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Microbial pathogens have evolved complex mechanisms to interface with host cells in order to evade host defenses and replicate. However, mammalian innate immune receptors detect the presence of molecules unique to the microbial world or sense the activity of virulence factors, activating antimicrobial and inflammatory pathways. We focus on how studies of the major virulence factor of one group of microbial pathogens, the type III secretion system (T3SS) of human pathogenic Yersinia , have shed light on these important innate immune responses. Yersinia are largely extracellular pathogens, yet they insert T3SS cargo into target host cells that modulate the activity of cytosolic innate immune receptors. This review covers both the host pathways that detect the Yersinia T3SS and the effector proteins used by Yersinia to manipulate innate immune signaling.

To counteract the deadly pathogens, i.e., Y. pestis, Y. enetrocolitica , and Y. pseudotuberculosis , we prepared a recombinant DNA construct lcrV-hsp70 encoding the bivalent fusion protein LcrV-HSP70. The lcrV gene of Y. pestis and hsp70 domain II DNA fragment of M. tuberculosis were amplified by PCR. The lcrV amplicon was first ligated in the pET vector using NcoI and BamHI restriction sites. Just downstream to the lcrV gene, the hsp70 domain II was ligated using BamHI and Hind III restriction sites. The in-frame and the orientation of cloned lcrV-hsp70 were checked by restriction analysis and nucleotide sequencing. The recombinant bivalent fusion protein LcrV-HSP70 was expressed in E. coli and purified by affinity chromatography. The vaccine potential of LcrV-HSP70 fusion protein was evaluated in formulation with alum. BALB/c mice were vaccinated, and the humoral and cellular immune responses were studied. The fusion protein LcrV-HSP70 induced a strong and significant humoral immune response in comparison to control animals. We also observed a significant difference in the expression levels of IFN-γ and TNF-α in LcrV-HSP70-immunized mice in comparison to control, HSP70, and LcrV groups. To test the protective efficacy of the LcrV-HSP70 fusion protein against plague and Yersiniosis, the vaccinated mice were challenged with Y. pestis, Y. enterocolitica , and Y. pseudotuberculosis separately. The bivalent fusion protein LcrV-HSP70 imparted 100% protection against the plague. In the case of Yersiniosis, on day 2 post challenge, there was a significant reduction in the number of CFU of Y. enterocolitica and Y. pseudotuberculosis in the blood (CFU/ml) and the spleen (CFU/g) of vaccinated animals in comparison to the LcrV, HSP70, and control group animals., (Copyright © 2020 Gupta, Narayan, Kumar and Verma.)

Any pathogen worth its salt has mechanisms to evade, subvert, or antagonize host innate immune responses induced by pattern recognition receptors. Resistance against such pathogens therefore requires alternative means to activate protective immune responses. Intriguingly, the receptors that regulate antimicrobial gene expression are coupled to cell death pathways that are activated by blockade of NF-κB and MAPK signaling. In this review, we discuss the regulation of apoptosis in response to pathogen disruption of immune signaling and the role of this cell death response in protection against such pathogens. Stanley often observed that bacterial pathogens are excellent cell biologists and immunologists, and he noted that studying pathogen-host interactions could pave the way to new insights about host biology. Indeed, how Yersinia and other pathogens disrupt innate immune signaling has provided new insight into these pathways and revealed new ways to think about immunogenic properties of apoptosis during bacterial infection., (Copyright © 2020. Published by Elsevier Ltd.)

A novel microcantilever sensor was batch fabricated for Yersinia detection. The microcantilever surface modification method was optimized by introducing a secondary antibody to increase the number of binding sites. A novel microfluidic platform was designed and fabricated successfully. A 30 μL solution could fully react with the microcantilever surface. Those routines enhanced the binding efficiency between the target and receptor on the microcantilever. With this novel designed microfluidic platform, the specific adsorption of 10 7 Yersinia on the beam surface with modified F1 antibody was significantly enhanced.

