TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG

Abstract

Toll-like receptor (TLR) proteins mediate cellular activation by microbes and microbial products. To delineate the role of TLR proteins in the development of host immune responses against mycobacteria, wild-type and TLR-deficient mice were infected with nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin (BCG). Two weeks after intraperitoneal challenge with BCG, few bacilli were present in the lungs of wild-type and TLR4(-/-) mice, whereas bacterial loads were tenfold higher in the lungs of infected TLR2(-/-) mice. BCG challenge in vitro strongly induced proinflammatory cytokine secretion by macrophages from wild-type and TLR4(-/-) mice but not by TLR2(-/-) macrophages. In contrast, intracellular uptake, intracellular bacterial growth, and suppression of intracellular bacterial growth in vitro by interferon-gamma (IFN-gamma) were similar in macrophages from all three mouse strains, suggesting that BCG growth in the lungs of TLR2(-/-) mice was a consequence of defective adaptive immunity. Antigenic stimulation of splenocytes from infected wild-type and TLR4(-/-) mice induced T cell proliferation in vitro, whereas T cells from TLR2(-/-) mice failed to proliferate. Unexpectedly, activated CD4(+) T cells from both TLR-deficient mouse strains secreted little IFN-gamma in vitro compared with control T cells. A role for TLR4 in the control of bacterial growth and IFN-gamma production in vivo was observed only when mice were infected with higher numbers of BCG. Thus, TLR2 and TLR4 appear to regulate distinct aspects of the host immune response against BCG.

A Novel Mechanism Underlying the Basic Defensive Response of Macrophages against Mycobacterium Infection

“…Consistent with our observations, the involvement of TLR2 following infection with M. tuberculosis and the ensuing responses of macrophages have been reported previously (21,22,24,25). Because BCG infection-induced ERK phosphorylation was significantly blocked by cytochalasin B or D (Supplemental Fig.…”

“…The mammalian innate immune system recognizes invading microorganisms by phagocytic receptors, such as TLRs and b 2 integrin (14)(15)(16)(17)(18). In fact, a role for TLRs in M. tuberculosis infection-induced macrophage death has been reported (19)(20)(21)(22)(23)(24)(25). However, the signaling pathway transmitting TLR activation to macrophage death remains unclear.…”

CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis

“…16 It appears striking that several studies investigating the role of TLRs and TLR associated molecules in mycobacterial infection are divergent in their results. 15,17,[33][34][35][36][37][38][39][40][41][42][43] The results of these studies differ from none, moderate or even strong effects because of the lack of a TLR or TLR associated molecule. To our knowledge, our study is novel in demonstrating that CD14 deficiency results in protection from inflammation induced destruction of the lungs.…”

“…In contrast, studies in which protective roles for TLR2, TLR4 or MyD88 were found, deficiencies of these molecules resulted in exaggerated inflammatory responses most likely because of the increased mycobacterial load, providing a more potent proinflammatory stimulus. 35,[37][38][39][40]42 It remains to be established which signalling receptor(s) mediate the CD14 dependent inflammation observed in WT mice in the present study.…”

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

“…Because of the dependence of the induction of EAE on MyD88, adjuvant was required to avoid tolerization. Indeed, mycobacterial PAMPs are recognized by TLR2/6 and TLR4 [20,21], mycobacterial DNA is rich in the TLR9 ligand CpG DNA [22], and PT is recognized by TLR4 [23]. To exclude the potential adjuvant effect of MT-containing CFA and of PT in response to TLR7 ligation, we assessed in vitro the effect of MT and PT on the activation of B cells and BM-derived pDCs.…”