| Title: |
MicroRNAs secreted by the parasitic nematode Brugia malayi disrupt lymphatic endothelial cell integrity. |
| Authors: |
Johnson, Hailey1 (AUTHOR), Banakis, Stephanie1 (AUTHOR), Chung, Matthew1 (AUTHOR), Ghedin, Elodie1 (AUTHOR), Voronin, Denis1 (AUTHOR) denis.voronin@nih.gov |
| Source: |
PLoS Neglected Tropical Diseases. 12/31/2024, Vol. 18 Issue 12, p1-18. 18p. |
| Subject Terms: |
*CELL permeability, *FILARIASIS, *NEGLECTED diseases, *ENDOTHELIAL cells, *LYMPHATICS |
| Abstract: |
Lymphatic filariasis (LF) is a neglected tropical disease affecting over 51 million people in 72 endemic countries. Causative agents of LF are mosquito-borne parasitic nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. The adult parasites impact the integrity of lymphatic vessels and damage valves, leading to a remodeling of the lymphatic system and lymphatic dilation. Chronic infections can develop into severe clinical manifestations, primarily lymphedema, hydrocoele, and elephantiasis. Mechanistic studies on the underlying pathology due to the parasite are necessary to better manage human filariasis. Since parasite molecules, such as microRNAs (miRNAs), can be found in secreted extracellular vesicles (EVs) and are transported between parasite and host cells, we hypothesized that these could also play a role in the development of pathology in LF. In this study, we tested two B. malayi miRNAs previously detected in vitro in the culture media of microfilarial stages of worms. While one is Brugia-specific (bma-miR-5864) and the other nematode-specific (bma-miR-86), both miRNAs are secreted in high abundance. We first examined the in vitro response by transcriptomic profiling of human lymphatic endothelial cells to treatment with these miRNAs, which allowed us to identify genes involved in maintaining the integrity of the lymphatic endothelium. We then measured the effect of these miRNAs on the regulation of proteins necessary for cell integrity, demonstrating downregulation leading to a significant increase in the permeability of the endothelium monolayer. With this study we identify parasite miRNAs involved in undermining the integrity of endothelial cells, thus potentially contributing to the development of pathology. These findings could pave the way for a novel treatment strategy where the inhibition of parasite-secreted molecules could slow the progression of LF pathology. From a broader perspective, the miRNAs secreted by filarial parasites could potentially be used in the future for diagnosing and monitoring disease progression or treatment efficacy. Author summary: Brugia malayi is a species of thread-like worms that reside in the human lymphatic system, leading to the chronic and socioeconomically devastating disease known as lymphatic filariasis. This filarial disease is characterized by significant damage to the lymphatic endothelium, which can result in lymphatic remodeling, disruption of lymphatic flow, and, in severe cases, the development of elephantiasis. To understand the mechanism behind the pathology of lymphatic filariasis, we focused on small regulatory molecules, microRNAs (miRNAs), secreted by the worms and that can interact with lymphatic endothelial cells. We demonstrated that two B. malayi miRNAs unique to nematodes, bma-miR-5864 and bma-miR-86, targeted human genes essential for maintaining the integrity of the lymphatic endothelium. Our findings suggest that these bma-miRNAs increase the permeability of the endothelial barrier, potentially causing lymphedema and contributing to lymphatic filariasis pathology. This research provides new insights into the molecular interactions between parasitic worms and the host's lymphatic system, which could inform therapeutic strategies. [ABSTRACT FROM AUTHOR] |
|
Copyright of PLoS Neglected Tropical Diseases is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Academic Search Complete |
|
Full text is not displayed to guests. |
Login for full access.
|
