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Infection and Immunity, January 2005, p. 298-307, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.298-307.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2

Abdul Q. Khan,1 Quanyi Chen,1 Zheng-Qi Wu,2 James C. Paton,3 and Clifford M. Snapper1*

Department of Pathology, Uniformed Services University of the Health Sciences,1 Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland,2 School of Molecular and Biomedical Sciences, University of Adelaide, South Australia, Australia3

Received 12 July 2004/ Returned for modification 24 August 2004/ Accepted 15 September 2004

Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88–/–, but not TLR2–/–, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killed Streptococcus pneumoniae capsular type 14 (S. pneumoniae type 14). This is correlated with analogous responses in splenic cytokine protein release in vitro following addition of S. pneumoniae type 14. Consistent with these data, naïve MyD88–/–, but not TLR2–/–, mice are more sensitive to killing following i.p. challenge with live S. pneumoniae type 14, relative to responses in wild-type mice. However, prior immunization of MyD88–/– mice with heat-killed S. pneumoniae type 14 protects against an otherwise-lethal challenge with live S. pneumoniae type 14. Surprisingly, both MyD88–/– and TLR2–/– mice exhibit striking and equivalent defects in elicitation of type 1 IgG isotypes (IgG3, IgG2b, and IgG2a), but not the type 2 IgG isotype, IgG1, specific for several protein and polysaccharide antigens, in response to i.p. challenge with heat-killed S. pneumoniae type 14. Of note, the type 1 IgG isotype titers specific for pneumococcal surface protein A are reduced in MyD88–/– mice but not TLR2–/– mice. These data suggest that distinct TLRs may differentially regulate innate versus adaptive humoral immunity to intact S. pneumoniae and are the first to implicate a role for TLR2 in shaping an in vivo type 1 IgG humoral immune response to a gram-positive extracellular bacterium.

* Corresponding author. Mailing address: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-3490. Fax: (301) 295-1640. E-mail: csnapper{at}usuhs.mil.

Editor: J. N. Weiser

Infection and Immunity, January 2005, p. 298-307, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.298-307.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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