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Salmonella enterica serovar Typhimurium (S. Tm) employs type III secretion system 1 and 2 (TTSS-1 and TTSS-2) to infect host tissues. In orogastric infections, both TTSSs manipulate host responses, increasing mucosal pathogen loads and eliciting inflammation. However, we still do not fully understand how virulence and inflammatory enteropathy are interconnected. Here, we investigate whether TTSS-2-dependent virulence contributes to epithelial barrier disruption and delineate its role in shaping inflammatory response profiles in the mouse gut. Using wild-type and TTSS-2 mutant S. Tm strains in antibiotic-pretreated mouse models, we demonstrate that intestinal epithelial destruction is promoted by TTSS-2 virulence. This effect is observed in both wild-type and immune-deficient C57BL/6J mice. Transcriptomic profiling together with immunofluorescence microscopy analysis reveals that wild-type S. Tm triggers a distinct, yet amplified immune response compared to a TTSS-2 mutant which is characterized by enhanced phagocyte recruitment and a unique transcriptional signature. These findings underscore the role of TTSS-2-mediated virulence in S. Tm gut infection, shaping distinct inflammatory microenvironments with potential implications for host-pathogen interaction studies.

Abstract Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time and pose significant public-health problems. Multidrug-resistant S. enterica serovar Typhi (S. Typhi) and nontyphoidal Salmonella (NTS) are on the increase and are often associated with HIV infection. Chronically infected hosts are often asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. Salmonella utilizes multiple ways to evade and modulate host innate and adaptive immune responses in order to persist in the presence of a robust immune response. Survival in macrophages and modulation of immune cells migration allow Salmonella to evade various immune responses. The ability of Salmonella to persist depends on a balance between immune responses that lead to the clearance of the pathogen and avoidance of damage to host tissues. This review discusses current knowledge about mechanisms Salmonella uses to persist systemically for long period of time in its host.

Necrosis has long been considered as a passive event resulting from a cell extrinsic stimulus, such as pathogen infection. Recent advances have refined this view and it is now well established that necrosis is tightly regulated at the cell level. Regulated necrosis can occur in the context of host–pathogen interactions, and can either participate in the control of infection or favor it. Here, we review the two main pathways implicated so far in bacteria-associated regulated necrosis: caspase 1-dependent pyroptosis and RIPK1/RIPK3-dependent necroptosis. We present how these pathways are modulated in the context of infection by a series of model bacterial pathogens.

National-based prospective surveillance of all-age patients with acute diarrhea was conducted in China between 2009‒2018. Here we report the etiological, epidemiological, and clinical features of the 152,792 eligible patients enrolled in this analysis. Rotavirus A and norovirus are the two leading viral pathogens detected in the patients, followed by adenovirus and astrovirus. Diarrheagenic Escherichia coli and nontyphoidal Salmonella are the two leading bacterial pathogens, followed by Shigella and Vibrio parahaemolyticus . Patients aged <5 years had higher overall positive rate of viral pathogens, while bacterial pathogens were more common in patients aged 18‒45 years. A joinpoint analysis revealed the age-specific positivity rate and how this varied for individual pathogens. Our findings fill crucial gaps of how the distributions of enteropathogens change across China in patients with diarrhea. This allows enhanced identification of the predominant diarrheal pathogen candidates for diagnosis in clinical practice and more targeted application of prevention and control measures. Diarrhoea is a major cause of morbidity and mortality in China. Here, the authors present results from a large sentinel surveillance scheme from 217 hospitals in all 31 provinces in mainland China, including ~150,000 patients with acute diarrhoea and covering years 2009-2018.

Microbial infections are controlled by host inflammatory responses that are initiated by innate immune receptors after recognition of conserved microbial products. As inflammation can also lead to disease, tissues that are exposed to microbial products such as the intestinal epithelium are subject to stringent regulatory mechanisms to prevent indiscriminate signalling through innate immune receptors. The enteric pathogen Salmonella enterica subsp. enterica serovar Typhimurium, which requires intestinal inflammation to sustain its replication in the intestinal tract, uses effector proteins of its type III secretion systems to trigger an inflammatory response without the engagement of innate immune receptors. Furthermore, S. Typhimurium uses a different set of effectors to restrict the inflammatory response to preserve host homeostasis. The S. Typhimurium–host interface is a remarkable example of the unique balance that emerges from the co-evolution of a pathogen and its host.In this Review, Galán discusses the mechanisms by which Salmonella enterica subsp. enterica serovar Typhimurium triggers inflammation in the intestinal tract through the activities of effector proteins as well as the mechanisms that are aimed at recovering host homeostasis after the inflammatory response.

