.16, tested by a selection of monoclonal antibodies, or between endotoxin liberation and sulfonamide resistance, when carrier and case isolates were studied separately. Meningococci isolated from cases had the following mean endotoxin titres: 320.5 in the meningitis group, 408.2 in the septicaemic group, 462.1 in the septicaemic and meningitis group, and 123.7 in the group with other systemic disease. E+ meningococci were isolated from 5/6 fatal cases. Thus, endotoxin liberation from meningococci is strongly, but not completely associated with establishment of meningococcal disease and with the presence of capsular polysaccharide.
The relationship between endotoxin liberation and invasiveness was studied in 50 strains of Neisseria meningitidis isolated from blood or cerebrospinal fluid (CSF) of 16 patients with invasive disease, from nasopharynx of 9 patients with upper respiratory tract symptoms, and from nasopharynx and rectum (1, serogroup W-135) in 25 persons examined for venereal disease. Meningococci varied in their ability to liberate endotoxin. Free endotoxin was partly a function of growth and seemed to be associated with certain properties of the individual strain. Strains isolated for patients with invasive disease liberated significantly more endotoxin than strains isolated from the venereal group (p less than 0.002). All 16 invasive strains were sulfonamide resistant, against 5/9 strains from patients with upper respiratory disease symptoms and only 4/25 strains from the venereal group. The difference between the invasive group and the venereal group was significant (p less than 0.002). Serogroup A, B, C meningococci liberated significantly more endotoxin than non-A, B, C strains (p = 0.01, and serogroup A, B, C strains isolated from nasopharynx tended to have a higher endotoxin release than non-A, B, C strains isolated from the same place (not significant). Serogroup B meningococci were most frequently isolated both from patients with invasive disease and from the nasopharynx of the persons examined for venereal disease. Serogroup B meningococci had significantly more free endotoxin when isolated from blood or CSF than when isolated from nasopharynx of presumably healthy persons (p = 0.002).
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