Abdel-Haleem, A. M. | Search bioRxiv

bioRxiv2022

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

TPL2 (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNAseq analysis indicates protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

neuroscience↗

bioRxiv2020

Integrated metabolic modeling, culturing and transcriptomics explains enhanced virulence of V. cholerae during co-infection with ETEC

Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models to explore the effect of co-infection of the diarrheagenic pathogen Vibrio cholerae (V. cholerae) with another enteric pathogen, enterotoxigenic E. coli (ETEC). Model predictions showed that V. cholerae metabolic capabilities were increased due to ample cross-feeding opportunities enabled by ETEC. This is in line with increased severity of cholera symptoms known to occur in patients with dual-infections by the two pathogens. In vitro co-culture systems confirmed that V. cholerae growth is enhanced in co-cultures relative to single-cultures. Further, expression levels of several V. cholerae metabolic genes were significantly perturbed as shown by dual RNAseq analysis of its co-cultures with different ETEC strains. A decrease in ETEC growth was also observed, probably mediated by non-metabolic factors. Single gene essentiality analysis predicted conditionally-independent genes that are essential for the pathogen’s growth in both single- and co-infection scenarios. Our results reveal growth differences that are of relevance to drug targeting and efficiency in polymicrobial infections.Importance Most studies proposing new strategies to manage and treat infections have been largely focused on identifying druggable targets that can inhibit a pathogen’s growth when it is the single cause of infection. In vivo, however, infections can be caused by multiple species. This is important to take into account when attempting to develop or use current antibacterials since their efficacy can change significantly between single and co-infections. In this study, we used genome-scale metabolic models (GEMs) to interrogate the growth capabilities of Vibrio cholerae (V. cholerae) in single and co-infections with enterotoxigenic E. coli (ETEC), which co-occur in large fraction of diarrheagenic patients. Co-infection model predictions showed that V. cholerae growth capabilities are enhanced in presence of ETEC relative to V. cholerae single-infection, through cross-fed metabolites made available to V. cholerae by ETEC. In vitro, co-cultures of the two enteric pathogens further confirmed model predictions showing an increased growth of V. cholerae in co-culture relative to V. cholerae single-cultures while ETEC growth was suppressed. Dual RNAseq analysis of the co-cultures also confirmed that the transcriptome of V. cholerae is distinct during co-infection compared to single infection scenarios where processes related to metabolism were significantly perturbed. Further, in silico gene-knock out simulations uncovered discrepancies in gene essentiality for V. cholerae growth between single and co-infections. Integrative model-guided analysis thus identified druggable targets that would be critical for V. cholerae growth in both single and co-infections, thus designing inhibitors against those targets would provide a broader spectrum coverage against cholera infections.View Full Text

systems biology↗

bioRxiv2019

Disruption of the coordination between host circadian rhythms and malaria parasite development alters the duration of the intraerythrocytic cycle

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 hours (depending on the species), suggesting a circadian basis to the asexual cell cycle, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit 24 h \"circadian\" periodicity in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 9% of Plasmodium falciparum genes show circadian transcription under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a circadian transcription profile and disrupting it in rodent malaria parasites shortens the IDC by 2-3 hours; (v) Multiple processes including DNA replication and the ubiquitin and proteasome pathways are affected by loss of coordination with host rhythms and by disruption of SR10. Our results show that malaria parasites are at least partly responsible for scheduling their IDCs explaining the fitness benefits of coordination with host rhythms.

genomics↗