Chappell Laura, Peguero Ricardo, Conner William R, Fowler Sommer, Cooper Brandon, Pfarr Kenneth, Hoerauf Achim, Lustigman Sara, Sakanari Judy, Sullivan William
Department of Molecular, Cellular and Developmental Biology University of California, Santa Cruz, CA 95064, USA.
Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA.
bioRxiv. 2025 Jan 26:2025.01.23.634442. doi: 10.1101/2025.01.23.634442.
The discovery of the endosymbiotic bacteria as an obligate symbiont of filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab and clinical studies have yielded promising results, recent animal studies reveal that levels may rebound following treatment with suboptimal doses of the antibiotic rifampicin. Previous work showed that a likely source of the bacterial rebound in females were dense clusters of in ovarian tissue. The number, size, and density of these clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the clusters in (wBp) and identify drugs that also target them. We have evidence that the clusters originate from newly formed sheath cells adjacent to the ovarian Distal Tip Cells. The dramatically enlarged volume of an infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered present within the sheath cells exhibit a distinct morphology and form direct connections with the oocyte membrane and possibly the cytoplasm. This includes membrane-based channels providing a connection between -infected sheath cells and oocytes. We also determined that the within the sheath cells are either quiescent or replicating at a very low rate. Screens of known antibiotics and other drugs revealed that two drugs, Fexinidazole and Corallopyronin A, significantly reduced the number of clustered located within the sheath cells.
内共生细菌作为丝虫线虫专性共生体的发现，已促使人们采用基于抗生素的方法治疗丝虫病。尽管实验室研究和临床研究已取得了有前景的结果，但最近的动物研究表明，用次优剂量的抗生素利福平治疗后，细菌数量可能会反弹。先前的研究表明，雌性体内细菌反弹的一个可能来源是卵巢组织中密集的 簇。尽管进行了抗生素治疗，但这些 簇的数量、大小和密度并未减少。在这里，我们定义了 （wBp）中 簇的细胞特征，并确定了也靶向它们的药物。我们有证据表明， 簇起源于与卵巢远端顶端细胞相邻的新形成的鞘细胞。受感染鞘细胞显著增大的体积与许多昆虫物种中内共生体诱导的含菌细胞惊人地相似。超微结构分析表明，鞘细胞内聚集的 呈现出独特的形态，并与卵母细胞膜以及可能与细胞质形成直接连接。这包括基于膜的通道，为受 感染的鞘细胞和卵母细胞之间提供连接。我们还确定，鞘细胞内的 要么处于静止状态，要么以非常低的速率复制。对已知抗生素和其他药物的筛选表明，两种药物，非昔硝唑和珊瑚虫素A，显著减少了鞘细胞内聚集的 的数量。
