| Yersinia pseudotuberculosis | |
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| Yersinia scanned with electron micrograph | |
| Specialty | Infectious disease |
| Yersinia pseudotuberculosis | |
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Scientific classification | |
| Domain: | Bacteria |
| Kingdom: | Pseudomonadati |
| Phylum: | Pseudomonadota |
| Class: | Gammaproteobacteria |
| Order: | Enterobacterales |
| Family: | Yersiniaceae |
| Genus: | Yersinia |
| Species: | Y. pseudotuberculosis |
| Binomial name | |
| Yersinia pseudotuberculosis (Pfeiffer 1889) Smith & Thal 1965 | |
Yersinia pseudotuberculosis is aGram-negativebacterium that causesFar East scarlet-like fever in humans, who occasionally get infectedzoonotically, most often through the food-borne route.[1] Animals are also infected byY. pseudotuberculosis. The bacterium isurease positive.
In animals,Y. pseudotuberculosis can causetuberculosis-like symptoms, including localized tissuenecrosis andgranulomas in thespleen,liver, andlymph nodes.
In humans, symptoms ofFar East scarlet-like fever are similar to those of infection withYersinia enterocolitica (fever and right-sided abdominal pain), except that the diarrheal component is often absent, which sometimes makes the resulting condition difficult to diagnose.Y. pseudotuberculosis infections can mimicappendicitis, especially in children and younger adults, and, in rare cases, the disease may cause skin complaints (erythema nodosum), joint stiffness and pain (reactive arthritis), or spread of bacteria to the blood (bacteremia).
Far East scarlet-like fever usually becomes apparent five to 10 days after exposure and typically lasts one to three weeks without treatment. In complex cases or those involvingimmunocompromised patients, antibiotics may be necessary for resolution;ampicillin,aminoglycosides,tetracycline,chloramphenicol, or acephalosporin may all be effective.[citation needed]
The recently described syndrome "Izumi-fever" has been linked to infection withY. pseudotuberculosis.[2]
The symptoms of fever and abdominal pain mimicking appendicitis (actually frommesenteric lymphadenitis)[3][4][5] associated withY. pseudotuberculosis infection are not typical of the diarrhea and vomiting from classical food poisoning incidents. AlthoughY. pseudotuberculosis is usually only able to colonize hosts by peripheral routes and cause serious disease in immunocompromised individuals, if this bacterium gains access to the blood stream, it has an LD50 comparable toY. pestis at only 10 CFU.[6]
Genetically, the pathogen causingplague,Y. pestis, is very similar toY. pseudotuberculosis. The plague appears to have diverged fromY. pseudotuberculosis relatively recently - about 1,500 to 20,000 years ago, and shortly before the first historically recorded outbreaks in humans.[7] A 2015 paper inCell argued for a divergence around 6,000 years ago.[8] These modern estimates differ dramatically from earlier suggestions in popular scientific literature which claimed thatY. pestis evolved in rodents "millions of years ago."[9]
To facilitate attachment, invasion, and colonization of its host, this bacterium possesses manyvirulence factors. Superantigens, bacterial adhesions, and the actions of Yops (which are bacterial proteins once thought to be "Yersinia outer membrane proteins") that are encoded on the "[plasmid] forYersinia virulence" – commonly known as the pYV – cause host pathogenesis and allow the bacteria to live parasitically.
The 70-kb pYV is critical toYersinia's pathogenicity, since it contains manygenes known to encode virulence factors and its loss gives avirulence of allYersinia species.[6] A 26-kb "core region" in the pYV contains theysc genes, which regulate the expression and secretion of Yops.[5] Many Ysc proteins also amalgamate to form a type-III secretory apparatus, which secretes many Yops into the host cellcytoplasm with the assistance of the "translocation apparatus", constructed of YopB and YopD.[10][11] The core region also includesyopN,yopB,yopD,tyeA,lcrG, andlcrV, which also regulate Yopsgene expression and help to translocate secretory Yops to the target cell.[5] For example, YopN and TyeA are positioned as a plug on the apparatus so only their conformational change, induced by their interaction with certain host cell membrane proteins, will cause the unblocking of the secretory pathway.[5][12] Secretion is regulated in this fashion so that proteins are not expelled into theextracellular matrix and elicit animmune response. Since this pathway gives secretion selectivity, it is a virulence factor.
