Mycobacterial PIMs Inhibit Host Inflammatory Responses through CD14-Dependent and CD14-Independent Mechanisms

Abstract

Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM1 isomer and PIM2 mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM1 and PIM2 analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM1 and PIM2 analogues. CD14 was dispensable for PIM1 and PIM2 analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM1 and PIM2 analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway.

HIV Disclosure and Transmission Risks to Sex Partners Among HIV-Positive Men

“…1,39,40 Misinformed beliefs and deficits in disclosure self-efficacy and risk reduction skills suggest promising avenues for interventions. Cognitive and behavioral interventions that focus on correcting misinformation and building risk reduction and communication skills have a long history of demonstrated efficacy in HIV prevention, 41,42 including interventions designed to reduce HIV transmission risks among men living with HIV. 43 However, there are surprisingly few interventions designed to assist people living with HIV to manage HIV disclosure to sex partners.…”

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

“…7). The PRR agonists like PIM 2 (15,(67)(68)(69) and MDP (70,71) are potent vaccine adjuvant candidates. Thus, our study has accentuated the cross-regulation of the respective PRR in a coactivation scenario, which can contribute to better understanding of the adjuvant utilities of Ac 2 PIM and MDP.…”

“…founding to several studies where PIM 2 was found to be proinflammatory in its function (10,12), several members of PIM family that are TLR2 agonists are majorly anti-inflammatory in nature and can suppress pro-inflammatory responses mediated by other PRRs (13)(14)(15). We sought to analyze the cross-regulation, if any, between PIM-induced TLR2 signaling and another PRR signaling like NOD2 pathway.…”

“…Functional consequences of PIM-induced TLR2 signaling span both pro-and anti-inflammatory capacities (10,(12)(13)(14)(15). Importantly, stimulation of PIM-TLR2 pathway down-regulates TLR4-induced pro-inflammatory signals (13).…”

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

“…Although one strategy has been published which allows the isolation of PIMs from the avirulent M. bovis BCG strain (18,(22)(23)(24) and M. tuberculosis H37Rv (22) and certain synthetic molecules (17,19,21), in this study we successfully developed a novel method for extracting and subsequently highly purifying and characterizing individual PIM species from the polar fraction of virulent M. tuberculosis H37Rv. The method developed here improves upon the previously published protocols primarily by using a French press to disrupt the bacterial cells, thereby increasing PIM yield.…”