The meningeal inflammatory response to a heat-killed mutant unencapsulated strain of type III group B Streptococcus (GBS) was studied in a newborn piglet model. GBS (10(9) colony-forming unit equivalents) or saline (control) was inoculated intraventricularly. Serial cerebrospinal fluid measurements were done at baseline and over the course of the next 24 h for cytochemical changes and production of tumor necrosis factor (TNF) and prostaglandins. In separate experiments, we defined the time course of early changes during the first 6 h and dose response relationship over a range of inocula 10(6) to 10(9) colony-forming unit equivalents. The intraventricular inoculation of the heat-killed unencapsulated GBS induced marked leukocytosis and increased protein by 6 h. These changes were preceded by a several hundredfold increase in TNF (maximum at 2 h) and prostaglandins (maximum at 2-4 h). The early and sharp rise in TNF suggests its pivotal role in initiating the inflammatory cascade. The magnitude of the inflammatory response increased with increasing bacterial dose over the range studied. To study the effect of encapsulation of GBS in the induction of meningeal inflammation, we compared the response to the unencapsulated mutant strain with that to the encapsulated parent strain. The encapsulated strain produced much smaller inflammatory changes, and only with high doses of bacteria. The GBS cell wall appeared to be the primary bacterial product triggering inflammation. Intraventricular injection of the heat-killed unencapsulated GBS with exposed cell wall can serve as a valid model for studying neonatal meningitis.