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Key Points Helicobacter pylori persistently colonizes the gastric mucosa of humans, infecting approximately 50% of the population worldwide. The prevalence of H. pylori is decreasing in most parts of the developed world owing to improved sanitation, reduced transmission and the more frequent use of antibiotics in childhood. Initial colonization of the hostile environment of the gastric mucosa by H. pylori requires specific adaptations, including flagellar motility, production of urease, chemotaxis and helical cell shape. To establish persistent infection, H. pylori has evolved to avoid recognition by pattern recognition receptors of the innate immune system and to preferentially activate receptors coupled to anti-inflammatory signalling pathways. The pathogen-associated molecular patterns of this bacterium are substantially less biologically active than those of related Gram-negative enteropathogens. Another H. pylori persistence strategy involves the prevention and manipulation of T cell-mediated adaptive immunity. Specific virulence factors are produced by all strains of H. pylori to block T cell activation, proliferation and effector functions, and to preferentially induce regulatory T cell responses rather than effector T cell responses. Asymptomatic carriers are more likely to preferentially generate T Reg responses and harbour denser H. pylori populations than patients with peptic ulcer disease. H. pylori causes gastric disease owing to its production of vacuolating cytotoxin and to a pathogenicity island-encoded type IV secretion system; both virulence determinants act together to promote the production of pro-inflammatory cytokines, to disrupt cell polarity and to cause tissue damage. The advantage of producing these virulence determinants for the bacterium remains poorly understood, but might involve improved iron acquisition or enhanced transmission. As a consequence of the loss of H. pylori from Western societies, the incidence of peptic ulcer disease and gastric cancer has continuously decreased in the affected populations. At the same time, allergies and chronic inflammatory disorders have become more common; epidemiological and experimental evidence suggests an inverse causal association between the loss of H. pylori and the rise in these immunological disorders. Helicobacter pylori resides exclusively in the hostile environment of the stomach in approximately 50% of the human population and is a strong risk factor for cancer. Here, Salama, Hartung and Müller describe how this bacterium establishes persistent colonization through the interplay of virulence determinants and the subversion and manipulation of the host's immune response. The bacterial pathogen Helicobacter pylori has co-evolved with humans and colonizes approximately 50% of the human population, but only causes overt gastric disease in a subset of infected hosts. In this Review, we discuss the pathogenesis of H. pylori and the mechanisms it uses to promote persistent colonization of the gastric mucosa, with a focus on recent insights into the role of the virulence factors vacuolating cytotoxin (VacA), cytotoxin-associated gene A (CagA) and CagL. We also describe the immunobiology of H. pylori infection and highlight how this bacterium manipulates the innate and adaptive immune systems of the host to promote its own persistence.

Parenting responsibilities can be particularly challenging for patients receiving mental health services, often resulting in a range of negative impacts on children. Incorporating a family-focused approach into the usual care of parents with mental illness has been recommended to promote patient recovery while supporting the well-being of children and the entire family unit. This study aimed to document the family-focused practices undertaken by psychiatrists working with parents who have a mental illness and to explore potential facilitators and barriers to these practices. A sequential explanatory mixed-method design was used, combining an online survey and individual interviews. Family-focused practices were reported by 27 psychiatrists through the French version of the Family-Focused Mental Health Practice Questionnaire. Follow-up qualitative individual interviews were conducted with 5 psychiatrists. Item-by-item analysis of the quantitative data was performed, followed by a thematic analysis of the qualitative data, integrating findings from both sources. Although psychiatrists acknowledge their patients' parenting role, most are reluctant to provide further support. Key barriers to family-focused practice include the predominantly individual-focused nature of psychiatric care, stigma, consent issues, and limited collaboration between adult and child services. Facilitators include psychiatrists' professional autonomy, personal experience, and confidence in conducting family meetings. Psychiatrists can play a pivotal role in identifying, acknowledging, and providing appropriate support to parents with mental illness and their families, including children. Developing comprehensive guidelines and targeted training is essential to equip psychiatrists with effective strategies for addressing parenting challenges in patients with complex mental health issues. Additionally, psychoeducational resources for children should be incorporated. Implementing these initiatives may lead to more compassionate, targeted care and improved outcomes for parents and their families.

Toll-like receptor TLR5 recognizes a conserved domain, termed D1, that is present in flagellins of several pathogenic bacteria but not in Helicobacter pylori . Highly virulent H. pylori strains possess a type IV secretion system (T4SS) for delivery of virulence factors into gastric epithelial cells. Here, we show that one of the H. pylori T4SS components, protein CagL, can act as a flagellin-independent TLR5 activator. CagL contains a D1-like motif that mediates adherence to TLR5 + epithelial cells, TLR5 activation, and downstream signaling in vitro. TLR5 expression is associated with H. pylori infection and gastric lesions in human biopsies. Using Tlr5 -knockout and wild-type mice, we show that TLR5 is important for efficient control of H. pylori infection. Our results indicate that CagL, by activating TLR5, may modulate immune responses to H. pylori . Toll-like receptor TLR5 recognizes a domain, D1, that is present in flagellins of several pathogenic bacteria but not in Helicobacter pylori . Here, the authors show that TLR5 can be activated independently of flagellin by a component of the H. pylori type IV secretion system that contains a D1-like motif.

VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirectly prevent H. pylori-specific T-cell responses and immune control of the infection. In particular, the ability of VacA-proficient H. pylori to skew T-cell responses towards regulatory T-cells and the effects of Tregs on H. pylori chronicity are highlighted. The by-stander effects of VacA-driven immunomodulation on extragastric diseases are discussed as well.

