Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins
Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins
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DOI：
10.1128/iai.74.1.594-601.2006
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发表时间：
2006-01-01
影响因子：
3.1
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Newman, RM;Salunkhe, P;Reed, JC
许多重要的细菌毒力因子充当哺乳动物蛋白质的模拟物，破坏正常的宿主细胞过程。为了鉴定先天免疫信号通路成分的细菌蛋白模拟物，我们在细菌基因组数据库中搜索了与哺乳动物 Toll 样受体 (TLR) 的 Toll/白介素-1 受体 (TIR) 结构域及其衔接蛋白同源的蛋白。我们在肠炎沙门氏菌血清型肠炎沙门氏菌基因组中鉴定了一个先前未表征的基因，我们将其命名为 tlpA（TIR 样蛋白 A），预计该基因编码类似于哺乳动物 TIR 结构域的蛋白质。我们表明，TlpA 在哺乳动物细胞中的过度表达会抑制哺乳动物含有 TIR 的蛋白 TLR4、IL-1 受体和 MyD88 诱导 NF-κa 反式激活和 DNA 结合活性的能力B，TIR 信号通路的下游靶标。此外，TlpA 模仿先前表征的沙门氏菌毒力因子 SipB，能够在哺乳动物细胞转染模型中诱导 caspase-1 激活。在使用人 THP1 巨噬细胞的细胞培养感染模型中，染色体 tlpA 基因的破坏导致强毒血清型肠炎菌株在细胞内存活和 IL-1 β 分泌方面存在缺陷。 tlpA 被破坏的细菌在小鼠中也表现出较低的致死率，进一步证实了该因素在发病机制中的重要作用。综上所述，我们的研究结果表明，细菌 TIR 样蛋白 TlpA 是一种新型原核调节剂，调节 NF-κ B 活性和 IL-1 β 分泌，有助于肠炎血清型毒力。
Many important bacterial virulence factors act as mimics of mammalian proteins to subvert normal host cell processes. To identify bacterial protein mimics of components of the innate immune signaling pathway, we searched the bacterial genome database for proteins with homology to the Toll/interleukin-1 receptor (TIR) domain of the mammalian Toll-like receptors (TLRs) and their adaptor proteins. A previously uncharacterized gene, which we have named tlpA (for TIR-like protein A), was identified in the Salmonella enterica serovar Enteritidis genome that is predicted to encode a protein resembling mammalian TIR domains, We show that overexpression of TlpA in mammalian cells suppresses the ability of mammalian TIR-containing proteins TLR4, IL-1 receptor, and MyD88 to induce the transactivation and DNA-binding activities of NF-kappa B, a downstream target of the TIR signaling pathway. In addition, TlpA mimics the previously characterized Salmonella virulence factor SipB in its ability to induce activation of caspase-1 in a mammalian cell transfection model. Disruption of the chromosomal tlpA gene rendered a virulent serovar Enteritidis strain defective in intracellular survival and IL-1 beta secretion in a cell culture infection model using human THP1 macrophages. Bacteria with disrupted tlpA also displayed reduced lethality in mice, further confirming an important role for this factor in pathogenesis. Taken together, our findings demonstrate that the bacterial TIR-like protein TlpA is a novel prokaryotic modulator of NF-kappa B activity and IL-1 beta secretion that contributes to serovar Enteritidis virulence.