Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction.
Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and...
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ftdoajarticles:oai:doaj.org/article:b3d99075d6474abf97d98820846b71aa 2023-05-15T15:11:11+02:00 Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. Elizabeth A Misch Murdo Macdonald Chaman Ranjit Bishwa R Sapkota Richard D Wells M Ruby Siddiqui Gilla Kaplan Thomas R Hawn 2008-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000231 https://doaj.org/article/b3d99075d6474abf97d98820846b71aa EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2330092?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000231 https://doaj.org/article/b3d99075d6474abf97d98820846b71aa PLoS Neglected Tropical Diseases, Vol 2, Iss 5, p e231 (2008) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2008 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000231 2022-12-31T14:08:54Z Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 2 5 e231 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Elizabeth A Misch Murdo Macdonald Chaman Ranjit Bishwa R Sapkota Richard D Wells M Ruby Siddiqui Gilla Kaplan Thomas R Hawn Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability. |
format |
Article in Journal/Newspaper |
author |
Elizabeth A Misch Murdo Macdonald Chaman Ranjit Bishwa R Sapkota Richard D Wells M Ruby Siddiqui Gilla Kaplan Thomas R Hawn |
author_facet |
Elizabeth A Misch Murdo Macdonald Chaman Ranjit Bishwa R Sapkota Richard D Wells M Ruby Siddiqui Gilla Kaplan Thomas R Hawn |
author_sort |
Elizabeth A Misch |
title |
Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
title_short |
Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
title_full |
Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
title_fullStr |
Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
title_full_unstemmed |
Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
title_sort |
human tlr1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2008 |
url |
https://doi.org/10.1371/journal.pntd.0000231 https://doaj.org/article/b3d99075d6474abf97d98820846b71aa |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 2, Iss 5, p e231 (2008) |
op_relation |
http://europepmc.org/articles/PMC2330092?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000231 https://doaj.org/article/b3d99075d6474abf97d98820846b71aa |
op_doi |
https://doi.org/10.1371/journal.pntd.0000231 |
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PLoS Neglected Tropical Diseases |
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2 |
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5 |
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e231 |
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