Type III secretion systems (T3SS) play a crucial role for virulence in many Gram-negative bacteria. After tight bacterial contact to host cells, the T3SS injects effector proteins into the host cells, which leads to cell invasion, tissue destruction and/or immune evasion. Over the last decade several attempts were made to characterize the host-cell interactions which precede and determine effector protein injection during infection. The development of the TEM-β-lactamase reporter was an important breakthrough to achieve this goal. By this means it was demonstrated that during infection with many Gram-negative pathogens such as Salmonella, Pseudomonas or Yersinia the main targets of T3SS are leukocytes of the myeloid lineage such as neutrophils, macrophages or dendritic cells. This is due to the recruitment of these cells to the site of infection, but also due to the specific interplay between bacterial and host cells. Comprehensive studies on Yersinia pestis, Yersinia enterocolitica and Yersinia pseudotuberculosis effector translocation show that adhesins such as Invasin (Inv), Yersinia adhesin A (YadA) and attachment and invasion locus (Ail) are critical for effector translocation. Here, mainly the complex interaction of YadA and Ail with various host cell receptor repertoires on leukocytes and the modulatory effects of serum factors direct effector translocation predominantly towards myeloid cells. The current understanding suggests that mostly protein based interactions between bacteria and host determine host cell specific effector translocation during Yersinia infection. However, for Shigella dysenteriae infection it was shown that glycan-glycan interactions can also play a critical role for the adhesion preceding effector translocation. In addition, the Shigella infection model revealed that the activation status of cells is a further criterium directing effector translocation into a distinct cell population. In this review the current understanding of the complex and species-specific interaction between bacteria and host cells leading to type III secretion is discussed., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The Yersinia effector proteins YopE and YopT are important bacterial virulence factors that are secreted into infected host cells and can inactivate Rho GTPases, like RhoA, Rac1, and Cdc42. In order to compensate for the consequences of this effect, the host cell can sense RhoA modifications and trigger a proinflammatory reaction to control the infection. This host response, known as pyrin inflammasome assembly, is normally prevented by another important effector, YopM, allowing Yersinia to counteract this conserved innate immune response. Once assembled, the pyrin inflammasome can activate caspase-1 via proteolysis, leading to IL-1β secretion and cell death through pyroptosis. Here we describe how to measure pyrin inflammasome assembly, in response to YopE or YopT activities, when macrophages are infected with yopM mutant Yersinia. Using primary mouse macrophages as host cells, we show how to detect this host response through the downstream events of pyrin dephosphorylation, caspase-1 proteolysis, IL-1β release, and pyroptosis.

The type of cell death triggered by a particular environmental stimulus influences the outcome of infection or inflammatory disease processes. The ability to identify the cell death pathway that is activated in response to infection is essential for understanding the pathogenesis and host response to infection. Activation of the cysteine protease caspase-1 in various inflammasome complexes indicates that cells are undergoing pyroptosis, a regulated, proinflammatory cell death. Inflammasome assembly and caspase activation can be measured by various methods ranging from detection of inflammasome-dependent cell death, cytokine secretion, cleavage of caspase-1, or the formation of "puncta" within the cell that contain inflammasome components, such as caspase-1 or the adapter protein ASC. Here we describe a method for detecting caspase-1 activation on a single cell level in the context of infection by the Gram-negative pathogen Yersinia using immunofluorescence microscopy. We previously used this approach to quantify caspase-1 puncta formation in cells containing Yersinia translocon components (Zwack et al., MBio 6:e02095-14, 2015). This is a modification of methods used previously by Broz et al. (Cell Host Microbe 8:471-483, 2010) and Case and Roy (MBio 2:e00117-11, 2011). By taking a microscopy-based approach that allows us to quantify puncta as well as other cell-biological features of infection (i.e., number of bacteria associated with a particular cell; levels of bacterial effector or translocon proteins in caspase-1 puncta-containing cells; or levels or localization of host cellular proteins), we can better quantify the heterogeneity between cells undergoing pyroptosis and cells that are not under the same infection conditions. These approaches have the potential to generate hypotheses that can enable further mechanistic insight into activation of pyroptosis in response to bacterial infection.

