image: To maintain a balance between the death of the host cell and saving a niche for survival and spread, Yptb uses a set of toxic proteins. The proteins exert their action through different signaling pathways. The activity of the crucial signaling pathways that determine the type of cell death is controlled simultaneously by several proteins, which can both mutually enhance each other’s effects or compete with each other. YopM activates PRK2 by preliminary binding and activating RSK1; caspase-3 is a cofactor in the activation of the latter. The downstream effector STAT3 stimulates the expression of the anti-inflammatory cytokine IL-10. Additionally, YopM has an anti-inflammatory effect through inhibition of the activity of caspase-1, which is part of the pyrin-inflammasome complex, and the synthesis of the pro-inflammatory cytokine IL-1, which induces a pro-inflammatory type of cell death, pyroptosis. YopM also exerts an anti-inflammatory effect through inhibition of the pro-inflammatory activity (activation of inflammasome assembly) of YopE and YopT. YopJ induces apoptotic cell death in macrophages but not in neutrophils through activation of caspase-8. In addition, YopJ prevents activation of the MAPKs (including TAK1 and MAP2 kinase) and downstream activation of JNK and/or p38 and NF-κB-dependent pathways. Redundantly, YopJ inhibits biosynthesis of PGE2, which is involved in the activation of NF-κB-dependent transcription of IL-1β. Thus, inhibiting the MAPK cascade leads to blocking IL-1β secretion and preventing pyroptosis. However, YopJ can also have a pro-inflammatory effect, activating inflammasome assembly via the RIPK1/caspase-8-dependent pathway, as well as stimulating GSDME- and GSDMD-dependent and controlling by RIPK1 and caspase-8 ROS activation and pore formation in neutrophils and macrophages, respectively. YpkA inhibits Rho GTPases and the rearrangement of the actin cytoskeleton directly or through phosphorylation of Gαq. In addition, YpkA can promote pore formation through phosphorylation of actin-binding proteins, such as VASP, EVL, WASP, WIP, and gelsolin. These pathways lead to pyroptosis. Meanwhile, the anti-inflammatory effect of YpkA also occurs through stimulation of caspase-3-mediated apoptosis. YopH inhibits ROS generation in neutrophils and apparently limits inflammation through inhibiting SKAP2-dependent ERK1/2 signaling pathway and FcγR-dependent signaling pathway, including phosphorylation of the proximal signaling proteins such as Syk, SLP-76, PLCγ2, and PRAM-1. YopE suppresses Rho GTPases and selectively inhibits caspase-1 and the release of IL-1β to protect host cells from pyroptosis via inactivating Rac2. Inhibition of RhoA, on the contrary, results in inflammasome activation. YopE manipulates the assembly of inflammasomes only in the absence of YopM. YopT cleaves RhoA GTPase, leading to the disruption of actin structures and contributing to pore formation and the anti-phagocytic effect of Yersinia. YopT also activates inflammasome assembly and cell death by pyroptosis. In this case, YopT acts slower than YopE and activates inflammasome assembly only in the absence of YopM. CNFY constitutively activates Rho GTPases. This leads to STAT3 activation, which may be involved in the anti-inflammatory response, including iNOS inhibition as described for HLT (identified as CNFY) in the early stage of incubation. In addition, RhoA stimulation by CNFY leads to suppression of inflammasome assembly. Conversely, Rac1 activation by the toxin through the PI3K/Akt/NF-κB signaling pathway prevents apoptosis. YPM binds directly to MHC II molecules and activates both innate immune cells and T cells, followed by a massive release of pro-inflammatory cytokines. Simultaneously, YPM stimulates IL-4 release, strengthening the Th2 immune profile apparently aimed to restrict inflammatory death of phagocytes. TsTYp modulates the accumulation of cAMP and ROS-mediated apoptosis, negatively associated with cAMP level. The toxin affects the level of cAMP in neutrophils and mononuclear cells in the opposite way. TcpYI blocks TIR signaling via binding to TIR. Akt, protein kinase B; cAMP, cyclic adenosine monophosphate; CNFY, cytotoxic necrotizing factor of Yersinia pseudotuberculosis; EVL, Ena/VASP-like protein; FADD, Fas-associated protein with death domain; Gαq, Gq protein alpha subunit; GSDM, gasdermin; JNK, c-Jun N-terminal kinase; ERK1/2, extracellular signal-regulated kinase 1/2; FcγR, Fc gamma receptor; GTPase, guanosine triphosphate hydrolase; HLT, heat-labile toxin; IL, interleukin; iNOS, inducible nitric oxide synthase; M, macrophage; MAPKs, mitogen-activated protein kinases; MHC, major histocompatibility complex; N, neutrophil; NF-κB, nuclear factor kappa B; p38, p38 mitogen-activated protein kinase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PLCγ2, phospholipase Cγ 2; PM, plasma membrane of the phagocyte; PRAM-1, PML-RARA regulated adaptor molecule 1; PRK2, protein kinase C-related kinase 2; RIPK1, receptor-interacting serine/threonine protein kinase 1; ROS, reactive oxygen species; RSK1, 90-kDa ribosomal S6 kinase; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; SKAP2, Src kinase-associated phosphoprotein-2; STAT3, signal transducer and activator of transcription 3; Syk, spleen tyrosine kinase; TAK1, transforming growth factor beta-activated kinase 1; TcpYI, Toll/interleukin-1 receptor domain-containing virulence protein of Y. pseudotuberculosis; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptor; TsTYp, thermostable toxin of Y. pseudotuberculosis; VASP, vasodilator-stimulated phosphoprotein; WASP, Wiskott-Aldrich syndrome protein; WIP, WASP-interacting protein; YPM, Y. pseudotuberculosis-derived mitogen.
