Comparative transcriptional profiling of the early host response to infection by typhoidal and non-typhoidal Salmonella serovars in human intestinal organoids
Autor: | Jason R. Spence, Basel H. Abuaita, Vincent B. Young, David R. Hill, Brooke Bons, Christiane E. Wobus, Courtney Fields, Mary X. D. O'Riordan, Ryan P. Berger, Veda K. Yadagiri, Sha Huang, Anna-Lisa E. Lawrence |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Bacterial Diseases
Serotype Salmonella Salmonellosis medicine.medical_treatment Gene Expression Mitochondrion Pathology and Laboratory Medicine medicine.disease_cause Biochemistry Epithelium Medical Conditions Animal Cells Gene expression Medicine and Health Sciences Cell Cycle and Cell Division Biology (General) Energy-Producing Organelles Salmonella enterica Cell cycle Bacterial Pathogens Mitochondria Intestines Organoids Infectious Diseases Cytokine Medical Microbiology Cell Processes Salmonella Infections Pathogens Anatomy Cellular Structures and Organelles Cellular Types Research Article QH301-705.5 Immunology Bioenergetics Biology Serogroup Microbiology Typhoid fever Immune system Enterobacteriaceae Downregulation and upregulation Virology Genetics medicine Humans Microbial Pathogens Molecular Biology Bacteria Gene Expression Profiling Organisms Biology and Life Sciences Epithelial Cells Cell Biology RC581-607 medicine.disease biology.organism_classification Embryonic stem cell Gastrointestinal Tract Biological Tissue Parasitology Immunologic diseases. Allergy Transcriptome Digestive System |
Zdroj: | PLoS Pathogens, Vol 17, Iss 10, p e1009987 (2021) PLoS Pathogens |
ISSN: | 1553-7374 1553-7366 |
Popis: | Salmonella enterica represents over 2500 serovars associated with a wide-ranging spectrum of disease; from self-limiting gastroenteritis to invasive infections caused by non-typhoidal serovars (NTS) and typhoidal serovars, respectively. Host factors strongly influence infection outcome as malnourished or immunocompromised individuals can develop invasive infections from NTS, however, comparative analyses of serovar-specific host responses have been constrained by reliance on limited model systems. Here we used human intestinal organoids (HIOs), a three-dimensional “gut-like” in vitro system derived from human embryonic stem cells, to elucidate similarities and differences in host responses to NTS and typhoidal serovars. HIOs discriminated between the two most prevalent NTS, Salmonella enterica serovar Typhimurium (STM) and Salmonella enterica serovar Enteritidis (SE), and typhoidal serovar Salmonella enterica serovar Typhi (ST) in epithelial cell invasion, replication and transcriptional responses. Pro-inflammatory signaling and cytokine output was reduced in ST-infected HIOs compared to NTS infections, consistent with early stages of NTS and typhoidal diseases. While we predicted that ST would induce a distinct transcriptional profile from the NTS strains, more nuanced expression profiles emerged. Notably, pathways involved in cell cycle, metabolism and mitochondrial functions were downregulated in STM-infected HIOs and upregulated in SE-infected HIOs. These results correlated with suppression of cellular proliferation and induction of host cell death in STM-infected HIOs and in contrast, elevated levels of reactive oxygen species production in SE-infected HIOs. Collectively, these results suggest that the HIO model is well suited to reveal host transcriptional programming specific to infection by individual Salmonella serovars, and that individual NTS may provoke unique host epithelial responses during intestinal stages of infection. Author summary Salmonella enterica is the major causative agent of bacterial infections associated with contaminated food and water. Salmonella enterica consists of over 2500 serovars of which Typhimurium (STM), Enteritidis (SE) and Typhi (ST) are the three major serovars with medical relevance to humans. These serovars elicit distinctive immune responses and cause different diseases in humans, including self-limiting diarrhea, gastroenteritis and typhoid fever. Differences in the human host response to these serovars are likely to be a major contributing factor to distinct disease outcomes but are not well characterized, possibly due to the limitations of human-derived physiological infection models. Distinct from immortalized epithelial cell culture models, human intestinal organoids (HIOs) are three-dimensional structures derived from embryonic stem cells that differentiate into intestinal mesenchymal and epithelial cells, mirroring key organizational aspects of the intestine. In this study, we used HIOs to monitor transcriptional changes during early stages of STM, SE and ST infection. Our comparative analysis showed that HIO inflammatory responses are the dominant response in all infections, but ST infection induces the weakest upregulation of inflammatory mediators relative to the other serovars. In addition, we identified several cellular processes, including cell cycle and mitochondrial functions, that were inversely regulated between STM and SE infection despite these serovars causing similar localized intestinal infection in humans. Our findings reinforce HIOs as an emerging model system to study Salmonella serovar infection and define global host transcriptional response profiles as a foundation for understanding human infection outcomes. |
Databáze: | OpenAIRE |
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