| 1. |
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| 2. |
- Besnard, E, et al.
(författare)
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The mTOR Complex Controls HIV Latency
- 2016
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Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 20:6, s. 785-797
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Billker, Oliver, et al.
(författare)
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Calcium Builds Strong Host-Parasite Interactions
- 2015
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 18:1, s. 9-10
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Forskningsöversikt (refereegranskat)abstract
- Apicomplexan parasite invasion of host cells is a multistep process, requiring coordinated events. In this issue of Cell Host & Microbe, Paul et al. (2015) and Philip and Waters (2015) leverage experimental genetics to show that the calcium-regulated protein phosphatase, calcinuerin, regulates invasion in multiple parasite species.
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| 4. |
- Billker, Oliver, et al.
(författare)
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Calcium-dependent signaling and kinases in apicomplexan parasites
- 2009
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 5:6, s. 612-622
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Tidskriftsartikel (refereegranskat)abstract
- Calcium controls many critical events in the complex life cycles of apicomplexan parasites including protein secretion, motility, and development. Calcium levels are normally tightly regulated and rapid release of calcium into the cytosol activates a family of calcium-dependent protein kinases (CDPKs), which are normally characteristic of plants. CDPKs present in apicomplexans have acquired a number of unique domain structures likely reflecting their diverse functions. Calcium regulation in parasites is closely linked to signaling by cyclic nucleotides and their associated kinases. This Review summarizes the pivotal roles that calcium- and cyclic nucleotide-dependent kinases play in unique aspects of parasite biology.
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| 5. |
- Billker, Oliver
(författare)
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CRISPRing the elephant in the room
- 2018
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 24:6, s. 754-755
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The importance of guanylyl-cyclases (GCs) in apicomplexa has remained elusive due to the large size of the genes. Two recent studies, including Brown and Sibley, 2018 in this issue of Cell Host & Microbe, make elegant use of genome editing with CRISPR-Cas9 to characterize roles of GCs in Toxoplasma and Plasmodium.
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| 6. |
- Blomgran, Robert, et al.
(författare)
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Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells
- 2012
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 11:1, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.
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| 7. |
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| 8. |
- Bäckhed, Fredrik, 1973, et al.
(författare)
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Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life
- 2015
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Ingår i: Cell Host & Microbe. - Cambridge : Elsevier BV. - 1931-3128 .- 1934-6069. ; 17:5, s. 690-703
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life.
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| 9. |
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| 10. |
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| 11. |
- Coppi, Alida, et al.
(författare)
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Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells
- 2007
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Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 2:5, s. 316-327
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Tidskriftsartikel (refereegranskat)abstract
- Malaria infection is initiated when Anopheles mosquitoes inject Plasmodium sporozoites into the skin. Sporozoites subsequently reach the liver, invading and developing within hepatocytes. Sporozoites contact and traverse many cell types as they migrate from skin to liver; however, the mechanism by which they switch from a migratory mode to an invasive mode is unclear. Here, we show that sporozoites of the rodent malaria parasite Plasmodium berghei use the sulfation level of host heparan sulfate proteoglycans (HSPGs) to navigate within the mammalian host. Sporozoites migrate through cells expressing low-sulfated HSPGs, such as those in skin and endothelium, while highly sulfated HSPGs of hepatocytes activate sporozoites for invasion. A calcium-dependent protein kinase is critical for the switch to an invasive phenotype, a process accompanied by proteolytic cleavage of the sporozoite's major surface protein. These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry.
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| 12. |
- Dolowschiak, Tamas, et al.
(författare)
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IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection.
- 2016
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 20:2
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Tidskriftsartikel (refereegranskat)abstract
- Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (ψ50: ∼48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-γ (IFN-γ)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-γ production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1β, TNF, and iNOS. Additionally, sustained IFN-γ fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIβ. These findings reveal a role for IFN-γ in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.
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| 13. |
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| 14. |
- Gomes, Ana Rita, et al.
(författare)
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A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite
- 2015
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Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 17:3, s. 404-413
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Tidskriftsartikel (refereegranskat)abstract
- The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Herp, Simone, et al.
