TY - JOUR
T1 - TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia
AU - Shah, Javeed A.
AU - Emery, Robyn
AU - Lee, Brian
AU - Venkatasubramanian, Sambasivan
AU - Simmons, Jason D.
AU - Brown, Melanie
AU - Hung, Chi F.
AU - Prins, Jan M.
AU - Verbon, Annelies
AU - Hawn, Thomas R.
AU - Skerrett, Shawn J.
N1 - Funding Information: We thank the families who participated in the study. We thank Kevin Hybiske, Meghan Zuck, and Stephen Hawn for valuable intellectual contributions and assay development. We also acknowledge the support of the Cell Analysis Flow Cytometry and Imaging Core in the Department of Immunology at the University of Washington. This work was supported by R01 AI136971, K08 AI102971, and VA R&D to JAS, R01 AI093646 to SJS, K24 AI137310 to TRH, K08 HL127075 to CFH. Lp strains were a gift of Klaus Heuner and Russell Vance. Publisher Copyright: © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires’ disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, Tollip−/− mice demonstrated significantly fewer bacterial colony-forming unit and increased cytokine responses from BAL fluid. Tollip−/− macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC ex vivo. This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16–0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies.
AB - Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires’ disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, Tollip−/− mice demonstrated significantly fewer bacterial colony-forming unit and increased cytokine responses from BAL fluid. Tollip−/− macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC ex vivo. This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16–0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies.
UR - http://www.scopus.com/inward/record.url?scp=85071908808&partnerID=8YFLogxK
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UR - https://www.ncbi.nlm.nih.gov/pubmed/31462698
U2 - https://doi.org/10.1038/s41385-019-0196-7
DO - https://doi.org/10.1038/s41385-019-0196-7
M3 - Article
C2 - 31462698
SN - 1933-0219
VL - 12
SP - 1382
EP - 1390
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 6
ER -