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Infection and Immunity, August 1999, p. 3750-3756, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Pneumolysin, a Protein Toxin of Streptococcus pneumoniae, Induces Nitric Oxide Production from Macrophages

Johann S. Braun,* Rodger Novak, Geli Gao, Peter J. Murray, and Jerry L. Shenep

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 25 January 1999/Returned for modification 19 March 1999/Accepted 5 May 1999

Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation is an essential element of antimicrobial immunity but can also contribute to host-induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO are produced, causing hypotension, a critical pathological feature of septic shock. In sepsis caused by gram-positive organisms, the bacterial factors contributing to host NO production are poorly characterized. We show that a soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component initiating NO production from macrophages. In contrast to wild-type bacteria, a mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine macrophages. Purified recombinant Pln induced NO production at low concentrations and independently of exogenous gamma interferon (IFN-gamma ) priming of RAW 264.7 macrophages. However, IFN-gamma was essential for Pln-induced NO production, since primary macrophages from mice lacking the IFN-gamma receptor or interferon regulatory factor 1, a transcription factor essential for iNOS expression, failed to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of tumor necrosis factor alpha and interleukin 6 production in macrophages. The properties of Pln, previously identified as a pore-forming hemolysin, also include a role as a general inflammatory agonist.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794. Phone: (901) 495-3486. Fax: (901) 495-3099. E-mail: johann.braun{at}stjude.org.

Infection and Immunity, August 1999, p. 3750-3756, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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