We analyzed the prevalence of resistance to extended-spectrum cephalosporins (ESCs) among clinical strains of Salmonella enterica collected by the Laboratory of Clinical Microbiology in the University Clinical Hospital Lozano Blesa in the region of Aragón (Spain), for which very few epidemiological information exists. A total of 2,092 strains of S. enterica were identified in stool samples from patients with gastroenteritis. Five isolates showed an extended-spectrum beta-lactamase (ESBL) phenotype: four isolates of S. enterica serotype Virchow harbored the ESBL-encoding bla CTX-M-9 gene and an isolate of serotype Enteritidis carried a bla CTX-M-1 gene, which, to the best of our knowledge, is described here for the first time in this serotype of S. enterica . The five ESC-resistant isolates were also resistant to spectinomycin, streptomycin, kanamycin, sulfonamides, tetracycline, and trimethoprim as well as to nalidixic acid. The ESBL isolate of serotype Enteritidis, however, remained susceptible to kanamycin and nalidixic acid. A class 1 integron of 1.5 kb was detected for the four serotype Virchow isolates with the gene cassette dfrA16 – aadA2 . The bla CTX-M-9 gene was carried by an ∼300-kb IncHI2 conjugative plasmid in the case of the S. enterica serotype Virchow isolates. The bla CTX-M-1 gene was carried by an ∼100-kb IncI1-N conjugative plasmid for the serotype Enteritidis ESC-resistant isolate. All the four ESC-resistant strains of S. enterica serotype Virchow clustered together in a Xba I pulsed-field gel electrophoresis, which also revealed a strong similarity between them and some pulsotypes of S. enterica serotype Virchow from France.

Galectin 8, a cytosolic lectin, is shown to function as a danger receptor that detects damaged vesicles and protects cells from bacterial infection by inducing autophagy. Sensing dangerous bacteria The galectins are carbohydrate-binding proteins that have a range of functions inside and outside the cell. They accumulate in the cytosol, which is normally devoid of complex carbohydrates, making them prime candidates for danger and/or pattern-recognition receptors. Here galectin-8 is identified as a danger receptor that protects cells against bacterial infection. It binds to host glycans exposed on bacteria-containing vesicles and recruits the ubiquitin-binding autophagy receptor NDP52 to clear the cytosol of invading bacteria. Autophagy defends the mammalian cytosol against bacterial infection 1 , 2 , 3 . Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating 4 , 5 , 6 , 7 , 8 , 9 . Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella -containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella -containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella , we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.

Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-γ release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-γ, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding.

Key Points Salmonella spp. deliver effector proteins into host cells to promote replication and survival. Effector proteins that are translocated by the Salmonella pathogenicity island 1 (SPI-1) type III secretion system (T3SS) are important for bacterial invasion into non-phagocytic cells. Effector proteins that are delivered by the SPI-2 T3SS modify the Salmonella -containing vacuole, associated endosomal membranes and associated proteins, all of which promote intracellular replication. Induction of inflammation enhances extracellular growth of salmonellae and enables them to outcompete the gut microbiota. Interplay between the host response pathways of autophagy and pyroptosis is involved in the detection of intracellular Salmonella spp. Distinct functions for many of the Salmonella effector proteins are not fully understood, and it is likely that many of their functions will only be elucidated when their activities are studied in the context of other effectors and are considered in a spatiotemporal context within the host. In this Review, Miller and colleagues discuss the arsenal of effector proteins that salmonellae use to manipulate their animal hosts, in addition to the host response to these infections. The authors also discuss the challenges ahead for unravelling the mechanistic details of effector function. Salmonellae invasion and intracellular replication within host cells result in a range of diseases, including gastroenteritis, bacteraemia, enteric fever and focal infections. In recent years, considerable progress has been made in our understanding of the molecular mechanisms that salmonellae use to alter host cell physiology; through the delivery of effector proteins with specific activities and through the modulation of defence and stress response pathways. In this Review, we summarize our current knowledge of the complex interplay between bacterial and host factors that leads to inflammation, disease and, in most cases, control of the infection by its animal hosts, with a particular focus on Salmonella enterica subsp. enterica serovar Typhimurium. We also highlight gaps in our knowledge of the contributions of salmonellae and the host to disease pathogenesis, and we suggest future avenues for further study.

Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.