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Nature Communications Aug 2023Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining...
Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.
Topics: Humans; Nuclear Receptor Subfamily 1, Group F, Member 3; Virulence; Th17 Cells; Inflammation; Colon
PubMed: 37591835
DOI: 10.1038/s41467-023-40622-1 -
Proceedings of the National Academy of... Nov 2023The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species, this can...
The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species, this can affect the health of humans as well as livestock. Here, we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of , a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography, and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of is yet to be fully realized.
Topics: Animals; Humans; Swine; Streptococcal Infections; Farms; Swine Diseases; Virulence; Streptococcus suis; Livestock
PubMed: 37963246
DOI: 10.1073/pnas.2307773120 -
Molecular Plant Pathology Oct 2023Gene silencing is a conserved mechanism in eukaryotes that dynamically regulates gene expression. In plants, gene silencing is critical for development and for... (Review)
Review
Gene silencing is a conserved mechanism in eukaryotes that dynamically regulates gene expression. In plants, gene silencing is critical for development and for maintenance of genome integrity. Additionally, it is a critical component of antiviral defence in plants, nematodes, insects, and fungi. To overcome gene silencing, viruses encode effectors that suppress gene silencing. A growing body of evidence shows that gene silencing and suppression of silencing are also used by plants during their interaction with nonviral pathogens such as fungi, oomycetes, and bacteria. Plant-pathogen interactions involve trans-kingdom movement of small RNAs into the pathogens to alter the function of genes required for their development and virulence. In turn, plant-associated pathogenic and nonpathogenic microbes also produce small RNAs that move trans-kingdom into host plants to disrupt pathogen defence through silencing of plant genes. The mechanisms by which these small RNAs move from the microbe to the plant remain poorly understood. In this review, we examine the roles of trans-kingdom small RNAs and silencing suppressors produced by nonviral microbes in inducing and suppressing gene silencing in plants. The emerging model is that gene silencing and suppression of silencing play critical roles in the interactions between plants and their associated nonviral microbes.
Topics: Gene Silencing; Plants; Virulence; Fungi; Antiviral Agents; RNA Interference; RNA, Small Interfering; Host-Pathogen Interactions
PubMed: 37438989
DOI: 10.1111/mpp.13362 -
Virulence Dec 2023Nipah virus (NiV) is a high-risk pathogen which can cause fatal infections in humans. The Indian isolate from the 2018 outbreak in the Kerala state of India...
Nipah virus (NiV) is a high-risk pathogen which can cause fatal infections in humans. The Indian isolate from the 2018 outbreak in the Kerala state of India showed ~ 4% nucleotide and amino acid difference in comparison to the Bangladesh strains of NiV and the substitutions observed were mostly not present in the region of any functional significance except for the phosphoprotein gene. The differential expression of viral genes was observed following infection in Vero (ATCC® CCL-81™) and BHK-21 cells. Intraperitoneal infection in the 10-12-week-old, Syrian hamster model induced dose dependant multisystemic disease characterized by prominent vascular lesions in lungs, brain, kidney and extra vascular lesions in brain and lungs. Congestion, haemorrhages, inflammatory cell infiltration, thrombosis and rarely endothelial syncitial cell formation were seen in the blood vessels. Intranasal infection resulted in respiratory tract infection characterised by pneumonia. The model showed disease characteristics resembling the human NiV infection except that of myocarditis similar to that reported by NiV-Malaysia and NiV-Bangladesh isolates in hamster model. The variation observed in the genome of the Indian isolate at the amino acid levels should be explored further for any functional significance.
Topics: Cricetinae; Animals; Humans; Nipah Virus; Virulence; Henipavirus Infections; Mesocricetus; Genomics; Gene Expression Profiling
PubMed: 37312405
DOI: 10.1080/21505594.2023.2224642 -
Cell Reports Aug 2023Clostridioides difficile produces toxins that damage the colonic epithelium, causing colitis. Variation in disease severity is poorly understood and has been attributed...
