Biology subjects

Hallgren, J.

Publications and source records attributed to Hallgren, J..

4 recordsLinked to original sources

bioRxiv2023

A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection

Mast cells (MCs) localize to mucosal tissues and contribute to innate immune defenses against infection. How MCs sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other closely related enterobacteria, we here demonstrate that MCs can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and MCs colocalize in the Salmonella-infected mouse gut. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure LPS, causes a slow and modest induction of MC cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human MCs triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to promote the full-blown MC response. Supernatants from S.Tm-infected MCs boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that MCs can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.

immunology↗

bioRxiv2023

Phosphate starvation decouples cell differentiation from DNA replication control in the dimorphic bacterium Caulobacter crescentus

Upon nutrient depletion, bacteria stop proliferating and undergo physiological and morphological changes to ensure their survival. Yet, how these processes are coordinated in response to distinct starvation conditions is poorly understood. Here we compare the cellular responses of Caulobacter crescentus to carbon (C), nitrogen (N) and phosphorus (P) starvation conditions. We find that DNA replication initiation and abundance of the replication initiator DnaA are, under all three starvation conditions, regulated by a common mechanism involving the inhibition of DnaA translation. By contrast, cell differentiation from a motile swarmer cell to a sessile stalked cell is regulated differently under the three starvation conditions. During C and N starvation, production of the signaling molecules (p)ppGpp is required to arrest cell development in the motile swarmer stage. By contrast, our data suggest that low (p)ppGpp levels under P starvation allow P-starved swarmer cells to differentiate into sessile stalked cells. Further, we show that limited DnaA abundance, and consequently absence of DNA replication initiation, is the main reason that prevents P-starved stalked cells from completing the cell cycle. Together, our findings demonstrate that C. crescentus decouples cell differentiation from DNA replication initiation under certain starvation conditions, two otherwise intimately coupled processes. We hypothesize that arresting the developmental program either as motile swarmer cells or as sessile stalked cells improves the chances of survival of C. crescentus during the different starvation conditions. Author SummaryBacteria frequently encounter periods of nutrient limitation. To ensure their survival, they dynamically modulate their own proliferation and cellular behaviors in response to nutrient availability. In many Alphaproteobacteria, progression through the cell cycle is tightly coupled to morphological transitions generating distinct cell types. Here, we show how starvation for either of the major nutrients carbon, nitrogen, or phosphorus affects this coupling between key cell cycle events and cell differentiation in the model bacterium Caulobacter crescentus. All three starvation conditions prevent cell proliferation by blocking DNA replication initiation. However, while carbon and nitrogen exhaustion cause cells to arrest the cell cycle as non-replicating motile cells, phosphorus starvation leads to accumulation of non-replicating sessile stalked cells. Our data demonstrate that starvation-dependent differences in (p)ppGpp signaling account for these different starvation responses. Together, our work provides insights into the mechanisms that allow bacteria to modulate their developmental program in response to changing environmental conditions.

microbiology↗

bioRxiv2023

C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is translated into dipeptide repeat proteins, among which poly-proline-arginine (PR) displays the most aggressive neurotoxicity in-vitro and in-vivo. PR partitions to the nucleus when expressed in neurons and other cell types. Using drosophila and primary rat cortical neurons as model systems, we show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR accumulates in the nucleolus, a site of ribosome biogenesis that regulates the cell stress response. We examined the effect of nucleolar PR accumulation and its impact on nucleolar function and determined that PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels, either genetically or by increasing its degradation, also prevented PR-mediated neurotoxic phenotypes both in in-vitro and in-vivo models. We also investigated whether PR could cause the senescence phenotype in neurons but observed none. Instead, we found induction of apoptosis via caspase-3 activation. In summary, we uncovered the central role of nucleolar dysfunction upon PR expression in the context of C9-ALS/FTD.

neuroscience↗

bioRxiv2022

DeepTMHMM predicts alpha and beta transmembrane proteins using deep neural networks

Transmembrane proteins span the lipid bilayer and are divided into two major structural classes, namely alpha helical and beta barrels. We introduce DeepTMHMM, a deep learning protein language model-based algorithm that can detect and predict the topology of both alpha helical and beta barrels proteins with unprecedented accuracy. DeepTMHMM (https://dtu.biolib.com/DeepTMHMM) scales to proteomes and covers all domains of life, which makes it ideal for metagenomics analyses.

bioinformatics↗