In patients with heart failure, reactivation of a fetal gene program, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a hallmark for maladaptive remodeling of the LV. The mechanisms that regulate this reactivation are incompletely understood. Histone acetylation and methylation affect the conformation of chromatin, which in turn governs the accessibility of DNA for transcription factors. Using human LV myocardium, we found that, despite nuclear export of histone deacetylase 4 (HDAC4), upregulation of ANP and BNP in failing hearts did not require increased histone acetylation in the promoter regions of these genes. In contrast, di- and trimethylation of lysine 9 of histone 3 (H3K9) and binding of heterochromatin protein 1 (HP1) in the promoter regions of these genes were substantially reduced. In isolated working murine hearts, an acute increase of cardiac preload induced HDAC4 nuclear export, H3K9 demethylation, HP1 dissociation from the promoter region, and activation of the ANP gene. These processes were reversed in hearts with myocyte-specific deletion of Hdac4. We conclude that HDAC4 plays a central role for rapid modifications of histone methylation in response to variations in cardiac load and may represent a target for pharmacological interventions to prevent maladaptive remodeling in patients with heart failure.

The genes encoding the histone acetyl-transferases (HATs) CREB binding protein (CREBBP) and EP300 are recurrently mutated in the activated B cell-like and germinal center (GC) B cell-like subtypes of diffuse large B cell lymphoma (DLBCL). Here, we introduced a patient mutation into a human DLBCL cell line using CRISPR and deleted Crebbp and Ep300 in the GC B cell compartment of mice. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c. and orthotopic xenograft models. Mice lacking Crebbp in GC B cells exhibited hyperproliferation of their GC compartment upon immunization, had reduced MHCII surface expression on GC cells, and developed accelerated MYC-driven lymphomas. Ep300 inactivation reproduced some, but not all, consequences of Crebbp inactivation. MHCII deficiency phenocopied the effects of CREBBP loss in spontaneous and serial transplantation models of MYC-driven lymphomagenesis, supporting the idea that the mutational inactivation of CREBBP promotes immune evasion. Indeed, the depletion of CD4⁺ T cells greatly facilitated the engraftment of lymphoma cells in serial transplantation models. In summary, we provide evidence that both HATs are bona fide tumor suppressors that control MHCII expression and promote tumor immune control; mutational inactivation of CREBBP, but not of EP300, has additional cell-intrinsic engraftment and growth-promoting effects.

Abstract The mid-twentieth century marks the proposed beginning of the Anthropocene, wherein human activities have irreversibly changed the environment, partly due to the accumulation of plastics from food packaging. Practice theories have contributed to understanding these activities, with some studies shifting the focus from isolated practices to the configurations they form to explain such significant social phenomena. This article uses the rise of packaging foods as an example to investigate how practices emerge as part of a configuration. Based on archival issues of the magazine Neue Verpackung (1948–1958)—pioneering magazine of the German packaging industry—I elaborate how the paradigm of rationalization orchestrated formerly separate practices toward converging and aligning, forming a configuration of densely interconnected and interdependent practices that eventually established food packaging as an essential component of transportation and retail sale. Insights into the emergence of a past configuration that remains relevant today can help transform current configurations, leading to the reduction of packaging waste.

Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens. The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter -host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori -specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3 + ) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.

Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma.

Since 2008, the open-access internet portal \"Embryotox\" has provided evidence-based information on drug safety during pregnancy and breastfeeding. The German website, designed for health care professionals, comprises fact sheets about 400 drugs and is maintained by the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy at the Charité - Universitätsmedizin Berlin. In 2024, it was accessed more than 5 million times. This study aimed to evaluate who is using the website, how it is being used, and to what extent it meets users' needs. Data were collected between 2022 and 2023 through a sequential mixed methods design incorporating explanatory and exploratory elements. Online questionnaire 1 contained questions on user characteristics, clinical specifics of use, comprehensibility, and changes in risk assessment or drug therapy following fact sheet use. Qualitative data were generated through semistructured phone interviews, with interviewees sampled from the main user groups identified in questionnaire 1 (patients, physicians, pharmacists, and midwives). Kuckartz's content analysis was used to analyze data on users' trust and the functions of website use for different stakeholder groups. Online questionnaire 2 collected data from the main user groups on their decision-making based on Embryotox fact sheets. This questionnaire was developed based on the findings from semistructured interviews on the functions of website use. Answers in both questionnaires included multiple-choice options or ratings on a Likert scale from 0 (not at all) to 10 (fully); data were analyzed using descriptive statistics. Questionnaire 1 was completed by 14,562 users, including 10,860 patients, 1676 physicians, 550 pharmacists, and 364 midwives. Of the physicians, 27.2% (456/1676) were obstetricians and gynecologists, and 22.7% (381/1676) were general practitioners. For physicians, the mean of comprehensibility ratings was 9.39 (pharmacists 9.25; midwives 9.14), and for patients 8.80. Following fact sheet use, 66.6% (9694/14,562) of all users changed their risk perception, and 22.3% (2252/10,083) of users in a specific treatment setting considered changing drug treatment. Qualitative content analysis revealed that users highly trusted the information in the fact sheets for a number of reasons, including recommendations from other users, the scientific basis of the website, and the authority of the Embryotox Center as a university-based specialist department for drug safety in pregnancy and lactation. Functions of fact sheet use differed depending on the stakeholder group. A total of 793 users, mostly physicians and patients, fully completed questionnaire 2, specifying typical clinical situations and benefits of fact sheet use for shared decision-making. Benefits included facilitating the decision-making process and increasing confidence in it. The information provided in the Embryotox fact sheets was generally perceived as both comprehensible and trustworthy, supporting and facilitating the decision-making process. Embryotox is used successfully by health care providers and patients in routine health care settings, helping to improve drug safety for pregnant and breastfeeding women.