Emma Slack

Last Name

Slack

First Name

Emma

ORCID

0000-0002-2473-1145

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09640 - Wetter Slack, Emma / Wetter Slack, Emma

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Publications 1 - 10 of 80

ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens
Proietti, Michele; Perruzza, Lisa; Scribano, Daniela; et al. (2019)
Nature Communications
T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The mutualistic co-evolution of host and microbes led to the relative tolerance of host’s immune system towards commensal microorganisms. The ATP-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. Here we show that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. Ectopic expression of Shigella flexneri periplasmic ATP-diphosphohydrolase (apyrase) abolishes ATP release by bacteria and improves the specific IgA response against live oral vaccines. Antibody responses primed in the absence of intestinal extracellular ATP (eATP) also provide superior protection from enteropathogenic infection. Thus, modulation of eATP in the small intestine can affect high-affinity IgA response against gut colonizing bacteria.
Microbiome-based interventions to modulate gut ecology and the immune system
Hitch, Thomas C.A.; Hall, Lindsay J.; Walsh, Sarah Kate; et al. (2022)
Mucosal Immunology
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice
Wotzka, Sandra Y.; Kreuzer, Markus; Maier, Lisa; et al. (2019)
Nature Microbiology
The microbiota confers colonization resistance, which blocks Salmonella gut colonization1. As diet affects microbiota composition, we studied whether food composition shifts enhance susceptibility to infection. Shifting mice to diets with reduced fibre or elevated fat content for 24 h boosted Salmonella Typhimurium or Escherichia coli gut colonization and plasmid transfer. Here, we studied the effect of dietary fat. Colonization resistance was restored within 48 h of return to maintenance diet. Salmonella gut colonization was also boosted by two oral doses of oleic acid or bile salts. These pathogen blooms required Salmonella’s AcrAB/TolC-dependent bile resistance. Our data indicate that fat-elicited bile promoted Salmonella gut colonization. Both E. coli and Salmonella show much higher bile resistance than the microbiota. Correspondingly, competitive E. coli can be protective in the fat-challenged gut. Diet shifts and fat-elicited bile promote S. Typhimurium gut infections in mice lacking E. coli in their microbiota. This mouse model may be useful for studying pathogen–microbiota–host interactions, the protective effect of E. coli, to analyse the spread of resistance plasmids and assess the impact of food components on the infection process.
Surface Cross-Linking by Macromolecular Tethers Enhances Virus-like Particles’ Resilience to Mucosal Stress Factors
Ali, Ahmed; Ganguillet, Suwannee; Turgay, Yagmur George; et al. (2024)
ACS Nano
Virus-like particles (VLPs) are emerging as nanoscaffolds in a variety of biomedical applications including delivery of vaccine antigens and cargo such as mRNA to mucosal surfaces. These soft, colloidal, and proteinaceous structures (capsids) are nevertheless susceptible to mucosal environmental stress factors. We cross-linked multiple capsid surface amino acid residues using homobifunctional polyethylene glycol tethers to improve the persistence and survival of the capsid to model mucosal stressors. Surface cross-linking enhanced the stability of VLPs assembled from Acinetobacter phage AP205 coat proteins in low pH (down to pH 4.0) and high protease concentration conditions (namely, in pig and mouse gastric fluids). Additionally, it increased the stiffness of VLPs under local mechanical indentation applied using an atomic force microscopy cantilever tip. Small angle X-ray scattering revealed an increase in capsid diameter after cross-linking and an increase in capsid shell thickness with the length of the PEG cross-linkers. Moreover, surface cross-linking had no effect on the VLPs' mucus translocation and accumulation on the epithelium of in vitro 3D human nasal epithelial tissues with mucociliary clearance. Finally, it did not compromise VLPs' function as vaccines in mouse subcutaneous vaccination models. Compared to PEGylation without cross-linking, the stiffness of surface cross-linked VLPs were higher for the same length of the PEG molecule, and also the lifetimes of surface cross-linked VLPs were longer in the gastric fluids. Surface cross-linking using macromolecular tethers, but not simple conjugation of these molecules, thus offers a viable means to enhance the resilience and survival of VLPs for mucosal applications.
Enchained growth and cluster dislocation: A possible mechanism for microbiota homeostasis
Bansept, Florence; Schumann-Moor, Kathrin; Diard, Médéric; et al. (2019)
PLoS Computational Biology
Immunoglobulin A is a class of antibodies produced by the adaptive immune system and secreted into the gut lumen to fight pathogenic bacteria. We recently demonstrated that the main physical effect of these antibodies is to enchain daughter bacteria, i.e. to cross-link bacteria into clusters as they divide, preventing them from interacting with epithelial cells, thus protecting the host. These links between bacteria may break over time. We study several models using analytical and numerical calculations. We obtain the resulting distribution of chain sizes, that we compare with experimental data. We study the rate of increase in the number of free bacteria as a function of the replication rate of bacteria. Our models show robustly that at higher replication rates, bacteria replicate before the link between daughter bacteria breaks, leading to growing cluster sizes. On the contrary at low growth rates two daughter bacteria have a high probability to break apart. Thus the gut could produce IgA against all the bacteria it has encountered, but the most affected bacteria would be the fast replicating ones, that are more likely to destabilize the microbiota. Linking the effect of the immune effectors (here the clustering) with a property directly relevant to the potential bacterial pathogeneicity (here the replication rate) could avoid to make complex decisions about which bacteria to produce effectors against.
