Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria.
Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria.
复制标题
DOI：
10.4049/jimmunol.1201545
复制
发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Tapping RI
中科院分区：
文献类型：
--
作者：
Hart BE;Tapping RI
我们最近发现I602 S是人类TLR 1的常见单核苷酸多态性，它极大地抑制细胞表面运输，赋予对TLR 1激动剂的低反应性，并保护免受麻风病和结核病的分枝杆菌疾病。由于分枝杆菌是已知的操纵TLR系统，以他们的优势，我们假设，低反应性602 S变异可能赋予保护，使主机克服这种免疫颠覆。我们报道，与携带TLR 1 602 I变异体的个体相比，来自纯合子TLR 1 602 S个体的原代人单核细胞和巨噬细胞对分枝杆菌诱导的巨噬细胞MHCII、CD 64和IFNγ应答下调具有抗性。此外，当用分枝杆菌激动剂攻击时，来自TLR 1 602 S/S个体的巨噬细胞抵抗宿主精氨酸酶-1的诱导;该酶消耗产生抗微生物活性氮中间体所需的细胞精氨酸储存。在用可溶性分枝杆菌衍生的激动剂刺激后观察到由TLR 1 602 S和TLR 1 602 I介导的细胞活化的差异，但用完整的分枝杆菌细胞则没有。综上所述，这些结果表明，TLR 1 602 S变体通过防止可溶性分枝杆菌产物（可能从肉芽肿释放）在髓样细胞与完整分枝杆菌相遇之前解除其武装来防止分枝杆菌疾病。
We have recently identified I602S as a frequent single nucleotide polymorphism of human TLR1 which greatly inhibits cell surface trafficking, confers hyporesponsiveness to TLR1 agonists, and protects against the mycobacterial diseases leprosy and tuberculosis. Since mycobacteria are known to manipulate the TLR system to their advantage, we hypothesize that the hyporesponsive 602S variant may confer protection by enabling the host to overcome this immune subversion. We report that primary human monocytes and macrophages from homozygous TLR1 602S individuals are resistant to mycobacterial-induced downregulation of macrophage MHCII, CD64, and IFNγ responses compared to individuals who harbor the TLR1 602I variant. Additionally, when challenged with mycobacterial agonists, macrophages from TLR1 602S/S individuals resist induction of host arginase-1; an enzyme that depletes cellular arginine stores required for production of antimicrobial reactive nitrogen intermediates. The differences in cell activation mediated by TLR1 602S and TLR1 602I are observed upon stimulation with soluble mycobacterial-derived agonists but not with whole mycobacterial cells. Taken together, these results suggest that the TLR1 602S variant protects against mycobacterial disease by preventing soluble mycobacterial products, perhaps released from granulomas, from disarming myeloid cells prior to their encounter with whole mycobacteria.
登录
查看更多内容
影响因子：
4.4
作者：
Banaiee, Niaz;Kincaid, Eleanor Z.;Ernst, Joel D.
通讯作者：
Ernst, Joel D.
DOI：
10.1084/jem.175.4.1111
发表时间：
1992-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan J;Xing Y;Magliozzo RS;Bloom BR
通讯作者：
Bloom BR
影响因子：
3.1
作者：
Cole, Leah E.;Shirey, Kari Ann;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
3.1
作者：
CHAN, J;FAN, X;BLOOM, BR
通讯作者：
BLOOM, BR
影响因子：
4.4
作者：
Johnson, Christopher M.;Lyle, Elizabeth A.;Tapping, Richard I.
通讯作者：
Tapping, Richard I.