Unique <b><i>Francisella</i></b> Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid

Abstract

Virulent Francisella tularensis subsp. tularensis (Ftt) is a dynamic, intracellular, bacterial pathogen. Its ability to evade and rapidly suppress host inflammatory responses is considered a key element for its profound virulence. We previously established that Ftt lipids play a role in inhibiting inflammation, but we did not determine the lipid species mediating this process. Here, we show that a unique, abundant, phosphatidylethanolamine (PE), present in Francisella, contributes to driving the suppression of inflammatory responses in human and mouse cells. Acyl chain lengths of this PE, C24: 0 and C10: 0, were key to the suppressive capabilities of Francisella PE. Addition of synthetic PE 24: 0–10: 0 resulted in the accumulation of PE in host cells for up to 24 h of incubation, and recapitulated the inhibition of inflammatory responses observed with native Ftt PE. Importantly, this novel PE significantly inhibited inflammatory responses driven by a medically and globally important flavivirus, dengue fever virus. Thus, targeting these lipids and/or the pathways that they manipulate represents a new strategy to combat immunosuppression engendered by Ftt, but they also show promise as a novel therapeutic intervention for significant viral infections.

Interferon Gamma Reprograms Host Mitochondrial Metabolism through Inhibition of Complex II To Control Intracellular Bacterial Replication

“…Differential modulation of mitochondrial metabolism by SchuS4 capsule and lipids compared to LVS is a potential mechanism, as well as variation in the ability of lipids between strains to suppress IFN-␥-associated transcriptional regulators of ACOD1 (22,(40)(41)(42). Regardless, once itaconate is produced, it does not control bacteria by exhibiting direct activity on the bacterial glyoxylate pathway, as has been reported with other pathogens (31)(32)(33).…”

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

“…Human monocyte cultures 46 were seeded in 48-well plates and transduced with a combination of vpx-vlp and shControl or shTRIM5 lentivirus for three hours followed by addition of IL-4 and GM-CSF-conditioned RPMI media. Conditioned media was replenished at 3 days post transduction (dpt).…”

Guanylate-Binding Proteins Are Critical for Effective Control of Francisella tularensis Strains in a Mouse Co-Culture System of Adaptive Immunity

“…The results also demonstrate that control of even highly virulent strains is achievable in the co-culture model, in agreement with previous data ( Mahawar et al., 2013 ; Griffin et al., 2015 ; Golovliov et al., 2016 ; Eneslätt et al., 2018 ; Lindgren et al., 2020 ), although the degree of control was less marked with the highly virulent SCHU S4 strain as compared to the LVS or F. novicida strains. Thus, the strain with the highest virulence, SCHU S4, demonstrated the most rapid replication and also was the least affected by the presence of immune cells, likely due to its potent immunomodulatory properties ( Melillo et al., 2010 ; Gillette et al., 2014 ; Ireland et al., 2018 ).…”

“…In addition, the immunomodulatory abilities of the LVS and SCHU S4 strains have been extensively studied ( Telepnev et al., 2005 ; Gavrilin et al., 2006 ; McCaffrey and Allen, 2006 ; Weiss et al., 2007 ; Bröms et al., 2011 ; Lindgren et al., 2013 ; Rabadi et al., 2016 ). Specifically, a number of potent immunosuppressive traits of SCHU S4 have been identified during infection of monocytic cells ( Melillo et al., 2010 ; Gillette et al., 2014 ; Ireland et al., 2018 ). In view of this background, we find it unsurprising that there were distinct cytokine patterns observed in response to infection with each of the three bacterial strains.…”