Toll-like receptor chaperone HSP90B1 and the immune response to Mycobacteria.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Interleukin-2/*genetics ; Membrane Glycoproteins/*genetics ; Mycobacterium tuberculosis/*genetics ; Toll-Like Receptor 2/*genetics ; Tuberculosis/*genetics; Animals ; Female ; Gene Editing ; Gene Expression Regulation/genetics ; Gene Expression Regulation/immunology ; Genetic Predisposition to Disease/genetics ; Haplotypes ; Humans ; Infant ; Interleukin-2/immunology ; Membrane Glycoproteins/immunology ; Mice ; Mycobacterium bovis/genetics ; Mycobacterium bovis/pathogenicity ; Mycobacterium tuberculosis/pathogenicity ; Myeloid Cells/immunology ; Myeloid Cells/microbiology ; Polymorphism, Single Nucleotide/genetics ; T-Lymphocytes/immunology ; T-Lymphocytes/microbiology ; Toll-Like Receptor 2/immunology ; Tuberculosis/microbiology

Rationale: HSP90B1, also known as gp96, is a chaperone for multiple Toll-like receptors (TLRs) and is necessary for TLR-mediated inflammatory responses in murine myeloid cells. The molecule is also expressed in T-cells though its specific role is unknown. We hypothesized that human HSP90B1 regulates monocyte and T-cell responses to Mycobacterium tuberculosis (Mtb) and bacilli Calmette-Guerin (BCG) and that its variants are associated with susceptibility to TB disease.
Methods: We screened 17 haplotype-tagging SNPs in the HSP90B1 gene region for association with BCG-induced T-cell cytokine responses using both an ex-vivo whole blood assay (N = 295) and an intracellular cytokine staining assay (N = 180) on samples collected 10 weeks after birth. Using a case-control study design, we evaluated the same SNPs for association with TB disease in a South African pediatric cohort (N = 217 cases, 604 controls). A subset of these SNPs was evaluated for association with HSP90B1 expression in human monocytes, monocyte-derived dendritic cells, and T-cells using RT-PCR. Lastly, we used CRISPR/Cas9 gene editing to knock down HSP90B1 expression in a human monocyte cell line (U937). Knockdown and control cell lines were tested for TLR surface expression and control of Mtb replication.
Results: We identified three SNPs, rs10507172, rs10507173 and rs1920413, that were associated with BCG-induced IL-2 secretion (p = 0.017 for rs10507172 and p = 0.03 for rs10507173 and rs1920413, Mann-Whitney, dominant model). SNPs rs10507172 and rs10507173 were associated with TB disease in an unadjusted analysis (p = 0.036 and 0.025, respectively, dominant model) that strengthened with sensitivity analysis of the definite TB cases, which included only those patients with microbiologically confirmed Mtb (p = 0.007 and 0.012, respectively). Knockdowns of HSP90B1 in monocyte cell lines with CRISPR did not alter TLR2 surface expression nor influence Mtb replication relative to controls.
Conclusion: Among infants, an HSP90B1 gene-region variant is associated with BCG-induced IL-2 production and may be associated with protection from TB disease. HSP90B1 knockdown in human monocyte-like cell lines did not influence TLR2 surface localization nor Mtb replication. Together, these data suggest that HSP90B1 regulates T-cell, but not monocyte, responses to mycobacteria in humans.
Competing Interests: The authors have declared that no competing interests exist.

Erratum in: PLoS One. 2020 Jul 2;15(7):e0235935. (PMID: 32614924)

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T32 HL007287 United States HL NHLBI NIH HHS; K08 AI102971 United States AI NIAID NIH HHS; R01 AI136921 United States AI NIAID NIH HHS; N01AI70022 United States AI NIAID NIH HHS; K24 AI137310 United States AI NIAID NIH HHS; L30 AI091018 United States AI NIAID NIH HHS

0 (Interleukin-2)
0 (Membrane Glycoproteins)
0 (TLR2 protein, human)
0 (Toll-Like Receptor 2)
0 (endoplasmin)

Date Created: 20181215 Date Completed: 20190507 Latest Revision: 20210226

20240829

PMC6294361

10.1371/journal.pone.0208940

30550567