(författare)
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Mucispirillum schaedleri Antagonizes Salmonella Virulence to Protect Mice against Colitis
- 2019
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 25:5, s. 681-694.e8
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Tidskriftsartikel (refereegranskat)abstract
- The microbiota and the gastrointestinal mucus layer play a pivotal role in protection against non-typhoidal Salmonella enterica serovar Typhimurium (S. Tm) colitis. Here, we analyzed the course of Salmonella colitis in mice lacking a functional mucus layer in the gut. Unexpectedly, in contrast to mucus-proficient littermates, genetically deficient mice were protected against Salmonellainduced gut inflammation in the streptomycin colitis model. This correlated with microbiota alterations and enrichment of the bacterial phylum Deferribacteres. Using gnotobiotic mice associated with defined bacterial consortia, we causally linked Mucispirillum schaedleri, currently the sole known representative of Deferribacteres present in the mammalian microbiota, to host protection against S. Tm colitis. Inhibition by M. schaedleri involves interference with S. Tm invasion gene expression, partly by competing for anaerobic electron acceptors. In conclusion, this study establishes M. schaedleri, a core member of the murine gut microbiota, as a key antagonist of S. Tm virulence in the gut.
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| 19. |
- Jern, Patric, et al.
(författare)
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Host-retrovirus arms race : trimming the budget.
- 2008
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Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 4:3, s. 196-7
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Tidskriftsartikel (refereegranskat)abstract
- In this issue of Cell Host & Microbe, OhAinle et al., 2008 report that APOBEC3H, a potent innate retroviral restriction factor in primates, lost its function twice independently during recent evolution in humans, stressing an ever present trade-off between benefit and cost of protection against pathogens.
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| 20. |
- Jin, Jing, et al.
(författare)
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Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane
- 2018
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Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 24:3, s. 417-
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Tidskriftsartikel (refereegranskat)abstract
- Neutralizing antibodies (NAbs) are traditionally thought to inhibit virus infection by preventing virion entry into target cells. In addition, antibodies can engage Fc receptors (FcRs) on immune cells to activate antiviral responses. We describe a mechanism by which NAbs inhibit chikungunya virus (CHIKV), the most common alphavirus infecting humans, by preventing virus budding from infected human cells and activating IgG-specific Fc gamma receptors. NAbs bind to CHIKV glycoproteins on the infected cell surface and induce glycoprotein coalescence, preventing budding of nascent virions and leaving structurally heterogeneous nucleocapsids arrested in the cytosol. Furthermore, NAbs induce clustering of CHIKV replication spherules at sites of budding blockage. Functionally, these densely packed glycoprotein-NAb complexes on infected cells activate Fc gamma receptors, inducing a strong, antibody-dependent, cell-mediated cytotoxicity response from immune effector cells. Our findings describe a triply functional antiviral pathway for NAbs that might be broadly applicable across virus-host systems, suggesting avenues for therapeutic innovation through antibody design.
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| 21. |
- Johansson, Malin E V, 1971, et al.
(författare)
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Is the intestinal goblet cell a major immune cell?
- 2014
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Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 15:3, s. 251-2
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports indicate that both the inflammasome (Wlodarska etal., 2014) and autophagy (Patel etal., 2013) pathways in goblet cells control mucin secretion, defects in which are linked to difficulties in clearing pathogenic bacteria and maintaining intestinal homeostasis and control colitis.
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| 22. |
- Johansson, Malin E V, 1971, et al.
(författare)
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Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization
- 2015
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Ingår i: Cell Host & Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 18:5, s. 582-592
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal mucus layer provides a barrier limiting bacterial contact with the underlying epithelium. Mucus structure is shaped by intestinal location and the microbiota. To understand how commensals modulate gut mucus, we examined mucus properties under germ-free (GF) conditions and during microbial colonization. Although the colon mucus organization of GF mice was similar to that of conventionally raised (Convr) mice, the GF inner mucus layer was penetrable to bacteria-sized beads. During colonization, in which GF mice were gavaged with Convr microbiota, the small intestine mucus required 5 weeks to be normally detached and colonic inner mucus 6 weeks to become impenetrable. The composition of the small intestinal microbiota during colonization was similar to Convr donors until 3 weeks, when Bacteroides increased, Firmicutes decreased, and segmented filamentous bacteria became undetectable. These findings highlight the dynamics of mucus layer development and indicate that studies of mature microbe-mucus interactions should be conducted weeks after colonization.
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| 23. |
- Kenny, Douglas J., et al.
