Chappell Laura, Peguero Ricardo, Conner William R, Fowler Sommer, Cooper Brandon S, Pfarr Kenneth, Hoerauf Achim, Lustigman Sara, Sakanari Judy, Sullivan William
Department of Molecular, Cellular and Developmental Biology, University of California, Santa Cruz, California, United States of America.
Department of Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York City, New York, United States of America.
PLoS Pathog. 2025 Sep 8;21(9):e1012929. doi: 10.1371/journal.ppat.1012929. eCollection 2025 Sep.
The discovery of the endosymbiotic bacteria Wolbachia 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 revealed that Wolbachia levels rebound following treatment with the antibiotic rifampicin. Previous work revealed that a potential source of the bacterial rebound in female worms were dense clusters of Wolbachia in ovarian tissue. The number, size, and density of these Wolbachia clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the Wolbachia clusters in Brugia pahangi (wBp) and identify drugs that target them. We show that the Wolbachia clusters originate from newly formed sheath cells adjacent to the distal tip cell. The dramatically enlarged volume of a Wolbachia-infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered Wolbachia present within the sheath cells have a distinct morphology from those present within the oocytes, and that the sheath cell membrane appears to have interdigitations with the adjacent oocyte membrane. This includes membrane-based channels that provide a connection between Wolbachia-infected sheath cells and oocytes. We determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of 11 known antibiotics and other drugs revealed that Fexinidazole, Corallopyronin A and Rapamycin reduced the number of Wolbachia clusters infecting sheath cells but only Fexinidazole and Corallopyronin A showed a highly significant difference (p < 0.0001) compared to the control group.
内共生细菌沃尔巴克氏体作为丝虫线虫的专性共生菌的发现，催生了基于抗生素的丝虫病治疗方法。虽然实验室和临床研究取得了令人鼓舞的结果，但最近的动物研究表明，用抗生素利福平治疗后，沃尔巴克氏体水平会反弹。此前的研究表明，雌性蠕虫中细菌反弹的一个潜在来源是卵巢组织中密集的沃尔巴克氏体簇。尽管进行了抗生素治疗，但这些沃尔巴克氏体簇的数量、大小和密度并未减少。在这里，我们定义了彭亨布鲁线虫（wBp）中沃尔巴克氏体簇的细胞特征，并鉴定了靶向它们的药物。我们表明，沃尔巴克氏体簇起源于与远端顶端细胞相邻的新形成的鞘细胞。被沃尔巴克氏体感染的鞘细胞体积显著增大，这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，鞘细胞内聚集的沃尔巴克氏体与卵母细胞内的沃尔巴克氏体具有不同的形态，并且鞘细胞膜似乎与相邻的卵母细胞膜有指状交叉。这包括基于膜的通道，为被沃尔巴克氏体感染的鞘细胞和卵母细胞之间提供连接。我们确定鞘细胞内的沃尔巴克氏体要么处于静止状态，要么以非常低的速率复制。对11种已知抗生素和其他药物的筛选表明，非昔硝唑、珊瑚虫素A和雷帕霉素减少了感染鞘细胞的沃尔巴克氏体簇的数量，但与对照组相比，只有非昔硝唑和珊瑚虫素A显示出极显著差异（p < 0.0001）。
