Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis.
BACKGROUND:Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. METHODOLOGY/PRINCIPAL FINDINGS:To better understand the pathogene...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-09-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0007697 |
| _version_ | 1819040617070592000 |
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| author | Britt J Andersen Bruce A Rosa Jonah Kupritz Aboulaye Meite Traye Serge Marla I Hertz Kurt Curtis Christopher L King Makedonka Mitreva Peter U Fischer Gary J Weil |
| author_facet | Britt J Andersen Bruce A Rosa Jonah Kupritz Aboulaye Meite Traye Serge Marla I Hertz Kurt Curtis Christopher L King Makedonka Mitreva Peter U Fischer Gary J Weil |
| author_sort | Britt J Andersen |
| collection | DOAJ |
| description | BACKGROUND:Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. METHODOLOGY/PRINCIPAL FINDINGS:To better understand the pathogenesis of AEs, we studied LF-patients from a treatment trial. Plasma levels of many filarial antigens increased post-treatment in individuals with AEs, and this is consistent with parasite death. Circulating immune complexes were not elevated in these participants, and the classical complement cascade was not activated. Multiple cytokines increased after treatment in persons with AEs. A transcriptomic analysis was performed for nine individuals with moderate systemic AEs and nine matched controls. Differential gene expression analysis identified a significant transcriptional signature associated with post-treatment AEs; 744 genes were upregulated. The transcriptional signature was enriched for TLR and NF-κB signaling. Increased expression of seven out of the top eight genes upregulated in persons with AEs were validated by qRT-PCR, including TLR2. CONCLUSIONS/SIGNIFICANCE:This is the first global study of changes in gene expression associated with AEs after treatment of lymphatic filariasis. Changes in cytokines were consistent with prior studies and with the RNAseq data. These results suggest that Wolbachia lipoprotein is involved in AE development, because it activates TLR2-TLR6 and downstream NF-κB. Additionally, LPS Binding Protein (LBP, which shuttles lipoproteins to TLR2) increased post-treatment in individuals with AEs. Improved understanding of the pathogenesis of AEs may lead to improved management, increased MDA compliance, and accelerated LF elimination. |
| first_indexed | 2024-12-21T09:11:56Z |
| format | Article |
| id | doaj.art-d1b96c65f47947db91c234e447e3d01e |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-21T09:11:56Z |
| publishDate | 2019-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-d1b96c65f47947db91c234e447e3d01e2022-12-21T19:09:13ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352019-09-01139e000769710.1371/journal.pntd.0007697Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis.Britt J AndersenBruce A RosaJonah KupritzAboulaye MeiteTraye SergeMarla I HertzKurt CurtisChristopher L KingMakedonka MitrevaPeter U FischerGary J WeilBACKGROUND:Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. METHODOLOGY/PRINCIPAL FINDINGS:To better understand the pathogenesis of AEs, we studied LF-patients from a treatment trial. Plasma levels of many filarial antigens increased post-treatment in individuals with AEs, and this is consistent with parasite death. Circulating immune complexes were not elevated in these participants, and the classical complement cascade was not activated. Multiple cytokines increased after treatment in persons with AEs. A transcriptomic analysis was performed for nine individuals with moderate systemic AEs and nine matched controls. Differential gene expression analysis identified a significant transcriptional signature associated with post-treatment AEs; 744 genes were upregulated. The transcriptional signature was enriched for TLR and NF-κB signaling. Increased expression of seven out of the top eight genes upregulated in persons with AEs were validated by qRT-PCR, including TLR2. CONCLUSIONS/SIGNIFICANCE:This is the first global study of changes in gene expression associated with AEs after treatment of lymphatic filariasis. Changes in cytokines were consistent with prior studies and with the RNAseq data. These results suggest that Wolbachia lipoprotein is involved in AE development, because it activates TLR2-TLR6 and downstream NF-κB. Additionally, LPS Binding Protein (LBP, which shuttles lipoproteins to TLR2) increased post-treatment in individuals with AEs. Improved understanding of the pathogenesis of AEs may lead to improved management, increased MDA compliance, and accelerated LF elimination.https://doi.org/10.1371/journal.pntd.0007697 |
| spellingShingle | Britt J Andersen Bruce A Rosa Jonah Kupritz Aboulaye Meite Traye Serge Marla I Hertz Kurt Curtis Christopher L King Makedonka Mitreva Peter U Fischer Gary J Weil Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. PLoS Neglected Tropical Diseases |
| title | Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. |
| title_full | Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. |
| title_fullStr | Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. |
| title_full_unstemmed | Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. |
| title_short | Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis. |
| title_sort | systems analysis based assessment of post treatment adverse events in lymphatic filariasis |
| url | https://doi.org/10.1371/journal.pntd.0007697 |
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