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Thrilled to share our new @cellhostmicrobe study! We found a central role for the alveolar epithelium in responding to IL-1 from #Legionella-infected alveolar macs by producing GM-CSF, which metabolically reprograms monocytes to amplify antibacterial inflammation. A thread (1/n) https://twitter.com/cellhostmicrobe/status/1297910988742758400
#Legionella pneumophila causes the severe pneumonia #LegionnairesDisease by replicating within alveolar macs. To do this, Legionella uses a T4SS to inject bacterial effectors that disarm host defenses. Several of these effectors potently block host protein synthesis. (2/n)
Paradoxically, we & others found that despite this host translational block, Legionella elicit a potent inflammatory response important for bacterial clearance. How can such a robust cytokine response be generated? (3/n) https://dx.plos.org/10.1371/journal.ppat.1000220
@russellevance & @MarrietTheSpy previously found that the effector-driven translational block induces effector-triggered immunity (ETI) in infected macrophages. ETI then leads to the hyperinduction of IL-1 & other key cytokines. (4/n) https://dx.plos.org/10.1371/journal.ppat.1001289
@ralphisberg’s lab & our lab then showed that IL-1 somehow bypassed the translational block & was still made in infected macs. However, TNF and IL-12 weren’t made due to the translational block, but were instead produced by bystander myeloid cells. (5/n) https://dx.plos.org/10.1371/journal.ppat.1004229
We found that IL-1 released by infected macs drove TNF & IL-12 production by bystander monocytes (MCs) & other recruited immune cells. Intriguingly, IL-1R signaling on these cells wasn’t responsible. How could IL-1 be orchestrating these responses? (6/n) https://www.pnas.org/content/112/24/7557
To our surprise, IL-1R on the alveolar epithelium was required for MCs to produce cytokines, indicating that the alveolar epithelium made an intermediary factor. Some hunting (& a bit of luck) allowed us to find that IL-1 induced the alveolar epithelium to make GM-CSF (7/n).
We next found that GM-CSF was required for MCs to produce cytokines. But how? Here again, some hunting led us to find that GM-CSF metabolically reprograms MCs to undergo increased aerobic glycolysis, which supports increased cytokine production & antibacterial defense. (8/n)
Congrats to the 1st author, my amazing & fearless postdoc Xin Liu! Xin is an immigrant on an J-9 visa & mother to a young child. We’re truly fortunate to have her in our lab. She has more stories to share soon. And Xin will be looking for faculty jobs in the coming year! (9/n)
Thanks to our wonderful lab manager Mark Boyer & former postdoc Alicia Holmgren, now at @uaanchorage. Thanks @BrodskyIgor, @KingOfPathogens, & @LauferTerri for helpful advice. Thank you to our reviewers & @galette86 at @cellhostandmicrobe for a positive review experience! (10/n)
Thank you to our funders @NIAIDFunding, @BWFUND @BWFPATH, & the @PennMedicine Linda Pechenik Montague Award for supporting our work! And thanks to those of you who made it to the end of this thread! (end)