(författare)
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Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level
- 2020
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 28:2, s. 245-257
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Tidskriftsartikel (refereegranskat)abstract
- The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a Glade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.
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| 24. |
- Kirienko, Natalia V., et al.
(författare)
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Pseudomonas aeruginosa Disrupts Caenorhabditis elegans Iron Homeostasis, Causing a Hypoxic Response and Death
- 2013
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 13:4, s. 406-416
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Tidskriftsartikel (refereegranskat)abstract
- The opportunistic pathogen Pseudomonas aeruginosa causes serious human infections, but effective treatments and the mechanisms mediating pathogenesis remain elusive. Caenorhabditis elegans shares innate immune pathways with humans, making it invaluable to investigate infection. To determine how P. aeruginosa disrupts host biology, we studied how P. aeruginosa kills C. elegans in a liquid-based pathogenesis model. We found that P. aeruginosa-mediated killing does not require quorum-sensing pathways or host colonization. A chemical genetic screen revealed that iron chelators alleviate P. aeruginosa-mediated killing. Consistent with a role for iron in P. aeruginosa pathogenesis, the bacterial siderophore pyoverdin was required for virulence and was sufficient to induce a hypoxic response and death in the absence of bacteria. Loss of the C. elegans hypoxia-inducing factor HIF-1, which regulates iron homeostasis, exacerbated P. aeruginosa pathogenesis, further linking hypoxia and killing. As pyoverdin is indispensable for virulence in mice, pyoverdin-mediated hypoxia is likely to be relevant in human pathogenesis.
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| 25. |
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| 26. |
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| 27. |
- Konradt, Christoph, et al.
(författare)
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The Shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism
- 2011
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 9:4, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- Shigella, the Gram-negative enteroinvasive bacterium that causes shigellosis, relies on its type III secretion system (TTSS) and injected effectors to modulate host cell functions. However, consequences of the interaction between Shigella and lymphocytes have not been investigated. We show that Shigella invades activated human CD4(+) T lymphocytes. Invasion requires a functional TTSS and results in inhibition of chemokine-induced T cell migration, an effect mediated by the TTSS effector IpgD, a phosphoinositide 4-phosphatase. Remarkably, IpgD injection into bystander T cells can occur in the absence of cell invasion. Upon IpgD-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP(2)), the pool of PIP(2) at the plasma membrane is reduced, leading to dephosphorylation of the ERM proteins and their inability to relocalize at one T cell pole upon chemokine stimulus, likely affecting the formation of the polarized edge required for cell migration. These results reveal a bacterial TTSS effector-mediated strategy to impair T cell function.
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| 28. |
- Kostic, Aleksandar D., et al.
(författare)
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The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes
- 2015
-
Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 17:2, s. 260-273
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Tidskriftsartikel (refereegranskat)abstract
- Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.
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| 29. |
- Kumar, Manish, et al.
(författare)
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MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway.
- 2015
-
Ingår i: Cell host & microbe. - : elsevier. - 1934-6069 .- 1931-3128. ; 17:3, s. 345-56
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Tidskriftsartikel (refereegranskat)abstract
- The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-κB pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1β, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1β. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.
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| 30. |
- Lannergård, Jonas, et al.
(författare)
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The Hypervariable Region of Streptococcus pyogenes M Protein Escapes Antibody Attack by Antigenic Variation and Weak Immunogenicity.
- 2011
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 10:2, s. 147-157
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Tidskriftsartikel (refereegranskat)abstract
- Sequence variation of antigenic proteins allows pathogens to evade antibody attack. The variable protein commonly includes a hypervariable region (HVR), which represents a key target for antibodies and is therefore predicted to be immunodominant. To understand the mechanism(s) of antibody evasion, we analyzed the clinically important HVR-containing M proteins of the human pathogen Streptococcus pyogenes. Antibodies elicited by M proteins were directed almost exclusively against the C-terminal part and not against the N-terminal HVR. Similar results were obtained for mice and humans with invasive S. pyogenes infection. Nevertheless, only anti-HVR antibodies protected efficiently against infection, as shown by passive immunizations. The HVR fused to an unrelated protein elicited no antibodies, implying that it is inherently weakly immunogenic. These data indicate that the M protein HVR evades antibody attack not only through antigenic variation but also by weak immunogenicity, a paradoxical observation that may apply to other HVR-containing proteins.
