Legionella pneumophila dysregulates mitochondrial homeostasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Jiaqi Fu
PROVIDER: PXD068272 | iProX | Wed Sep 10 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Legionella pneumophila is an intracellular pathogen that uses a type IV secretion system called Dot/Icm to translocate over 330 effector proteins into the infected cells. To explore the collective impact of Dot/Icm effectors on host cell processes, we created a library of 14 L. pneumophila genomic mutant strains lacking effector-rich regions (a total of 85 effector genes deleted) and used the multi-deletion mutants to interrogate host-pathogen interactions. We then performed bulk mRNAseq profilling of PMA-differentiated THP1 macrophages after infection with WT, Dot/Icm-deficient mutant, or genomic mutant strains of Legionella pneumophila 130b (18h post-infection, MOI 10).
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Project description:The RNA binding protein CsrA is the master regulator of the bi-phasic life cycle of Legionella pneumophila governing virulence expression in this intracellular pathogen. The goal of the study was to use deep sequencing of RNA enriched by co-immunoprecipitation with epitope tagged CsrA to identify CsrA-associated transcripts at the genome level. We found 478 mRNAs or non-coding RNAs to be targets of CsrA. Among those major regulators including FleQ, the regulator of flagella expression, LqsR, the regulator of quorum sensing and RpoS implicated in stress response were identified. The expression of over 40 type IV secreted effector proteins important for intracellular survival and virulence are under the control of CsrA. Combined with transcriptomics, whole shotgun proteomics of a wild type and a CsrA mutant strain and functional analyses of several CsrA-targeted RNAs we identified the first riboswitch in L. pneumophila, a thiamine pyrophosphate riboswitch, and discovered a new mode of regulation by CsrA that allows L. pneumophila to regulate the pentose phosphate pathway and the glycolysis combined or individually although they share genes in a single operon. Our results further underline the indispensable role of CsrA in the life cycle of L. pneumophila and provide new insights into its regulatory roles and mechanisms.
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Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.
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Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.
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