Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction.
Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction.
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DOI：
10.1371/journal.ppat.1005137
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发表时间：
2015-09
期刊：
影响因子：
6.7
通讯作者：
Sriskandan S
中科院分区：
文献类型：
--
作者：
Lynskey NN;Banerji S;Johnson LA;Holder KA;Reglinski M;Wing PA;Rigby D;Jackson DG;Sriskandan S
宿主淋巴网络是病原体传播的重要渠道。事实上，致命的人类病原体A组链球菌倾向于诱导淋巴系统和引流淋巴结的病理学，然而，疾病结局的潜在基础和后续后果目前尚不清楚。在这里，我们报告说，透明质酸胶囊的A组链球菌是一个重要的毒力决定因素，在体内的淋巴嗜性，并进一步，我们确定了淋巴管内皮受体-1作为关键的主机受体胶囊透明质酸在淋巴系统。干扰这种相互作用在体内阻止细菌传播到局部引流淋巴结，并在一个超包囊M18菌株的情况下，重新定向链球菌进入血液循环，这表明在链球菌感染的表现中的关键作用。我们的研究结果揭示了一种新的功能，细菌荚膜多糖在指导淋巴嗜性，与疾病病理学的潜在影响。已知病原体不仅通过体循环而且通过淋巴网络侵入宿主，但是后一途径的潜在机制和疾病结果的后果尚未得到充分研究。重要的人类病原体A组链球菌是影响淋巴管和引流淋巴结的许多临床综合征的原因，例如淋巴管炎和淋巴结炎。这些病理是如何精心策划的，以及它们在严重感染发展中的意义目前尚不清楚。在这项研究中，我们表明，由A组链球菌分泌的透明质酸胶囊是细菌扩散到引流淋巴结的关键，我们证明，这是由于与淋巴管内皮受体-1的特异性相互作用。在小鼠感染模型中，这种受体的基因缺失或功能阻断阻止了链球菌转运到引流淋巴结，这反过来又增强了细菌扩散到血液循环中。总之，这些结果定义了一种新的A组链球菌荚膜和淋巴管内皮受体-1之间的相互作用，作为一个关键的轴，在建立这种病原体的淋巴嗜性，在主机的疾病严重程度的明确影响。
The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology. Pathogens are known to invade the host not only via the systemic circulation but also via the lymphatic network, however the mechanisms underlying the latter route and the consequences for disease outcome have not been well studied. The important human pathogen, group A streptococcus, is responsible for a number of clinical syndromes affecting both the lymphatic vessels and draining lymph nodes, such as lymphangitis and lymphadenitis. How such pathologies are orchestrated, and their significance in the development of serious infection are currently unknown. In this study, we show that the hyaluronan capsule secreted by group A streptococcus is critical for bacterial spread to draining lymph nodes, and we demonstrate that this occurs as a result of a specific interaction with the lymphatic vessel endothelial receptor-1. Genetic deletion or functional blockade of this receptor prevented streptococcal transit to draining lymph nodes in a murine model of infection, which in turn enhanced bacterial spread into the blood circulation. Together these results define a novel interaction between the group A streptococcal capsule and the lymphatic endothelial receptor-1 as a critical axis in the establishment of lymphatic tropism for this pathogen, with clear implications for disease severity in the host.