The acute-phase response is triggered by the presence of infectious agents and danger signals which indicate hazards for the integrity of the mammalian body. One central feature of this response is the sequestration of iron into storage compartments including macrophages. This limits the availability of this essential nutrient for circulating pathogens, a host defence strategy known as 'nutritional immunity'. Iron metabolism and the immune response are intimately linked. In infections, the availability of iron affects both the efficacy of antimicrobial immune pathways and pathogen proliferation. However, host strategies to withhold iron from microbes vary according to the localization of pathogens: Infections with extracellular bacteria such as Staphylococcus aureus, Streptococcus, Klebsiella or Yersinia stimulate the expression of the iron-regulatory hormone hepcidin which targets the cellular iron-exporter ferroportin-1 causing its internalization and blockade of iron egress from absorptive enterocytes in the duodenum and iron-recycling macrophages. This mechanism disrupts both routes of iron delivery to the circulation, contributes to iron sequestration in the mononuclear phagocyte system and mediates the hypoferraemia of the acute phase response subsequently resulting in the development of anaemia of inflammation. When intracellular microbes are present, other strategies of microbial iron withdrawal are needed. For instance, in macrophages harbouring intracellular pathogens such as Chlamydia, Mycobacterium tuberculosis, Listeria monocytogenes or Salmonella Typhimurium, ferroportin-1-mediated iron export is turned on for the removal of iron from infected cells. This also leads to reduced iron availability for intra-macrophage pathogens which inhibits their growth and in parallel strengthens anti-microbial effector pathways of macrophages including the formation of inducible nitric oxide synthase and tumour necrosis factor. Iron plays a key role in infectious diseases both as modulator of the innate immune response and as nutrient for microbes. We need to gain a more comprehensive understanding of how the body can differentially respond to infection by extra- or intracellular pathogens. This knowledge may allow us to modulate mammalian iron homeostasis pharmaceutically and to target iron-acquisition systems of pathogens, thus enabling us to treat infections with novel strategies that act independent of established antimicrobials., (Copyright © 2018. Published by Elsevier GmbH.)

Human-pathogenic Yersinia produce plasmid-encoded Yersinia outer proteins (Yops), which are necessary to down-regulate anti-bacterial responses that constrict bacterial survival in the host. These Yops are effectively translocated directly from the bacterial into the target cell cytosol by the type III secretion system (T3SS). Cell-penetrating peptides (CPPs) in contrast are characterized by their ability to autonomously cross cell membranes and to transport cargo - independent of additional translocation systems. The recent discovery of bacterial cell-penetrating effector proteins (CPEs) - with the prototype being the T3SS effector protein YopM - established a new class of autonomously translocating immunomodulatory proteins. CPEs represent a vast source of potential self-delivering, anti-inflammatory therapeutics. In this review, we give an update on the characteristic features of the plasmid-encoded Yops and, based on recent findings, propose the further development of these proteins for potential therapeutic applications as natural or artificial cell-penetrating forms of Yops might be of value as bacteria-derived biologics.

The innate immune response is a central element of the initial defense against bacterial and viral pathogens. Macrophages are key innate immune cells that upon encountering pathogen-associated molecular patterns respond by producing cytokines, including IFN-β. In this study, we identify a novel role for RIPK1 and RIPK3, a pair of homologous serine/threonine kinases previously implicated in the regulation of necroptosis and pathologic tissue injury, in directing IFN-β production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-β synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-β production may be elicited in an analogous fashion using LPS in bone marrow-derived macrophages upon inhibition of caspases. Notably, this regulation requires kinase activities of both RIPK1 and RIPK3, but not the necroptosis effector protein, MLKL. Mechanistically, we provide evidence that necrosome-like RIPK1 and RIPK3 aggregates facilitate canonical TRIF-dependent IFN-β production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-β is markedly induced by avirulent strains of Gram-negative bacteria, Yersinia and Klebsiella , and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-β during the host inflammatory responses to bacterial infection and suggest that the axis in which these kinases operate may represent a target for bacterial virulence factors., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The innate immune system plays an essential role in initiating the early response against microbial infection, as well as instructing and shaping subsequent responses. Microbial pathogens are enormously diverse in terms of the niches they occupy, their metabolic properties and requirements, and the cellular pathways that they target. Nevertheless, innate sensing of pathogens triggers a relatively stereotyped set of responses that involve transcriptional induction of key inflammatory mediators, as well as post-translational assembly and activation of a multiprotein inflammatory complex termed 'the inflammasome.' Along with classical Pattern Recognition Receptors, the inflammasome activation pathway has emerged as a key regulator of tissue homeostasis and immune defense. Components of the inflammasome generally exist within the cell in a soluble, monomeric state, and oligomerize in response to diverse enzymatic activities associated with infection or cellular stress. Inflammasome assembly triggers activation of the pro-enzyme caspase-1, resulting in the cleavage of caspase-1 targets. The most extensively studied targets are the cytokines of the IL-1 family, but the recent discovery of Gasdermin D as a novel target of caspase-1 and the related inflammatory caspase, caspase-11, has begun to mechanistically define the links between caspase-1 activation and cell death. Cell death is a hallmark of macrophage infection by many pathogens, including the gram-negative bacterial pathogens of the genus Yersinia. Intriguingly, the activities of the Yersinia-secreted effector proteins and the type III secretion system (T3SS) itself have been linked to both inflammasome activation and evasion during infection. The balance between these activating and inhibitory activities shapes the outcome of Yersinia infection. Here, we describe the current state of knowledge on interactions between Yersinia and the inflammasome system, with the goal of integrating these findings within the general framework of inflammasome responses to microbial pathogens.

