Analysis of KSHV B lymphocyte lineage tropism in human tonsil reveals efficient infection of CD138+ plasma cells.
Analysis of KSHV B lymphocyte lineage tropism in human tonsil reveals efficient infection of CD138+ plasma cells.
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DOI：
10.1371/journal.ppat.1008968
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发表时间：
2020-10
期刊：
影响因子：
6.7
通讯作者：
Totonchy J
中科院分区：
文献类型：
--
作者：
Aalam F;Nabiee R;Castano JR;Totonchy J
尽管有25年的研究，卡波西肉瘤疱疹病毒（KSHV）在B淋巴细胞的基础病毒学仍然知之甚少。本研究试图通过描述KSHV的B淋巴细胞谱系特异性嗜性来填补我们理解中的关键空白。在这里，我们使用淋巴细胞来源于40人扁桃体标本，以确定B淋巴细胞谱系KSHV在我们的体外模型系统从头感染的早期目标。我们的扁桃体标本的免疫多样性的特点，并确定扁桃体淋巴细胞对KSHV感染的总体易感性有很大的不同捐助者。我们证明了多种B淋巴细胞亚型对KSHV感染敏感，并将CD 138+浆细胞鉴定为从头KSHV感染的高度靶向细胞类型。我们确定扁桃体B细胞谱系的感染主要是潜伏的，很少有谱系有助于裂解性复制。我们探讨了使用CD 138和硫酸肝素蛋白多糖作为B淋巴细胞感染的附着因子，并得出结论，他们不发挥实质性的作用。最后，我们确定宿主T细胞微环境影响B淋巴细胞的从头感染过程。这些结果提高了我们对KSHV在幼稚人类宿主中传播和早期KSHV感染生物学的理解，并为进一步表征KSHV在B淋巴细胞谱系中的分子病毒学奠定了基础。KSHV感染与B细胞和内皮细胞中的癌症相关，特别是在免疫抑制的情况下。关于KSHV如何传播以及它最初如何在新宿主中建立感染的知之甚少。唾液被认为是KSHV人际传播的主要途径，使扁桃体成为KSHV在新的人类宿主中复制的第一个位点。我们的研究检查了从40名人类供体的扁桃体中提取的B细胞中的KSHV感染，以确定最初针对感染的B细胞类型，并检查其他免疫细胞的存在（或不存在）如何影响KSHV感染的初始阶段。我们发现，多种来源于扁桃体的B细胞亚型可以感染KSHV。有趣的是，浆细胞（成熟的抗体分泌B细胞）是高度靶向的细胞类型。这些结果为进一步研究KSHV在不同类型的B细胞中的特异性生物学奠定了基础，这一努力可能有助于我们最终发现如何防止这些细胞中感染的建立或揭示阻止与KSHV感染相关的B细胞癌症进展的新方法。
Despite 25 years of research, the basic virology of Kaposi Sarcoma Herpesviruses (KSHV) in B lymphocytes remains poorly understood. This study seeks to fill critical gaps in our understanding by characterizing the B lymphocyte lineage-specific tropism of KSHV. Here, we use lymphocytes derived from 40 human tonsil specimens to determine the B lymphocyte lineages targeted by KSHV early during de novo infection in our ex vivo model system. We characterize the immunological diversity of our tonsil specimens and determine that overall susceptibility of tonsil lymphocytes to KSHV infection varies substantially between donors. We demonstrate that a variety of B lymphocyte subtypes are susceptible to KSHV infection and identify CD138+ plasma cells as a highly targeted cell type for de novo KSHV infection. We determine that infection of tonsil B cell lineages is primarily latent with few lineages contributing to lytic replication. We explore the use of CD138 and heparin sulfate proteoglycans as attachment factors for the infection of B lymphocytes and conclude that they do not play a substantial role. Finally, we determine that the host T cell microenvironment influences the course of de novo infection in B lymphocytes. These results improve our understanding of KSHV transmission and the biology of early KSHV infection in a naïve human host, and lay a foundation for further characterization of KSHV molecular virology in B lymphocyte lineages. KSHV infection is associated with cancer in B cells and endothelial cells, particularly in the context of immune suppression. Very little is known about how KSHV is transmitted and how it initially establishes infection in a new host. Saliva is thought to be the primary route of person-to-person transmission for KSHV, making the tonsil a likely first site for KSHV replication in a new human host. Our study examines KSHV infection in B cells extracted from the tonsils of 40 human donors in order to determine what types of B cells are initially targeted for infection and examine how the presence (or absence) of other immune cells influence the initial stages of KSHV infection. We found that a variety of B cell subtypes derived from tonsils can be infected with KSHV. Interestingly, plasma cells (mature antibody-secreting B cells) were a highly targeted cell type. These results lay the foundation for further studies into the specific biology of KSHV in different types of B cells, an effort that may help us ultimately discover how to prevent the establishment of infection in these cells or reveal new ways to halt the progression of B cell cancers associated with KSHV infection.
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