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Frontiers in Immunology 2019In primary infection with , it has been reported-without consideration of 's functions-that humoral immunity plays no role in the clearance of bacteria. In fact,... (Review)
Review
In primary infection with , it has been reported-without consideration of 's functions-that humoral immunity plays no role in the clearance of bacteria. In fact, targets and suppresses several aspects of humoral immunity, including B cell lymphopoiesis, B cell activation, and IgG production. In particular, the suppression of IgG-secreting plasma cell maintenance allows the persistence of in tissues. Therefore, the critical role(s) of humoral immunity in the response to infection, especially at the late phase, should be re-investigated. The suppression of IgG plasma cell memory strongly hinders vaccine development against non-typhoidal (NTS) because can also reduce humoral immune memory against other bacteria and viruses, obtained from previous vaccination or infection. We propose a new vaccine against that would not impair humoral immunity, and which could also be used as a treatment for antibody-dependent autoimmune diseases to deplete pathogenic long-lived plasma cells, by utilizing the 's own suppression mechanism of humoral immunity.
Topics: Animals; B-Lymphocytes; Host-Pathogen Interactions; Humans; Immunity, Humoral; Plasma Cells; Salmonella; Salmonella Infections
PubMed: 32038650
DOI: 10.3389/fimmu.2019.03155 -
Applied and Environmental Microbiology Jul 2019spp. are among the most important foodborne pathogens and the third leading cause of human death among diarrheal diseases worldwide. Animals are the primary source of... (Meta-Analysis)
Meta-Analysis
spp. are among the most important foodborne pathogens and the third leading cause of human death among diarrheal diseases worldwide. Animals are the primary source of this pathogen, and animal-based foods are the main transmission route to humans. Thus, understanding the global epidemiology of serovars is key to controlling and monitoring this bacterium. In this context, this study aimed to evaluate the prevalence and diversity of serovars in animal-based foods (beef, pork, poultry, and seafood) throughout the five continents (Africa, the Americas [North and Latin America], Asia, Europe, and Oceania). The meta-analysis consisted of a chemometric assessment (hierarchical cluster analysis and principal component analysis) to identify the main epidemiological findings, including the prevalence and diversity of the serovars in each matrix. Regarding the serovar distribution, Typhimurium presented a cosmopolitan distribution, reported in all four assessed matrices and continents; poultry continues to play a central role in the dissemination of the Enteritidis serovar to humans, and Anatum and Weltevreden were the most frequently found in beef and seafood, respectively. Additionally, we recommended careful monitoring of certain serovars, such as Derby, Agona, Infantis, and Kentucky. Finally, given the scientific data regarding the most frequently reported serovars and which matrices constitute the main vehicles for the transmission of this pathogen, control programs may be improved, and specific interventions may be implemented in an attempt to reduce the risk of this pathogen reaching humans. Salmonellosis is caused by spp. and is the third leading cause of death among food-transmitted diseases. This pathogen is commonly disseminated in domestic and wild animals, and the infection's symptoms are characterized by acute fever, nausea, abdominal pain, and diarrhea. The animals are the primary source of salmonellae, and animal-based foods are the main transmission route to humans. Therefore, data collected from these sources could contribute to future global interventions for effective control and surveillance of along the food chain. In light of this, the importance of our research is in identifying the prevalence of serovars in four animal-based food matrices (pork, poultry, beef, and seafood) and to evaluate the importance that each matrix has as the primary source of this pathogen to humans.
Topics: Animals; Food Microbiology; Prevalence; Salmonella Infections, Animal; Salmonella enterica; Serogroup
PubMed: 31053586
DOI: 10.1128/AEM.00591-19 -
Nature Reviews. Microbiology Nov 2021Microbial infections are controlled by host inflammatory responses that are initiated by innate immune receptors after recognition of conserved microbial products. As... (Review)
Review
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.
Topics: Animals; Host-Pathogen Interactions; Humans; Inflammation; Salmonella Infections; Salmonella typhimurium
PubMed: 34012042
DOI: 10.1038/s41579-021-00561-4 -
Nature Jun 2021Ubiquitylation is a widespread post-translational protein modification in eukaryotes and marks bacteria that invade the cytosol as cargo for antibacterial autophagy. The...
