Toll-Like Receptors 2 and 4 Cooperate in the Control of the Emerging Pathogen Brucella microti

Abstract

Toll-like receptors (TLRs) recognize pathogen-derived molecules and play a critical role during the host innate and adaptive immune response. Brucella spp. are intracellular gram-negative bacteria including several virulent species, which cause a chronic zoonotic infection in a wide range of mammalian hosts known as brucellosis. A new Brucella species, Brucella microti, was recently isolated from wild rodents and found to be highly pathogenic in mice. Using this species-specific model, it was previously found that CD8+ T cells are required to control this infection. In order to find out the role of TLR-mediated responses in the control of this pathogen, the course of infection of B. microti was analyzed over 3 weeks in wild-type (WT) and TLR knock out (KO) mice including TLR2−/−, TLR4−/−, TLR9−/−, TLR2×4−/− and TLR2×4×9−/−. WT and single TLR2, TLR4 and TLR9 KO mice similarly control infection in liver and spleen. In contrast, bacterial clearance was delayed in TLR2×4−/− and TLR2×4×9−/− mice at 7 and 14 days post-infection. This defect correlated with impaired maturation and pro-inflammatory cytokine production in B. microti-infected dendritic cells from TLR2×4−/− and TLR2×4×9−/− mice. Finally, it was found that Tc cells from TLR2×4−/− and TLR2×4×9−/− mice showed reduced ability to inhibit growth of B. microti in macrophages, suggesting the involvement of TLR2 and 4 in the generation of specific Tc cells. Our findings indicate that TLR2 and TLR4 are required to control B. microti infection in mice and that this effect could be related to its participation in the maturation of dendritic cells and the generation of specific CD8+ Tc cells.

Rickettsia Lipid A Biosynthesis Utilizes the Late Acyltransferase LpxJ for Secondary Fatty Acid Addition

“…Therefore, we infer that Rickettsia LpxJ is also important in maintaining ideal membrane dynamics and facilitating molecular interactions at the host-pathogen interface that are required for adhesion and invasion of mammalian cells. Additionally, lipid A is the endotoxic component of LPS ( 47 ), and activation of TLR4 is critical for bacterial clearance in mouse models of Rickettsia infection ( 27 , 48 ), as well as other intracellular parasites ( 49 – 51 ). These data, as well as a recent report highlighting host-specific differences in lipid A gene expression ( 52 ), suggest a role for LpxJ in Rickettsia virulence, making this enzyme a tempting target for mutational studies in vivo .…”

The Role of Innate Immunity in Pulmonary Infections

“…TLR2 recognizes a variety of PAMPs, including lipoproteins, lipopeptides, β -glucans, glycoproteins, and zymosans, thereby recruiting TIR domain-containing adaptor protein (e.g., myeloid differentiation factor 88 (MyD88), Toll-IL-1R domain-containing adapter protein (TIRAP), TIR domain-containing adapter inducing IFN- β (TRIF), or TRIF-related adapter molecule (TRAM)) [ 14 , 113 ]. TLR2 signaling is essential for bacterial clearance and survival in the lung of mice infected with S. pneumoniae , P. Aeruginosa , L. pneumophila , Brucella melitensis , Acinetobacter baumannii , Mycoplasma , M. tuberculosis , and S. aureus , indicating the importance of the TLR2 pathway for protecting the host [ 13 , 114 – 124 ] ( Figure 1 ). In most cases, TLR2 forms heterodimers with TLR1 and/or TLR6 [ 122 ].…”

Macrophage cytokine responses to commensal Gram-positive Lactobacillus salivarius strains are TLR2-independent and Myd88-dependent

“…The consequences of MAMP-PRR recognition are diverse and largely dependent on the molecular and biochemical characteristics of both the bacterial and host cells which interact with one another 21 . When hosts are infected with pathogens such as Listeria monocytogenes, Porphyromonas gingivalis and Brucella microti, recognition of their respective MAMPs by TLRs trigger inflammatory responses that aid in their clearance and are thus protective to the host [22][23][24] . However, other pathogens such as Salmonella typhimurium require initial MAMP-TLR recognition for inducing production of specific virulence factors that provide them with a survival benefit by evading host immune surveillance 25 .…”