In contrast to theysc andyop genes listed above, the Yops that act directly on host cells to cause cytopathologic effects – "effector Yops" – are encoded bypYV genes external to this core region.[5] The sole exception is LcrV, which is also known as the "versatile Yop" for its two roles as an effector Yop and as a regulatory Yop.[5] The combined function of these effector Yops permits the bacteria to resist internalization by immune and intestinal cells and to evade the bactericidal actions ofneutrophils andmacrophages. Inside the bacterium, these Yops are bound bypYV-encoded Sycs (specific Yop chaperones), which prevent premature interaction with other proteins and guide the Yops to a type-III secretory apparatus.[11] In addition to the Syc-Yop complex, Yops are also tagged for type III secretion either by the first 60nt in their correspondingmRNA transcript or by their corresponding first 20N-terminalamino acids.[4]LcrV, YopQ, YopE, YopT, YopH, YpkA, YopJ, YopM, and YadA are all secreted by the type-III secretory pathway.[4][5][12] LcrV inhibits neutrophilchemotaxis andcytokine production, allowingY. pseudotuberculosis to form large colonies without inducing systemic failure[12] and, with YopQ, contributes to the translocation process by bringing YopB and YopD to the eukaryoticcell membrane for pore-formation.[4][13] By causing actin filament depolymerisation, YopE, YopT, and YpkA resistendocytosis by intestinal cells andphagocytosis while giving cytotoxic changes in the host cell. YopT targets Rho GTPase, commonly named "RhoA", and uncouples it from the membrane, leaving it in an inactive RhoA-GDI (guanine nucleotide dissociation inhibitor)-bound state[14] whereas YopE and YpkA convert Rho proteins to their inactive GDP-bound states by expressing GTPase activity.[12] YpkA also catalysesserine autophosphorylation, so it may have regulatory functions inYersinia[15] or undermine host cell immune response signal cascades since YpkA is targeted to the cytoplasmic side of the host cell membrane.[16] YopH acts on host focal adhesion sites by dephosphorylating severalphosphotyrosine residues onfocal adhesion kinase (FAK) and the focal adhesion proteinspaxillin and p130.[17] Since FAK phosphorylation is involved in uptake of yersiniae[18] as well asT cell andB cell responses to antigen-binding,[12] YopH elicits antiphagocytic and other anti-immune effects. YopJ, which shares anoperon with YpkA, "...interferes with the mitogen-activated protein (MAP) kinase activities of c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase",[19] leading to macrophageapoptosis.[4] In addition, YopJ inhibits TNF-α release from many cell types, possibly through an inhibitory action on NF-κB, suppressing inflammation and the immune response.[20] By secretion through a type III pathway and localization in the nucleus by a vesicle-associated, microtubule-dependent method, YopM may alter host cell growth by binding to RSK (ribosomal S6 kinase), which regulates cell cycle regulation genes.[12] YadA has lost its adhesion,[21]opsonisation-resisting, phagocytosis-resisting, andrespiratory burst-resisting functions[22][23] inY. pseudotuberculosis due to aframeshift mutation by a single base-pair deletion inyadA in comparison toyadA inY. enterocolitica, yet it still is secreted by type III secretion.[24] Theyop genes,yadA,ylpA, and thevirC operon are considered the "Yop regulon" since they are coregulated by pYV-encoded VirF.virF is in turn thermoregulated. At 37 degrees Celsius, chromosomally encoded Ymo, which regulatesDNA supercoiling around thevirF gene, changes conformation, allowing for virF expression, which then up-regulates the Yop regulon.[25]
