Requirement for TLR9 in the Immunomodulatory Activity of Propionibacterium acnes

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-α and IFN-γ in response to LPS, lipid A, synthetic lipopeptide Pam3CysK4, 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-γ is a key mediator of these effects, and enhanced IFN-γ 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-γ by P. acnes.

TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae

“…Hence, Pn14 has access to the endosomal compartment necessary for TLR9-mediated activation by CpG-containing DNA (46). In contrast to our findings, defects in cytokine production have been observed in TLR9 -/-mice in response to heat-inactivated Brucella abortus (47), live Mycobacterium tuberculosis (48), and heat-inactivated Propionibacterium acnes (49). In this regard, DNA from distinct bacterial species express different proportions of unmethylated CpG which correlates directly with their TLR9-dependent immunostimulatory properties (44,50).…”

Malaria primes the innate immune response due to interferon-γ induced enhancement of toll-like receptor expression and function

“…Thus, it is reasonable to assume that the mechanism by which TLR9 mediates priming of host innate responses during malaria is by mediating parasite recognition and initiating IFN␥ production. This assumption is strongly supported by findings in the Propionibacterium model in which TLR9-mediated production of IFN␥ and IL12 is required to induce priming (32). Thus, we believe that the initial activation of innate immune responses is initiated by activation of TLR9 and induction of IL12 by innate immune cells (e.g., DCs and macrophages) resulting in production of IFN␥ by NK and T cells (33,34).…”

Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide

“…Administration of CpG ODN to mice induces transient splenomegaly (26). The immunomodulatory effects of Propionibacterium acnes on the spleen, such as the induction of splenomegaly and hypersensitivity (27,28) to different TLR agonists, were recently shown to be dependent on TLR9 (53). The enhanced sensitivity upon P. acnes infection appears to be due to a rapid, enhanced inflammatory response.…”