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| 31. |
- Lauber, Chris, et al.
(författare)
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Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses
- 2017
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 22:3, s. 387-399,e1-e6
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the similar to 1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via proteinprimed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.
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| 32. |
- Lozach, Pierre-Yves, et al.
(författare)
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Entry of bunyaviruses into mammalian cells
- 2010
-
Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 7:6, s. 488-499
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Tidskriftsartikel (refereegranskat)abstract
- The Bunyaviridae constitute a large family of enveloped animal viruses, many members of which cause serious diseases. However, early bunyavirus-host cell interactions and entry mechanisms remain largely uncharacterized. Investigating Uukuniemi virus, a bunyavirus of the genus Phlebovirus, we found that virus attachment to the cell surface was specific but inefficient, with 25% of bound viruses being endocytosed within 10 min, mainly via noncoated vesicles. The viruses entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomes. Acid-activated penetration, occurring 20-40 min after internalization, required maturation of early to late endosomes. The pH threshold for viral membrane fusion was 5.4, and entry was sensitive to temperatures below 25 degrees C. Together, our results indicate that Uukuniemi virus penetrates host cells by acid-activated membrane fusion from late endosomal compartments. This study also highlights the importance of the degradative branch of the endocytic pathway in facilitating entry of late-penetrating viruses.
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| 33. |
- Meinzer, Ulrich, et al.
(författare)
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Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction
- 2012
-
Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 11:4, s. 337-351
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Tidskriftsartikel (refereegranskat)abstract
- Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1 beta. Finally, IL-1 beta within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.
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| 34. |
- Modrzynska, Katarzyna, et al.
(författare)
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A Knockout Screen of ApiAP2 Genes Reveals Networks of Interacting Transcriptional Regulators Controlling the Plasmodium Life Cycle
- 2017
-
Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 21:1, s. 11-22
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Tidskriftsartikel (refereegranskat)abstract
- A family of apicomplexa-specific proteins containing AP2 DNA-binding domains (ApiAP2s) was identified in malaria parasites. This family includes sequence-specific transcription factors that are key regulators of development. However, functions for the majority of ApiAP2 genes remain unknown. Here, a systematic knockout screen in Plasmodium berghei identified ten ApiAP2 genes that were essential for mosquito transmission: four were critical for the formation of infectious ookinetes, and three were required for sporogony. We describe non-essential functions for AP2-O and AP2-SP proteins in blood stages, and identify AP2-G2 as a repressor active in both asexual and sexual stages. Comparative transcriptomics across mutants and developmental stages revealed clusters of co-regulated genes with shared cis promoter elements, whose expression can be controlled positively or negatively by different ApiAP2 factors. We propose that stage-specific interactions between ApiAP2 proteins on partly overlapping sets of target genes generate the complex transcriptional network that controls the Plasmodium life cycle.
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| 35. |
- Moonens, Kristof, et al.
(författare)
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Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
- 2016
-
Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 19:1, s. 55-66
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Tidskriftsartikel (refereegranskat)abstract
- The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.
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| 36. |
- Müller, Thomas R., et al.
(författare)
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Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant
- 2024
-
Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 32:2, s. 156-161.e3
-
Tidskriftsartikel (refereegranskat)abstract
- T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory T cells can effectively cross-recognize new SARS-CoV-2 variants with a broad array of mutations, such as the emergent hypermutated BA.2.86 variant. Here, we report in two separate cohorts, including healthy controls and individuals with chronic lymphocytic leukemia, that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or vaccination demonstrate resilient immune recognition of BA.2.86. In both cohorts, we found largely preserved SARS-CoV-2 spike-specific CD4+ and CD8+ T cell magnitudes against mutated spike epitopes of BA.2.86. Functional analysis confirmed that both cytokine expression and proliferative capacity of SARS-CoV-2 spike-specific T cells to BA.2.86-mutated spike epitopes are similarly sustained. In summary, our findings indicate that memory CD4+ and CD8+ T cells continue to provide cell-mediated immune recognition to highly mutated emerging variants such as BA.2.86.
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| 37. |
- Naama, Maria, et al.
(författare)
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Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress
- 2023
-
Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 31:3, s. 433-446
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Tidskriftsartikel (refereegranskat)abstract
- Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.
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| 38. |
- Olsson, Lisa M., 1984, et al.