Y. pseudotuberculosis adheres strongly to intestinal cells via chromosomally encoded proteins[4] so that Yop secretion may occur, to avoid being removed byperistalsis, and to invade target host cells. A transmembrane protein,invasin, facilitates these functions by binding to host cell αβ1integrins.[26] Through this binding, the integrins cluster, thereby activating FAK, and causing a corresponding reorganization of the cytoskeleton.[4][26] Subsequent internalization of bound bacteria occurs when the actin-depolymerising Yops are not being expressed.[12] The protein encoded on the "attachment invasion locus" named Ail also bestows attachment and invasive abilities upon Yersiniae[27] while interfering with the binding of complement on the bacterial surface.[28] To increase binding specificity, the fibrillar pH6 antigen targets bacteria to target intestinal cells only when thermoinduced.[29]
Certain strains ofYersinia pseudotuberculosis express a superantigenic exotoxin, YPM, or theY. pseudotuberculosis-derived mitogen, from the chromosomalypm gene.[30] YPM specifically binds and causes the proliferation of T lymphocytes expressing the Vβ3, Vβ7, Vβ8, Vβ9, Vβ13.1, and Vβ13.2 variable regions[31] withCD4+ T cell preference, although activation of some CD8+T cells occurs.[3] This T cell expansion can causesplenomegaly coupled withIL-2 andIL-4 overproduction.[32] Since administering anti-TNF-α and anti-IFN-γ monoclonalantibodies neutralizes YPM toxicityin vivo,[30] these cytokines are largely responsible for the damage caused indirectly by theexotoxin. Strains that carry the exotoxin gene are rare in Western countries, where the disease, when at all apparent, manifests itself largely with minor symptoms, whereas more than 95% of strains from Far Eastern countries containypm[33] and are correlated with Izumi fever andKawasaki disease.[34]Although the superantigen poses the greatest threat to host health, all virulence factors contribute toY. pseudotuberculosis viabilityin vivo and define the bacterium's pathogenic characteristics.Y. pseudotuberculosis can live extracellularly due to its formidable mechanisms of phagocytosis andopsonisation resistance through the expression of Yops and the type III pathway;[11] yet, by limited pYV action, it can populate host cells, especially macrophages, intracellularly to further evade immune responses and be disseminated throughout the body.[35]
| YpM | |||||||
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 crystal structure of yersinia pseudotuberculosis-derived mitogen (ypm) | |||||||
| Identifiers | |||||||
| Symbol | YpM | ||||||
| Pfam | PF09144 | ||||||
| InterPro | IPR015227 | ||||||
| SCOP2 | 1pm4 /SCOPe /SUPFAM | ||||||
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Yersinia pseudotuberculosis-derived mitogens (YpM) aresuperantigens, which are able to excessively activateT cells bybinding to the T cellreceptor. Since YpM can activate large numbers of the T cell population, this leads the release of inflammatorycytokines.
Members of this family ofYersinia pseudotuberculosismitogens adopt a sandwichstructure consisting of 9 strands in two beta sheets, in ajelly roll fold topology. YpM molecular weight is about 14 kDa. Structurally, it is unlike any other superantigen, but is remarkably similar to thetumour necrosis factor and viral capsid proteins. This suggests a possible evolutionary relationship.[36]
Some highly similar homologous variants of YPM have been characterized, including YPMa, YPMb, and YPMc.
Numerousbacterial small non-coding RNAs have been identified to play regulatory functions. Some can regulate the virulence genes. 150 unannotated sRNAs were identified by sequencing ofY. pseudotuberculosis RNA libraries from bacteria grown at 26 °C and 37 °C, suggesting they may play a role in pathogenesis.[37] By using single-moleculefluorescence in situ hybridisation smFISH technique it was shown that the number of YSR35 RNA increased 2.5 times upon temperature shift from 25 °C to 37 °C.[38] Another study uncovered that a temperature-induced global reprogramming of central metabolic functions are likely to support intestinal colonization of the pathogen. Environmentally controlled regulatory RNAs coordinate control of metabolism and virulence allowing rapid adaptation and high flexibility during life-style changes.[39] High-throughput RNA structure probing identified many thermoresponsive RNA structures.[40]
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