Interplay between trauma and Pseudomonas entomophila infection in flies: a central role of the JNK pathway and of CrebA

Abstract

In mammals, both sterile wounding and infection induce inflammation and activate the innate immune system, and the combination of both challenges may lead to severe health defects, revealing the importance of the balance between the intensity and resolution of the inflammatory response for the organism’s fitness. Underlying mechanisms remain however elusive. Using Drosophila, we show that, upon infection with the entomopathogenic bacterium Pseudomonas entomophila (Pe), a sterile wounding induces a reduced resistance and increased host mortality. To identify the molecular mechanisms underlying the susceptibility of wounded flies to bacterial infection, we analyzed the very first steps of the process by comparing the transcriptome landscape of infected (simple hit flies, SH), wounded and infected (double hit flies, DH) and wounded (control) flies. We observed that overexpressed genes in DH flies compared to SH ones are significantly enriched in genes related to stress, including members of the JNK pathway. We demonstrated that the JNK pathway plays a central role in the DH phenotype by manipulating the Jra/dJun activity. Moreover, the CrebA/Creb3-like transcription factor (TF) and its targets were up-regulated in SH flies and we show that CrebA is required for mounting an appropriate immune response. Drosophila thus appears as a relevant model to investigate interactions between trauma and infection and allows to unravel key pathways involved.

Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses

“…Peroxisome-dependent defects in Rho1 signaling decrease host survival of systemic infection To determine a role for the plasmatocyte peroxisome-GTPase axis in host defense, we assessed the survival of control Hml > UAS-GFP (Hml) flies with WT plasmatocytes or Hml > Pex5-i flies with peroxisome-depleted plasmatocytes expressing different Rho variants after needlestick infection with the entomopathogenic bacterium Pseudomonas entomophila (P.e.) (Ragheb et al, 2017). We used P.e.…”

Shared enhancer gene regulatory networks between wound and oncogenic programs

“…We also confirm the strong involvement of JAK/STAT, as the eGRN of Signal-transducer and activator of transcription protein at 92E (Stat92E) is specifically active in the wound response clusters (Figure 3.a), in agreement with the enrichment for the Stat92E binding motif in the woundspecific accessible regions (NES=3.6) and the co-expression of the unpaired ligands (upd1/2/3, Figure 1.c). Other transcription factors with induced eGRN activity in both wound clusters include the Cyclic-AMP response element binding protein A (CrebA, CREB3L2 ortholog, involved in resistance to infection), Cap'n'collar (Cnc, Nrf1/2 ortholog, involved in oxidative stress response), and Cryptocephal (Crc, ATF4 ortholog, involved in unfolded protein response)(Figure 3.a), three basic-leucine zipper (bZip) TFs known to be involved in stress response (Brock et al, 2017;Brown et al, 2021;Ragheb et al, 2017;Sorge et al, 2020;Sykiotis and Bohmann, 2008;Troha et al, 2018). Interestingly, we note an additional upregulation of both Stat92E and AP-1 GRN activity in the peripodial epithelium (PE) of the wounded disc (Figure 3.a).…”

ninaDregulates cholesterol homeostasis from the midgut which protects against neurodegeneration

“…Cholesterol levels were not restored in jou- deleted flies upon expression of ninaD-RNAi exclusively in the fat body with Lsp2-GAL4 or Cg-GAL4 drivers (Figure 2G, H, I). Since the Lsp2-GAL4 line is also expressed at different developmental stages, we use a conditional adult-specific expression line, the Lsp2-GS (Ragheb et al, 2017), to restrict the expression of the ninaD-RNAi into the fat body only in adulthood. As for the Lsp2-GAL4, the expression of the ninaD-RNAi did not rescue the jou phenotypes, since the different forms of cholesterol were not restored compared to the non-induced flies (Figure 2G, H, I).…”