Mycobacterial para-Hydroxybenzoic Acid-Derivatives (pHBADs) and Related Structures Induce Macrophage Innate Memory

TY - JOUR

T1 - Mycobacterial para-Hydroxybenzoic Acid-Derivatives (pHBADs) and Related Structures Induce Macrophage Innate Memory

AU - Lundahl, Mimmi

AU - Lynch, Dylan M.

AU - Barnes, Danielle

AU - McSweeney, Lauren

AU - Gorman, Aoife

AU - Lebre, Filipa

AU - Gordon, Stephen V.

AU - Lavelle, Ed C.

AU - Scanlan, Eoin M.

N1 - Funding Information: M.L. was funded by a Trinity College Dublin postgraduate studentship, E.M.S. and D.M.L. are funded by Science Foundation Ireland (SFI) under Grant number 15/CDA/3310. E.C.L. was funded by SFI under Grant number 12/IA/1421 and the SFI Research Centre, Advanced Materials and BioEngineering Research (AMBER) under Grant number SFI/12/RC/2278. S.V.G. acknowledges funding from SFI award 15/IA/3154. Publisher Copyright: Copyright © 2020 American Chemical Society.

PY - 2020/9/18

Y1 - 2020/9/18

N2 - Macrophages are key immune cells for combatting Mycobacterium tuberculosis. However, M. tuberculosis possesses means to evade macrophage bactericidal responses by, for instance, secretion of the immunomodulatory para-hydroxybenzoic acid derivatives (pHBADs). While these molecules have been implicated in inhibiting macrophage responses in an acute context, little is known about their ability to reprogram macrophages via induction of long-term innate memory. Since innate memory has been highlighted as a promising strategy to augment bactericidal immune responses against M. tuberculosis, investigating corresponding immune evasion mechanisms is highly relevant. Our results reveal for the first time that pHBAD I and related molecules (unmethylated pHBAD I and the hexose l-rhamnose) reduce macrophage bactericidal mechanisms in both the short- A nd the long-term. Moreover, we demonstrate how methyl-p-anisate hinders bactericidal responses soon after exposure yet results in enhanced pro-inflammatory responses in the long-term. This work highlights new roles for these compounds in M. tuberculosis pathogenesis.

AB - Macrophages are key immune cells for combatting Mycobacterium tuberculosis. However, M. tuberculosis possesses means to evade macrophage bactericidal responses by, for instance, secretion of the immunomodulatory para-hydroxybenzoic acid derivatives (pHBADs). While these molecules have been implicated in inhibiting macrophage responses in an acute context, little is known about their ability to reprogram macrophages via induction of long-term innate memory. Since innate memory has been highlighted as a promising strategy to augment bactericidal immune responses against M. tuberculosis, investigating corresponding immune evasion mechanisms is highly relevant. Our results reveal for the first time that pHBAD I and related molecules (unmethylated pHBAD I and the hexose l-rhamnose) reduce macrophage bactericidal mechanisms in both the short- A nd the long-term. Moreover, we demonstrate how methyl-p-anisate hinders bactericidal responses soon after exposure yet results in enhanced pro-inflammatory responses in the long-term. This work highlights new roles for these compounds in M. tuberculosis pathogenesis.

KW - Bacteria

KW - Circuits

KW - Immunology

KW - Infectious diseases

KW - Peptides and proteins

UR - https://www.scopus.com/pages/publications/85091264029

U2 - 10.1021/acschembio.0c00378

DO - 10.1021/acschembio.0c00378

M3 - Article

C2 - 32786261

AN - SCOPUS:85091264029

SN - 1554-8929

VL - 15

SP - 2415

EP - 2421

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 9

ER -