Ubiquitylation is a widespread post-translational protein modification in eukaryotes and marks bacteria that invade the cytosol as cargo for antibacterial autophagy. The identity of the ubiquitylated substrate on bacteria is unknown. Here we show that the ubiquitin coat on Salmonella that invade the cytosol is formed through the ubiquitylation of a non-proteinaceous substrate, the lipid A moiety of bacterial lipopolysaccharide (LPS), by the E3 ubiquitin ligase ring finger protein 213 (RNF213). RNF213 is a risk factor for moyamoya disease, which is a progressive stenosis of the supraclinoid internal carotid artery that causes stroke (especially in children). RNF213 restricts the proliferation of cytosolic Salmonella and is essential for the generation of the bacterial ubiquitin coat, both directly (through the ubiquitylation of LPS) and indirectly (through the recruitment of LUBAC, which is a downstream E3 ligase that adds M1-linked ubiquitin chains onto pre-existing ubiquitin coats). In cells that lack RNF213, bacteria do not attract ubiquitin-dependent autophagy receptors or induce antibacterial autophagy. The ubiquitylation of LPS on Salmonella that invade the cytosol requires the dynein-like core of RNF213, but not its RING domain. Instead, ubiquitylation of LPS relies on an RZ finger in the E3 shell. We conclude that ubiquitylation extends beyond protein substrates and that ubiquitylation of LPS triggers cell-autonomous immunity, and we postulate that non-proteinaceous substances other than LPS may also become ubiquitylated.
Topics: Adenosine Triphosphatases; Animals; Autophagy; Cell Line; HeLa Cells; Humans; Lipopolysaccharides; Mice; RING Finger Domains; Salmonella Infections; Salmonella typhimurium; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34012115
DOI: 10.1038/s41586-021-03566-4 -
Nature Microbiology Oct 2023Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response...
Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen Salmonella, through delivery of antimicrobial itaconate. Here we show that the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) orchestrates this defence response by scaffolding a complex between RAB32 and aconitate decarboxylase 1, which synthesizes itaconate from mitochondrial precursors. Itaconate delivery to Salmonella-containing vacuoles was impaired and Salmonella replication increased in LRRK2-deficient cells. Loss of LRRK2 also restored virulence of a Salmonella mutant defective in neutralizing this RAB32-dependent host defence pathway in mice. Cryo-electron tomography revealed tether formation between Salmonella-containing vacuoles and host mitochondria upon Salmonella infection, which was significantly impaired in LRRK2-deficient cells. This positions LRRK2 centrally within a host defence mechanism, which may have favoured selection of a common familial Parkinson's disease mutant allele in the human population.
Topics: Humans; Mice; Animals; Parkinson Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Salmonella Infections; Salmonella
PubMed: 37640963
DOI: 10.1038/s41564-023-01459-y -
The Lancet. Infectious Diseases Dec 2019Non-typhoidal salmonella invasive disease is a major cause of global morbidity and mortality. Malnourished children, those with recent malaria or sickle-cell anaemia,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Non-typhoidal salmonella invasive disease is a major cause of global morbidity and mortality. Malnourished children, those with recent malaria or sickle-cell anaemia, and adults with HIV infection are at particularly high risk of disease. We sought to estimate the burden of disease attributable to non-typhoidal salmonella invasive disease for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017.
METHODS
We did a systematic review of scientific databases and grey literature, and estimated non-typhoidal salmonella invasive disease incidence and mortality for the years 1990 to 2017, by age, sex, and geographical location using DisMod-MR, a Bayesian meta-regression tool. We estimated case fatality by age, HIV status, and sociodemographic development. We also calculated the HIV-attributable fraction and estimated health gap metrics, including disability-adjusted life-years (DALYs).
FINDINGS
We estimated that 535 000 (95% uncertainty interval 409 000-705 000) cases of non-typhoidal salmonella invasive disease occurred in 2017, with the highest incidence in sub-Saharan Africa (34·5 [26·6-45·0] cases per 100 000 person-years) and in children younger than 5 years (34·3 [23·2-54·7] cases per 100 000 person-years). 77 500 (46 400-123 000) deaths were estimated in 2017, of which 18 400 (12 000-27 700) were attributable to HIV. The remaining 59 100 (33 300-98 100) deaths not attributable to HIV accounted for 4·26 million (2·38-7·38) DALYs in 2017. Mean all-age case fatality was 14·5% (9·2-21·1), with higher estimates among children younger than 5 years (13·5% [8·4-19·8]) and elderly people (51·2% [30·2-72·9] among those aged ≥70 years), people with HIV infection (41·8% [30·0-54·0]), and in areas of low sociodemographic development (eg, 15·8% [10·0-22·9] in sub-Saharan Africa).
INTERPRETATION
We present the first global estimates of non-typhoidal salmonella invasive disease that have been produced as part of GBD 2017. Given the high disease burden, particularly in children, elderly people, and people with HIV infection, investigating the sources and transmission pathways of non-typhoidal salmonella invasive disease is crucial to implement effective preventive and control measures.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Female; Geography, Medical; Global Burden of Disease; Humans; Incidence; Male; Prevalence; Risk Factors; Salmonella; Salmonella Infections; Socioeconomic Factors
PubMed: 31562022
DOI: 10.1016/S1473-3099(19)30418-9 -
Science (New York, N.Y.) Jul 2020The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as Here,...
