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Crosstalk between leukocytes triggers differential immune responses against Salmonella enterica serovars Typhi and Paratyphi.

ABSTRACT: Enteric fevers, caused by the Salmonella enterica serovars Typhi (ST), Paratyphi A (PA) and Paratyphi B (PB), are life-threatening illnesses exhibiting very similar clinical symptoms but with distinct epidemiologies, geographical distributions and susceptibilities to antimicrobial treatment. Nevertheless, the mechanisms by which the host recognizes pathogens with high levels of homology, such as these bacterial serovars, remain poorly understood. Using a three-dimensional organotypic model of the human intestinal mucosa and PA, PB, and ST, we observed significant differences in the secretion patterns of pro-inflammatory cytokines and chemokines elicited by these serovars. These cytokines/chemokines were likely to be co-regulated and influenced the function of epithelial cells, such as the production of IL-8. We also found differing levels of polymorphonuclear leukocyte (PMN) migration among various infection conditions that either included or excluded lymphocytes and macrophages (Mϕ), strongly suggesting feedback mechanisms among these cells. Blocking experiments showed that IL-1β, IL-6, IL-8, TNF-α and CCL3 cytokines were involved in the differential regulation of migration patterns. We conclude that the crosstalk among the lymphocytes, Mϕ, PMN and epithelial cells is cytokine/chemokine-dependent and bacterial-serotype specific, and plays a pivotal role in orchestrating the functional efficiency of the innate cells and migratory characteristics of the leukocytes.

SUBMITTER: Salerno-Goncalves R

PROVIDER: S-EPMC6709971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Of the > 2000 serovars of Salmonella enterica subspecies I, most cause self-limiting gastrointestinal disease in a wide range of mammalian hosts. However, S. enterica serovars Typhi and Paratyphi A are restricted to the human host and cause the similar systemic diseases typhoid and paratyphoid fever. Genome sequence similarity between Paratyphi A and Typhi has been attributed to convergent evolution via relatively recent recombination of a quarter of their genomes. The accumulation of pseudogenes is a key feature of these and other host-adapted pathogens, and overlapping pseudogene complements are evident in Paratyphi A and Typhi. RESULTS:We report the 4.5 Mbp genome of a clinical isolate of Paratyphi A, strain AKU_12601, completely sequenced using capillary techniques and subsequently checked using Illumina/Solexa resequencing. Comparison with the published genome of Paratyphi A ATCC9150 revealed the two are collinear and highly similar, with 188 single nucleotide polymorphisms and 39 insertions/deletions. A comparative analysis of pseudogene complements of these and two finished Typhi genomes (CT18, Ty2) identified several pseudogenes that had been overlooked in prior genome annotations of one or both serovars, and identified 66 pseudogenes shared between serovars. By determining whether each shared and serovar-specific pseudogene had been recombined between Paratyphi A and Typhi, we found evidence that most pseudogenes have accumulated after the recombination between serovars. We also divided pseudogenes into relative-time groups: ancestral pseudogenes inherited from a common ancestor, pseudogenes recombined between serovars which likely arose between initial divergence and later recombination, serovar-specific pseudogenes arising after recombination but prior to the last evolutionary bottlenecks in each population, and more recent strain-specific pseudogenes. CONCLUSION:Recombination and pseudogene-formation have been important mechanisms of genetic convergence between Paratyphi A and Typhi, with most pseudogenes arising independently after extensive recombination between the serovars. The recombination events, along with divergence of and within each serovar, provide a relative time scale for pseudogene-forming mutations, affording rare insights into the progression of functional gene loss associated with host adaptation in Salmonella.

Project description:BackgroundEnteric fever, a systemic infection caused by Salmonella enterica serovars Typhi and Paratyphi A, remains a major cause of morbidity and mortality in low-income and middle-income countries. Enteric fever is preventable through the provision of clean water and adequate sanitation and can be successfully treated with antibiotics. However, high levels of antimicrobial resistance (AMR) compromise the effectiveness of treatment. We provide estimates of the prevalence of AMR S Typhi and S Paratyphi A in 75 endemic countries, including 30 locations without data.MethodsWe used a Bayesian spatiotemporal modelling framework to estimate the percentage of multidrug resistance (MDR), fluoroquinolone non-susceptibility (FQNS), and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections for 1403 administrative level one districts in 75 endemic countries from 1990 to 2019. We incorporated data from a comprehensive systematic review, public health surveillance networks, and large multicountry studies on enteric fever. Estimates of the prevalence of AMR and the number of AMR infections (based on enteric fever incidence estimates by the Global Burden of Diseases study) were produced at the country, super-region, and total endemic area level for each year of the study.FindingsWe collated data from 601 sources, comprising 184 225 isolates of S Typhi and S Paratyphi A, covering 45 countries over 30 years. We identified a decline of MDR S Typhi in south Asia and southeast Asia, whereas in sub-Saharan Africa, the overall prevalence increased from 6·0% (95% uncertainty interval 4·3-8·0) in 1990 to 72·7% (67·7-77·3) in 2019. Starting from low levels in 1990, the prevalence of FQNS S Typhi increased rapidly, reaching 95·2% (91·4-97·7) in south Asia in 2019. This corresponded to 2·5 million (1·5-3·8) MDR S Typhi infections and 7·4 million (4·7-11·3) FQNS S Typhi infections in endemic countries in 2019. The prevalence of third-generation cephalosporin-resistant S Typhi remained low across the whole endemic area over the study period, except for Pakistan where prevalence of third-generation cephalosporin resistance in S Typhi reached 61·0% (58·0-63·8) in 2019. For S Paratyphi A, we estimated low prevalence of MDR and third-generation cephalosporin resistance in all endemic countries, but a drastic increase of FQNS, which reached 95·0% (93·7-96·1; 3·5 million [2·2-5·6] infections) in 2019.InterpretationThis study provides a comprehensive and detailed analysis of the prevalence of MDR, FQNS, and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections in endemic countries, spanning the last 30 years. Our analysis highlights the increasing levels of AMR in this preventable infection and serves as a resource to guide urgently needed public health interventions, such as improvements in water, sanitation, and hygiene and typhoid fever vaccination campaigns.FundingFleming Fund, UK Department of Health and Social Care; Wellcome Trust; and Bill and Melinda Gates Foundation.

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Crosstalk between leukocytes triggers differential immune responses against Salmonella enterica serovars Typhi and Paratyphi.

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