(författare)
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Dynamics of the normal gut microbiota: A longitudinal one-year population study in Sweden
- 2022
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 30:5
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Tidskriftsartikel (refereegranskat)abstract
- Temporal dynamics of the gut microbiota potentially limit the identification of microbial features associated with health status. Here, we used whole-genome metagenomic and 16S rRNA gene sequencing to characterize the intra- and inter-individual variations of gut microbiota composition and functional potential of a disease-free Swedish population (n = 75) over one year. We found that 23% of the total compositional variance was explained by intra-individual variation. The degree of intra-individual compositional variability was negatively associated with the abundance of Faecalibacterium prausnitzii (a butyrate producer) and two Bifidobacterium species. By contrast, the abundance of facultative anaerobes and aerotolerant bacteria such as Escherichia coli and Lactobacillus acidophilus varied extensively, independent of compositional stability. The contribution of intra-individual variance to the total variance was greater for functional pathways than for microbial species. Thus, reliable quantification of microbial features requires repeated samples to address the issue of intra-individual variations of the gut microbiota.
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| 39. |
- Pino, Paco, et al.
(författare)
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A tetracycline-repressible transactivator system to study essential genes in malaria parasites
- 2012
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 12:6, s. 824-834
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Tidskriftsartikel (refereegranskat)abstract
- A major obstacle in analyzing gene function in apicomplexan parasites is the absence of a practical regulatable expression system. Here, we identified functional transcriptional activation domains within Apicomplexan AP2 (ApiAP2) family transcription factors. These ApiAP2 transactivation domains were validated in blood-, liver-, and mosquito-stage parasites and used to create a robust conditional expression system for stage-specific, tetracycline-dependent gene regulation in Toxoplasma gondii, Plasmodium berghei, and Plasmodium falciparum. To demonstrate the utility of this system, we created conditional knockdowns of two essential P. berghei genes: profilin (PRF), a protein implicated in parasite invasion, and N-myristoyltransferase (NMT), which catalyzes protein acylation. Tetracycline-induced repression of PRF and NMT expression resulted in a dramatic reduction in parasite viability. This efficient regulatable system will allow for the functional characterization of essential proteins that are found in these important parasites.
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| 40. |
- Roswall, Josefine, et al.
(författare)
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Developmental trajectory of the healthy human gut microbiota during the first 5 years of life
- 2021
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Ingår i: Cell Host & Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 29:5
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Tidskriftsartikel (refereegranskat)abstract
- The gut is inhabited by a densely populated ecosystem, the gut microbiota, that is established at birth. However, the succession by which different bacteria are incorporated into the gut microbiota is still relatively unknown. Here, we analyze the microbiota from 471 Swedish children followed from birth to 5 years of age, collecting samples after 4 and 12 months and at 3 and 5 years of age as well as from their mothers at birth using 16S rRNA gene profiling. We also compare their microbiota to an adult Swedish population. Genera follow 4 different colonization patterns during establishment where Methanobrevibacter and Christensenellaceae colonize late and do not reached adult levels at 5 years. These late colonizers correlate with increased alpha diversity in both children and adults. By following the children through age-specific community types, we observe that children have individual dynamics in the gut microbiota development trajectory.
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| 41. |
- Russell, Andrew J.C., et al.
(författare)
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Regulators of male and female sexual development are critical for the transmission of a malaria parasite
- 2023
-
Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 31:2, s. 305-319.e10
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Tidskriftsartikel (refereegranskat)abstract
- Malaria transmission to mosquitoes requires a developmental switch in asexually dividing blood-stage parasites to sexual reproduction. In Plasmodium berghei, the transcription factor AP2-G is required and sufficient for this switch, but how a particular sex is determined in a haploid parasite remains unknown. Using a global screen of barcoded mutants, we here identify genes essential for the formation of either male or female sexual forms and validate their importance for transmission. High-resolution single-cell transcriptomics of ten mutant parasites portrays the developmental bifurcation and reveals a regulatory cascade of putative gene functions in the determination and subsequent differentiation of each sex. A male-determining gene with a LOTUS/OST-HTH domain as well as the protein interactors of a female-determining zinc-finger protein indicate that germ-granule-like ribonucleoprotein complexes complement transcriptional processes in the regulation of both male and female development of a malaria parasite.
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| 42. |
- Sangaré, Lamba Omar, et al.
