Toll-Like Receptor 6 Plays an Important Role in Host Innate Resistance to Brucella abortus Infection in Mice

Almeida, Leonardo Augusto de; Macedo, Gilson Costa; Marinho, Fábio V.; Gomes, Marco Túlio R.; Corsetti, Patrícia Paiva; Silva, Aristóbolo M.; Cassataro, Juliana; Giambartolomei, Guillermo H.; Oliveira, Sérgio C.

doi:10.1128/iai.01356-12

Cited by 43 publications

(36 citation statements)

References 45 publications

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“…Higher exposition of outer membrane proteins (Omp) in rough strains, compared to smooth strains, has been indicated as responsible for the stronger DC maturation in infection by rough strains [39]. The maturation and activation of DCs along with cytokine secretion after B. abortus infection seem to be dependent of caspase-2 and TLR6 [38,41]. Caspase-2 plays different roles during rough and smooth strains infections, being critical to mouse DC maturation and cytokine production in rough strains infection, whereas in infection by smooth strains it promotes the cell death, favoring bacterial dissemination [38].…”

Section: Cellsmentioning

confidence: 98%

Immune response triggered by Brucella abortus following infection or vaccination

Dorneles

Teixeira-Carvalho

Araújo

et al. 2015

Vaccine

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Section: Cellsmentioning

confidence: 98%

Immune response triggered by Brucella abortus following infection or vaccination

Dorneles

Teixeira-Carvalho

Araújo

et al. 2015

Vaccine

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“…In Brucella abortus infection, TLR6 is implicated in NF-kB-dependent IL-12 production (15). TLR6 deficiency results in higher Mycobacterium avium infection in lung (16) or in higher Aspergillus fumigatus burden in C57BL/6 mice (17).…”

mentioning

confidence: 99%

Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Pandey

Chandel

Srivastava

et al. 2014

The Journal of Immunology

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TLRs recognize pathogen-expressed Ags and elicit host-protective immune response. Although TLR2 forms heterodimers with TLR1 or TLR6, recognizing different ligands, differences in the functions of these heterodimers remain unknown. In this study, we report that in Leishmania major-infected macrophages, the expression of TLR1 and TLR2, but not TLR6, increased; TLR2–TLR2 association increased, but TLR2–TLR6 association diminished. Lentivirus-expressed TLR1–short hairpin RNA (shRNA) or TLR2–shRNA administration reduced, but TLR6–shRNA increased L. major infection in BALB/c mice. Corroboratively, Pam3CSK4 (TLR1–TLR2 ligand) and peptidoglycan (TLR2 ligand) increased L. major infection but reduced TLR9 expression, whereas pegylated bisacycloxypropylcysteine (BPPcysMPEG; TLR2–TLR6 ligand) reduced L. major number in L. major-infected macrophages, accompanied by increased TLR9 expression, higher IL-12 production, and inducible NO synthase expression. Whereas MyD88, Toll/IL-1R adaptor protein, and TNFR-α–associated factor 6 recruitments to TLR2 were not different in Pam3CSK4-, peptidoglycan-, or BPPcysMPEG-treated macrophages, only BPPcysMPEG enhanced p38MAPK and activating transcription factor 2 activation. BPPcysMPEG conferred antileishmanial functions to L. major-infected BALB/c-derived T cells in a macrophage–T cell coculture and in BALB/c mice; the protection was TLR6 dependent and IL-12 dependent, and it was accompanied by reduced regulatory T cell number. BPPcysMPEG administration during the priming with fixed L. major protected BALB/c mice against challenge L. major infection; the protection was accompanied by low IL-4 and IL-10, but high IFN-γ productions and reduced regulatory T cells. Thus, BPPcysMPEG, a novel diacylated lipopeptide ligand for TLR2–TLR6 heterodimer, induces IL-12–dependent, inducible NO synthase–dependent, T-reg–sensitive antileishmanial protection. The data reveal a novel dimerization partner-dependent duality in TLR2 function.

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“…This signaling can result in arthritis and osteoclastogenesis in murine models of bacterium-induced focal complications (25)(26)(27). Host cells reportedly recognize Brucella through TLR2, TLR4, TLR6, and TLR9 (28)(29)(30)(31)(32). To determine if MyD88 signaling is important for Brucella-induced arthritis, we investigated joint inflammatory responses in MyD88 Ϫ/Ϫ mice following footpad infection with Brucella.…”

mentioning

confidence: 99%

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

et al. 2017

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Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis, and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report C57BL/6 WT mice infected via the footpad with 10 3 to 10 6 CFU of Brucella spp. display neutrophil and monocyte infiltration of the joint space and surrounding musculoskeletal tissue. Joint inflammation is detectable as early as 1 day postinfection and peaks 1 to 2 weeks later, after which WT mice are able to slowly resolve inflammation. B and T cells were dispensable for the onset of swelling but required for resolution of joint inflammation and infection. At early time points, MyD88 Ϫ/Ϫ mice display decreased joint inflammation, swelling, and proinflammatory cytokine levels relative to WT mice. Subsequently, swelling of MyD88 Ϫ/Ϫ joints surpassed WT joint swelling, and resolution of joint inflammation was prolonged. Joint bacterial loads in MyD88 Ϫ/Ϫ mice were significantly greater than those in WT mice by day 3 postinfection and at all time points thereafter. In addition, MyD88 Ϫ/Ϫ joint inflammatory cytokine levels on day 3 and beyond were similar to WT levels. Collectively these data demonstrate MyD88 signaling mediates early inflammatory responses in the joint but also contributes to subsequent clearance of Brucella and resolution of inflammation. This work also establishes a mouse model for studying Brucellainduced arthritis, musculoskeletal complications, and systemic responses, which will lead to a better understanding of focal complications of brucellosis.KEYWORDS arthritis, osteomyelitis, Brucella, brucellosis, MyD88, musculoskeletal B rucella spp. infect over 500,000 individuals each year, making brucellosis one of the most common global zoonoses (1). The most prevalent species that infect humans are Brucella melitensis, Brucella abortus, and Brucella suis (2). Transmission to humans typically occurs through the consumption of unpasteurized dairy products or via aerosol following contact with contaminated meat products (3, 4). Although vaccination of livestock has reduced disease incidence, no licensed human vaccine is available, and brucellosis has recently been designated a neglected zoonotic disease by the World Health Organization (5, 6). Osteoarticular and musculoskeletal inflammation are the most common focal complications of human brucellosis and occur in 40 to 80% of Brucella-infected patients (7,8). This arthritis is thought to arise from the hematogenous spread of Brucella to the joints, as viable brucellae can be found within the synovial fluid of infected patients (9, 10). Arthritis can manifest as peripheral arthritis, sacroiliitis, and spondylitis, which are most common in children, young adults and older adults, respectively (7,8,11,12). Inflammation of the joint synovium is pre...

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Toll-Like Receptor 6 Plays an Important Role in Host Innate Resistance to Brucella abortus Infection in Mice

Cited by 43 publications

References 45 publications

Immune response triggered by Brucella abortus following infection or vaccination

Immune response triggered by Brucella abortus following infection or vaccination

Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

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