Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease.

Abstract

Toll-like receptors (TLRs) are involved in pathogen recognition by the innate immune system. Different TLRs and the adaptor molecule myeloid differentiation factor 88 (MyD88) were previously shown to mediate in vitro cell activation induced by group B streptococcus (GBS). The present study examined the potential in vivo roles of TLR2 and MyD88 during infection with GBS. When pups were infected locally with a low bacterial dose, none of the TLR2- or MyD88-deficient mice, but all of the wild-type ones, were able to prevent systemic spread of GBS from the initial focus. Bacterial burden was higher in MyD88- than in TLR2-deficient mice, indicating a more profound defect of host defense in the former animals. In contrast, a high bacterial dose induced high level bacteremia in both mutant and wild-type mice. Under these conditions, however, TLR2 or MyD88 deficiency significantly protected mice from lethality, concomitantly with decreased circulating levels of TNF-alpha and IL-6. Administration of anti-TNF-alpha Abs to wild-type mice could mimic the effects of TLR2 or MyD88 deficiency and was detrimental in the low dose model, but protective in the high dose model. In conclusion, these data highlight a dual role of TLR2 and MyD88 in the host defense against GBS sepsis and strongly suggest TNF-alpha as the molecular mediator of bacterial clearance and septic shock.

• Authors: Giuseppe Mancuso, Angelina Midiri, Concetta Beninati, Carmelo Biondo, Roberta Galbo, Shizuo Akira, Philipp Henneke, Douglas Golenbock, Giuseppe Teti
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 172 Issue 10 Pg. 6324-9 (May 15 2004) ISSN: 0022-1767 [Print] United States
• PMID: 15128822 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Differentiation
• Membrane Glycoproteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Cell Surface
• Receptors, Immunologic
• Toll-Like Receptor 2
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha

Topics

• Adaptor Proteins, Signal Transducing
• Aging (genetics, immunology)
• Animals
• Animals, Newborn (genetics, growth & development, immunology)
• Antigens, Differentiation (genetics, physiology)
• Disease Models, Animal
• Dose-Response Relationship, Immunologic
• Genetic Predisposition to Disease
• Immunity, Innate (genetics)
• Membrane Glycoproteins (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88
• Receptors, Cell Surface (deficiency, genetics, physiology)
• Receptors, Immunologic (deficiency, genetics, physiology)
• Sepsis (genetics, immunology)
• Streptococcal Infections (genetics, immunology, mortality)
• Streptococcus agalactiae (immunology, pathogenicity)
• Toll-Like Receptor 2
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, physiology)