Abstract
Propionibacterium acnes (formerly Corynebacterium parvum) is part of the human flora and, as such, is associated with several human pathologies. It possesses strong immunomodulatory activities, which makes this bacterium interesting for prophylactic and therapeutic vaccination. The bacterial component(s) and the host receptor(s) involved in the induction of these activities are poorly understood. We show in this study that TLR9 is crucial in generating the characteristic effects of killed P. acnes priming in the spleen, such as extramedullary hemopoiesis and organ enlargement, and granuloma formation in the liver. Furthermore, the ability to overproduce TNF-alpha and IFN-gamma in response to LPS, lipid A, synthetic lipopeptide Pam(3)CysK(4), or whole killed bacteria was present in P. acnes-primed wild-type, but not TLR9(-/-), mice. Finally, P. acnes priming failed to induce enhanced resistance to murine typhoid fever in TLR9(-/-) mice. Thus, TLR9 plays an essential role in the induction of immunomodulatory effects by P. acnes. Because IFN-gamma is a key mediator of these effects, and enhanced IFN-gamma mRNA expression was absent in spleen and liver of P. acnes-primed TLR9(-/-) mice, we conclude that TLR9 is required for the induction of IFN-gamma by P. acnes.
Highlights
Propionibacterium acnes is a member of normal flora of skin and gastrointestinal tract
Using wild-type mice and mice deficient in TLR9, we demonstrate that this intracellular receptor is essential for the induction of the immunomodulatory effects by P. acnes
The absence of P. acnes-induced effects in TLR9Ϫ/Ϫ mice was paralleled by the absence of induction of IFN-␥ mRNA in spleen and liver
Summary
Propionibacterium acnes (formerly Corynebacterium parvum) is a member of normal flora of skin and gastrointestinal tract. P. acnes-treated mice develop a state of hypersensitivity to bacterial LPS [12, 13]. The maximum LPS sensitization is reached on day 7 after P. acnes administration By this time, compared with unsensitized controls, hypersensitive mice produce up to 1000 times higher levels of proinflammatory cytokines, such as TNF-␣, in response to LPS. Treatment with P. acnes induces hypersensitivity to LPS, and to bacterial lipopeptides and possibly other pathogen-associated molecular patterns (16 – 18). The TLR9 ligands, bacterial DNA and synthetic CpG oligodeoxynucleotide, were shown to induce splenomegaly as well as extramedullary hemopoiesis [27] and to sensitize mice to LPS [28]. In this study using TLR9-deficient mice, we demonstrate the requirement for TLR9 in the induction of IFN-␥ and in the resulting characteristic effects of P. acnes priming
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