Credit: Lyudmila S. Dolmatova
Yersinia pseudotuberculosis (Yptb), a gram-negative bacterium, is known to cause severe intestinal infections that can disseminate to internal organs, particularly the liver. In this essay, we summarize the current understanding of the mechanisms by which Yptb utilizes its plasmid- and chromosome-encoded proteins to evade host immune responses and promote bacterial colonization of the liver. This review focuses on the immunomodulatory effects of Yptb toxins, specifically their role in modulating phagocyte activity and promoting bacterial survival.
Yersinia pseudotuberculosis and its Pathogenicity
Yptb primarily causes intestinal infections, with outbreaks reported in cold temperate regions of Europe and North America. However, Far East scarlet-like fever (FESLF), a severe variant of Yptb infection, has been noted in Russia and Japan, characterized by a higher incidence of liver damage. Yptb disseminates from the intestine to organs such as the liver via the bloodstream, where it persists and causes abscesses, hepatitis, and sepsis.
Bacterial Defense Mechanisms: Plasmid-encoded Effector Proteins
Yptb expresses several plasmid-encoded effector proteins (Yops) belonging to the Type III secretion system (T3SS), which are critical for suppressing phagocytic activity. These Yops, including YopM, YopH, YopE, and YopT, are injected into host cells, primarily phagocytes, to disrupt their function. The master regulator LcrF controls the expression of these effector proteins in response to temperature changes and other environmental stimuli.
Role of YopM in Bacterial Colonization
YopM, a 42-54 kDa protein, promotes Yptb colonization of the liver and other organs by reducing inflammation and stimulating the production of anti-inflammatory cytokines, particularly interleukin (IL)-10. YopM promotes nuclear translocation of STAT3, leading to increased IL-10 expression, which aids bacterial survival. Studies have shown that the presence of YopM significantly contributes to liver colonization, while its absence results in reduced bacterial load.
YopM selectively targets polymorphonuclear leukocytes (PMNs) and inflammatory Kupffer cells in the liver, promoting their apoptotic death. This proapoptotic effect is mediated by caspase-3 and is specific to the liver, suggesting a tissue-specific mechanism of action. Additionally, YopM has been found to reduce the numbers of dendritic cells in the liver, further modulating the immune response.
Chromosome-encoded Toxins and Their Role
In addition to plasmid-encoded toxins, chromosome-encoded proteins such as YPM, CNF Y, and TsTYp also play a significant role in Yptb virulence. These toxins have been identified primarily in Far Eastern strains of Yptb, which exhibit a higher degree of virulence and tissue damage. These toxins, through various mechanisms, contribute to the suppression of host immune responses and promotion of bacterial colonization.
Conclusions and Future Directions
This review highlights the intricate mechanisms employed by Yptb to evade host immune responses and promote bacterial colonization of the liver. The plasmid- and chromosome-encoded toxins play pivotal roles in modulating phagocyte activity and promoting bacterial survival. A comprehensive understanding of these immunomodulatory effects will pave the way for developing novel therapeutic strategies to combat Yptb infections and associated liver damage.
Future research should focus on elucidating the detailed molecular mechanisms of Yptb toxins, particularly their interactions with host immune cells and signaling pathways. Additionally, studies comparing the virulence of different Yptb strains from various geographical regions will provide valuable insights into the evolution and epidemiology of this pathogen. The development of novel antimicrobials targeting these toxins may offer effective treatment options for patients with Yptb infections.
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The study was recently published in the Gene Expression.
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Journal
Gene Expression
Article Title
Phagocyte-targeted Effects of Yersinia pseudotuberculosis Proteins and Their Role in Bacterial Colonization of the Liver
Article Publication Date
2-Aug-2024