(författare)
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In Vivo CRISPR Screen Identifies TgWIP as a Toxoplasma Modulator of Dendritic Cell Migration
- 2019
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 26:4, s. 478-492
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Tidskriftsartikel (refereegranskat)abstract
- Toxoplasma can reach distant organs, especially the brain, leading to a lifelong chronic phase. However, genes involved in related in vivo processes are currently unknown. Here, we use focused CRISPR libraries to identify Toxoplasma genes that affect in vivo fitness. We focus on TgWIP, whose deletion affects Toxoplasmadissemination to distant organs. We show that TgWIP is secreted into the host cell upon invasion and interacts with the host WAVE regulatory complex and SHP2 phosphatase, both of which regulate actin dynamics. TgWIP affects the morphology of dendritic cells and mediates the dissolution of podosomes, which dendritic cells use to adhere to extracellular matrix. TgWIP enhances the motility and transmigration of parasitized dendritic cells, likely explaining its effect on in vivofitness. Our results provide a framework for systemic identification of Toxoplasmagenes with in vivo effects at the site of infection or on dissemination to distant organs, including the brain.
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| 43. |
- Schröder, Björn O., et al.
(författare)
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Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration
- 2018
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Ingår i: Cell Host & Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 23:1, s. 27-40
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Tidskriftsartikel (refereegranskat)abstract
- Diet strongly affects gut microbiota composition, and gut bacteria can influence the colonic mucus layer, a physical barrier that separates trillions of gut bacteria from the host. However, the interplay between a Western style diet (WSD), gut microbiota composition, and the intestinal mucus layer is less clear. Here we show that mice fed a WSD have an altered colonic microbiota composition that causes increased penetrability and a reduced growth rate of the inner mucus layer. Both barrier defects can be prevented by transplanting microbiota from chow-fed mice. In addition, we found that administration of Bifidobacterium longum was sufficient to restore mucus growth, whereas administration of the fiber inulin prevented increased mucus penetrability in WSD-fed mice. We hypothesize that the presence of distinct bacteria is crucial for proper mucus function. If confirmed in humans, these findings may help to better understand diseases with an affected mucus layer, such as ulcerative colitis.
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| 44. |
- Sebastian, Sarah, et al.
(författare)
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A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs
- 2012
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 12:1, s. 9-19
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Tidskriftsartikel (refereegranskat)abstract
- Calcium-dependent protein kinases (CDPKs) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. Using the rodent malaria parasite Plasmodium berghei, we show that CDPK1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. Knockdown of CDPK1 in sexual stages resulted in developmentally arrested parasites and prevented mosquito transmission, and these effects were independent of the previously proposed function for CDPK1 in regulating parasite motility. In-depth translational and transcriptional profiling of arrested parasites revealed that CDPK1 translationally activates mRNA species in the developing zygote that in macrogametes remain repressed via their 3' and 5'UTRs. These findings indicate that CDPK1 is a multifunctional protein that translationally regulates mRNAs to ensure timely and stage-specific protein expression.
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| 45. |
- Sellin, Mikael E., et al.
(författare)
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Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa
- 2014
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 16:2, s. 237-248
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Tidskriftsartikel (refereegranskat)abstract
- The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.
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| 46. |
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| 47. |
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| 48. |
- Sixt, Barbara Susanne
(författare)
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Keeping the home intact—lessons from Chlamydia
- 2022
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Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 30:4, s. 475-479
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 5 years ago, my colleagues and I revealed the Chlamydia trachomatis virulence factor CpoS as a suppressor of host cell-autonomous immunity. Here, I reflect on the events that inspired and enabled this research and place our discoveries in context to past and most recent discoveries in the field.
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| 49. |
- Sixt, Barbara Susanne, et al.
(författare)
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The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs
- 2017
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 21:1, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway. Disruption of STING, but not cGAS or IRF3, attenuated cell death, suggesting that STING mediates Chlamydia-induced cell death independent of its role in regulating interferon responses. CpoS-deficient strains are attenuated in their ability to propagate in cell culture and are cleared faster from the murine genital tract, highlighting the importance of CpoS for Chlamydia pathogenesis.
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| 50. |
- Soderberg-Naucler, C
(författare)
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CMV and NK Cells: An Unhealthy Tryst?
- 2016
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Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 19:3, s. 277-279
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Tidskriftsartikel (refereegranskat)
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