The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on infection and facilitates the delivery of itaconate to the -containing vacuole. Mice defective in IRG1 rescued the virulence defect of a serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.
Topics: Animals; Cell Line; Host-Pathogen Interactions; Humans; Hydro-Lyases; Mice; Salmonella Infections; Salmonella enterica; Salmonella typhimurium; Succinates; Virulence; rab GTP-Binding Proteins
PubMed: 32703879
DOI: 10.1126/science.aaz1333 -
MSystems Feb 2023The spread of multidrug-resistant zoonotic pathogens, such as Salmonella, within livestock is of concern for food safety. The spread of Salmonella on the farm is...
The spread of multidrug-resistant zoonotic pathogens, such as Salmonella, within livestock is of concern for food safety. The spread of Salmonella on the farm is escalated by superspreaders, which shed the pathogen at high numbers with their feces. However, there are currently no biomarkers to identify potential superspreaders. Kempf and coworkers determined that a potent early inflammatory response to Salmonella infection and changes in the microbiota composition are associated with the superspreader phenotype in pigs (F. Kempf, G. Cordoni, A.M. Chaussé, R. Drumo, et al., , in press, https://doi.org/10.1128/msystems.00852-22). Since these biomarkers only develop during Salmonella infection, additional work is needed to predict animals that have the potential to become superspreaders.
Topics: Animals; Swine; Salmonella Infections; Salmonella; Microbiota; Feces
PubMed: 36815796
DOI: 10.1128/msystems.01199-22 -
Microbes and Infection 2022Salmonella infection is known to cause a 50% reduction in the lifespan of Caenorhabditis elegans. But the mechanism behind this reduction is not reported. The current...
Salmonella infection is known to cause a 50% reduction in the lifespan of Caenorhabditis elegans. But the mechanism behind this reduction is not reported. The current study deals with the Salmonella infection mediated egg retention in the worm leading to various developmental and morphological defects and disruption of temporal regulation of developmental timing in C. elegans. Worm's delayed egg-laying response to Salmonella infection causes several defects in eggs, including over-folding of developing embryo, increased egg size, and losing the osmotic stress resistance. Also, the infected eggs show delayed and reduced hatching. With significantly downregulated lin-28a, col-72 and col-87, we observed a disrupted L2, but L3, L4, and adult developmental stages reach faster during infection. The precocious development of L3, L4, and the adult stage is further indicated by upregulation of stage-specific genes viz. rnh-1.3, col-158 and col-176 (L3), col-17, col-38 and col-49 (L4), and col-19, col-7 (adult). The significant upregulation of the flp-1 gene indicates reduced egglaying, and the flp-1(ok2811) null mutant further supported the Salmonella infectionmediated phenotype. Similar phenotypes are primarily evident in multiple generations up to F5 and F6. Salmonella infection causes a range of developmental anomalies and shortening of worm life span through various regulatory pathways.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Neuropeptides; Phenotype; Salmonella Infections; Salmonella typhimurium
PubMed: 34756991
DOI: 10.1016/j.micinf.2021.104894 -
PLoS Pathogens Jul 2021Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less...
Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion. Experimental follow-up redefined ARHGEF26's role in Salmonella epithelial cell infection. Specifically, we identified complex serovar-by-host interactions whereby ARHGEF26 stimulation of S. Typhi and S. Typhimurium invasion into host cells varied in magnitude and effector-dependence based on host cell type. While ARHGEF26 regulated SopB- and SopE-mediated S. Typhi (but not S. Typhimurium) infection of HeLa cells, the largest effect of ARHGEF26 was observed with S. Typhimurium in polarized MDCK cells through a SopB- and SopE2-independent mechanism. In both cell types, knockdown of the ARHGEF26-associated protein DLG1 resulted in a similar phenotype and serovar specificity. Importantly, we show that ARHGEF26 plays a critical role in S. Typhimurium pathogenesis by contributing to bacterial burden in the enteric fever murine model, as well as inflammation in the colitis infection model. In the enteric fever model, SopB and SopE2 are required for the effects of Arhgef26 deletion on bacterial burden, and the impact of sopB and sopE2 deletion in turn required ARHGEF26. In contrast, SopB and SopE2 were not required for the impacts of Arhgef26 deletion on colitis. A role for ARHGEF26 on inflammation was also seen in cells, as knockdown reduced IL-8 production in HeLa cells. Together, these data reveal pleiotropic roles for ARHGEF26 during infection and highlight that many of the interactions that occur during infection that are thought to be well understood likely have underappreciated complexity.
Topics: Animals; Genetic Predisposition to Disease; Guanine Nucleotide Exchange Factors; HeLa Cells; Humans; Inflammation; Mice; Salmonella Infections; Salmonella typhi
PubMed: 34242364
DOI: 10.1371/journal.ppat.1009713