Clostridioides difficile produces toxins that damage the colonic epithelium, causing colitis. Variation in disease severity is poorly understood and has been attributed to host factors and virulence differences between C. difficile strains. We test 23 epidemic ST1 C. difficile clinical isolates for their virulence in mice. All isolates encode a complete Tcd pathogenicity locus and achieve similar colonization densities. However, disease severity varies from lethal to avirulent infections. Genomic analysis of avirulent isolates reveals a 69-bp deletion in the cdtR gene, which encodes a response regulator for binary toxin expression. Deleting the 69-bp sequence in virulent R20291 strain renders it avirulent in mice with reduced toxin gene transcription. Our study demonstrates that a natural deletion within cdtR attenuates virulence in the epidemic ST1 C. difficile isolates without reducing colonization and persistence. Distinguishing strains on the basis of cdtR may enhance the specificity of diagnostic tests for C. difficile colitis.
Topics: Animals; Mice; Virulence; Clostridioides difficile; Clostridioides; Genomics; Colitis; Bacterial Proteins
PubMed: 37523264
DOI: 10.1016/j.celrep.2023.112861 -
Virulence Dec 2024Enterohemorrhagic (EHEC) is an important zoonotic pathogen that is a major cause of foodborne diseases in most developed and developing countries and can cause... (Review)
Review
Enterohemorrhagic (EHEC) is an important zoonotic pathogen that is a major cause of foodborne diseases in most developed and developing countries and can cause uncomplicated diarrhoea, haemorrhagic colitis, and haemolytic uraemic syndrome. O islands (OIs), which are unique genomic islands in EHEC O157:H7, are composed of 177 isolated genomic features and harbour 26% of the total genes that are absent in the non-pathogenic K-12 genome. In the last twenty years, many OI-encoded proteins have been characterized, including proteins regulating virulence, motility, and acid resistance. Given the critical role of regulatory proteins in the systematic and hierarchical regulation of bacterial biological processes, this review summarizes the OI-encoded regulatory proteins in EHEC O157:H7 characterized to date, emphasizing OI-encoded regulatory proteins for bacterial virulence, motility, and acid resistance. This summary will be significant for further exploration and understanding of the virulence and pathogenesis of EHEC O157:H7.
Topics: Humans; Genomic Islands; Escherichia coli O157; Transcription Factors; Enterohemorrhagic Escherichia coli; Virulence; Escherichia coli Infections; Escherichia coli Proteins
PubMed: 38357901
DOI: 10.1080/21505594.2024.2313407 -
Antimicrobial Resistance and Infection... Nov 2023Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is gradually becoming the dominant nosocomial pathogens in the healthcare setting.
BACKGROUND
Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is gradually becoming the dominant nosocomial pathogens in the healthcare setting.
METHODS
A retrospective study was conducted on patients with CR-KP from July 2021 to May 2022 in a teaching hospital. We identified bacterial isolates, collected the clinical data, and performed antimicrobial susceptibility testing, hypermucoviscosity string test, antimicrobial and virulence-associated genotype, as well as multi-locus sequence typing. CR-hvKP was defined as the presence of some combination of rmpA and/or rmpA2 with iucA, iroB, or peg-344. SPSS was used for data analysis. Univariate logistic regression analyses were used for risk factor and all statistically significant variables were included in the multivariate model. Statistical significance was taken to be P < 0.05.
RESULTS
A total of 69 non-duplicated CR-KP isolates were collected, 27 of which were CR-hvKP. Out of the 69 CR-KP strains under investigation, they were distributed across 14 distinct sequence types (STs), wherein ST11 exhibited the highest prevalence, constituting 65.2% (45/69) of the overall isolates. The principal carbapenemase genes identified encompassed bla, bla, and bla, with bla prevailing as the predominant type, accounting for 73.9% (51/69). A total of 69 CR-KP strains showed high resistance to common clinical antibiotics, with the exception of ceftazidime/avibactam. The ST11 (P = 0.040), ST65 (P = 0.030) and bla ST11 clones (P = 0.010) were found to be highly related to hvKp. Regarding the host, tracheal intubation (P = 0.008), intracranial infection (P = 0.020) and neutrophil count (P = 0.049) were significantly higher in the patients with CR-hvKP. Multivariate analysis showed tracheal intubation to be an independent risk factor for CR-hvKP infection (P = 0.030, OR = 4.131). According to the clinical data we collected, tracheal intubation was performed mainly in the elderly with severe underlying diseases, which implied that CR-hvKP has become prevalent among elderly patients with comorbidities.