Host control of the microbiome: Mechanisms, evolution, and disease
Wilde, Jacob; Slack, Emma; Foster, Kevin R. (2024)
Science
Many species, including humans, host communities of symbiotic microbes. There is a vast literature on the ways these microbiomes affect hosts, but here we argue for an increased focus on how hosts affect their microbiomes. Hosts exert control over their symbionts through diverse mechanisms, including immunity, barrier function, physiological homeostasis, and transit. These mechanisms enable hosts to shape the ecology and evolution of microbiomes and generate natural selection for microbial traits that benefit the host. Our microbiomes result from a perpetual tension between host control and symbiont evolution, and we can leverage the host’s evolved abilities to regulate the microbiota to prevent and treat disease. The study of host control will be central to our ability to both understand and manipulate microbiotas for better health.
“EvoVax” – A rationally designed inactivated Salmonella Typhimurium vaccine induces strong and long-lasting immune responses in pigs
Lentsch, Verena; Aslani, Selma; Echtermann, Thomas; et al. (2023)
Vaccine
Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm) poses a considerable threat to public health due to its zoonotic potential. Human infections are mostly foodborne, and pork and pork products are ranked among the top culprits for transmission. In addition, the high percentage of antibiotic resistance, especially in monophasic S.Tm, limits treatment options when needed. Better S.Tm control would therefore be of benefit both for farm animals and for safety of the human food chain. A promising pre-harvest intervention is vaccination. In this study we tested safety and immunogenicity of an oral inactivated S.Tm vaccine, which has been recently shown to generate an “evolutionary trap” and to massively reduce S.Tm colonization and transmission in mice. We show that this vaccine is highly immunogenic and safe in post-weaning pigs and that administration of a single oral dose results in a strong and long-lasting serum IgG response. This has several advantages over existing – mainly live – vaccines against S.Tm, both in improved seroconversion and reduced risk of vaccine-strain persistence and reversion to virulence.
Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition
Kroon, Sanne; Malcic, Dejan; Weidert, Lena; et al. (2025)
Nature Communications
Endotoxin-driven systemic immune activation is a common hallmark across various clinical conditions. During acute critical illness, elevated plasma lipopolysaccharide triggers non-specific systemic immune activation. In addition, a compositional shift in the gut microbiota, including an increase in gut-luminal opportunistic pathogens, is observed. Whether a causal link exists between acute endotoxemia and abundance of gut-luminal opportunistic pathogens is incompletely understood. Here, we model acute, pathophysiological lipopolysaccharide concentrations in mice and show that systemic exposure promotes a 100–10’000-fold expansion of Klebsiella pneumoniae, Escherichia coli, Enterococcus faecium and Salmonella Typhimurium in the gut within one day, without overt enteropathy. Mechanistically, this is driven by a Toll-like receptor 4-dependent increase in gut-luminal oxygen species levels, which transiently halts microbiota fermentation and fuels growth of gut-luminal facultative anaerobic pathogens through oxidative respiration. Thus, systemic immune activation transiently perturbs microbiota homeostasis and favours opportunistic pathogens, potentially increasing the risk of infection in critically ill patients.
Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection
Haas, Anna; Zimmermann, Kathrin; Graw, Frederik; et al. (2011)
Gut
Salmonella Typhimurium screen identifies shifts in mixed-acid fermentation during gut colonization
Nguyen, Bidong D.; Sintsova, Anna; Schubert, Christopher; et al. (2024)
Cell Host & Microbe
How enteric pathogens adapt their metabolism to a dynamic gut environment is not yet fully understood. To investigate how Salmonella enterica Typhimurium (S.Tm) colonizes the gut, we conducted an in vivo transposon mutagenesis screen in a gnotobiotic mouse model. Our data implicate mixed-acid fermentation in efficient gut-luminal growth and energy conservation throughout infection. During initial growth, the pathogen utilizes acetate fermentation and fumarate respiration. After the onset of gut inflammation, hexoses appear to become limiting, as indicated by carbohydrate analytics and the increased need for gluconeogenesis. In response, S.Tm adapts by ramping up ethanol fermentation for redox balancing and supplying the TCA cycle with α-ketoglutarate for additional energy. Our findings illustrate how S.Tm flexibly adapts mixed fermentation and its use of the TCA cycle to thrive in the changing gut environment. Similar metabolic wiring in other pathogenic Enterobacteriaceae may suggest a broadly conserved mechanism for gut colonization.

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Emma Slack

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