CONCLUSIONS
The prevalence of CR-hvKP may be higher than expected in the healthcare setting. CR-hvKP is gradually becoming the dominant nosocomial pathogen, and its prevalence and treatment will be a major challenge. It is essential to enhance clinical awareness and management of CR-hvKP infection.
Topics: Humans; Aged; Virulence; Klebsiella pneumoniae; Multilocus Sequence Typing; Retrospective Studies; Klebsiella Infections; Anti-Bacterial Agents; Carbapenems; Cross Infection
PubMed: 37953357
DOI: 10.1186/s13756-023-01331-y -
Disease Models & Mechanisms Oct 2023Invasive fungal infections represent a significant global health problem, and present several clinical challenges, including limited treatment options, increasing rates... (Review)
Review
Invasive fungal infections represent a significant global health problem, and present several clinical challenges, including limited treatment options, increasing rates of antifungal drug resistance and compounding comorbidities in affected patients. Metals, such as copper, iron and zinc, are critical for various biological and cellular processes across phyla. In mammals, these metals are important determinants of immune responses, but pathogenic microbes, including fungi, also require access to these metals to fuel their own growth and drive expression of major virulence traits. Therefore, host immune cells have developed strategies to either restrict access to metals to induce starvation of invading pathogens or deploy toxic concentrations within phagosomes to cause metal poisoning. In this Review, we describe the mechanisms regulating fungal scavenging and detoxification of copper, iron and zinc and the importance of these mechanisms for virulence and infection. We also outline how these metals are involved in host immune responses and the consequences of metal deficiencies or overloads on how the host controls invasive fungal infections.
Topics: Animals; Humans; Copper; Virulence; Metals; Iron; Zinc; Invasive Fungal Infections; Mammals
PubMed: 37905492
DOI: 10.1242/dmm.050393 -
Emerging Microbes & Infections Dec 2023H6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in birds globally. To investigate the current situation and characteristics of H6 AIVs...
H6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in birds globally. To investigate the current situation and characteristics of H6 AIVs circulating in China, we analysed the epidemiology, genetic evolution and pathogenic features of this subtype. During 2000-2021, H6 subtype AIVs spread widely through Southern China and presented high host diversity. On analysing 171 H6 viruses isolated during 2009-2021, dynamic reassortments were observed among H6 and other co-circulating AIV subtypes, and these generated a total of 16 different genotypes. A few H6N6 strains possessed L226 and S228 mutations of hemagglutinin (H3 numbering), which may enhance the affinity of H6 viruses to human receptors. H6N6 viruses also exhibited divergent pathogenicity and growth profiles and . Some of the H6N6 viruses could infect mice without mammalian adaptation, and even caused death in this species. Therefore, our study demonstrated that the H6 AIVs posed a potential threat to human health and highlighted the urgent need for continued surveillance and evaluation of the H6 influenza viruses circulating in the field.
Topics: Animals; Mice; Humans; Influenza in Birds; Birds; Influenza A virus; Orthomyxoviridae; Virulence; China; Phylogeny; Mammals
PubMed: 36440484
DOI: 10.1080/22221751.2022.2151380 -
Nature Communications Aug 2023Extracellular vesicles (EVs) are important for cell-to-cell communication in animals. EVs also play important roles in plant-microbe interactions, but the underlying...
Extracellular vesicles (EVs) are important for cell-to-cell communication in animals. EVs also play important roles in plant-microbe interactions, but the underlying mechanisms remain elusive. Here, proteomic analyses of EVs from the soybean (Glycine max) root rot pathogen Phytophthora sojae identify the tetraspanin family proteins PsTET1 and PsTET3, which are recognized by Nicotiana benthamiana to trigger plant immune responses. Both proteins are required for the full virulence of P. sojae. The large extracellular loop (EC2) of PsTET3 is the key region recognized by N. benthamiana and soybean cells in a plant receptor-like kinase NbSERK3a/b dependent manner. TET proteins from oomycete and fungal plant pathogens are recognized by N. benthamiana thus inducing immune responses, whereas plant-derived TET proteins are not due to the sequence divergence of sixteen amino acids at the C-terminal of EC2. This feature allows plants to distinguish self and non-self EVs to trigger active defense responses against pathogenic eukaryotes.
Topics: Proteomics; Phytophthora; Plant Proteins; Virulence; Extracellular Vesicles; Glycine max; Plant Diseases
PubMed: 37573360
DOI: 10.1038/s41467-023-40623-0