The seroprevalence of Salmonella spp., pathogenic Yersinia spp., Toxoplasma gondii and Trichinella spp. was studied in 1353 finishing pigs from 259 farms that were allocated according to farm types: large fattening farms (≥ 1000 pig places), small fattening farms (< 1000 pig places) and farrow-to-finish farms. The antibodies were analysed with commercial ELISA kits in meat juice samples that were collected at Finnish slaughterhouses. Salmonella antibodies were rare (3% of pigs, 14% of farms) when the cut-off optical density (OD) value 0.2 was used. Antibodies to pathogenic Yersinia spp. and T. gondii were detected in 57% of pigs and 85% of farms (OD ≥ 0.3) and in 3% of pigs and 9% of farms (OD ≥ 0.15), respectively. No antibodies to Trichinella spp. were detected (OD ≥ 0.3). The European Food Safety Authority (EFSA) considers Salmonella spp., Yersinia enterocolitica, T. gondii and Trichinella spp. as the most relevant biological hazards in the context of meat inspection of pigs. The seroprevalence of these important zoonotic pathogens was low in Finland, except that of Yersinia. The seroprevalence of Toxoplasma was significantly higher in pigs originating from small-scale fattening farms (P < 0.05). Strong positive correlation was observed at the animal level between Salmonella and Yersinia seropositivity and between Salmonella and Toxoplasma seropositivity (P < 0.05). We suggest that these results reflect the level and importance of biosecurity measures applied on the farms. Meat juice serology at slaughter is a useful tool for targeting measures to control these pathogens. The information obtained from analyses should be used as part of the food chain information (FCI)., (© 2014 Blackwell Verlag GmbH.)

Numerous pathogenic microorganisms secrete small molecule chelators called siderophores defined by their ability to bind extracellular ferric iron, making it bioavailable to microbes. Recently, a siderophore produced by uropathogenic Escherichia coli, yersiniabactin, was found to also bind copper ions during human infections. The ability of yersiniabactin to protect E. coli from copper toxicity and redox-based phagocyte defenses distinguishes it from other E. coli siderophores. Here we compare yersiniabactin to other extracellular copper-binding molecules and review how copper-binding siderophores may confer virulence-associated gains of function during infection pathogenesis., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Phosphoinositides control key cellular processes including vesicular trafficking and actin polymerization. Intracellular bacterial pathogens manipulate phosphoinositide metabolism in order to promote their uptake by target cells and to direct in some cases the biogenesis of their replication compartments. In this chapter, we review the molecular strategies that major pathogens including Listeria, Mycobacterium, Shigella, Salmonella, Legionella and Yersinia use to hijack phosphoinositides during infection. This article is part of a Special Issue entitled Phosphoinositides., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The ability to regenerate immobilized proteins like recombinant antigens (rAgs) on surfaces is an unsolved problem for flow-based immunoassays on microarray analysis systems. The regeneration on microarray chip surfaces is achieved by changing the protein structures and desorption of antibodies. Afterwards, reactivation of immobilized protein antigens is necessary for reconstitution processes. Any backfolding should be managed in a way that antibodies are able to detect the protein antigens in the next measurement cycle. The regeneration of rAg microarrays was examined for the first time on the MCR3 flow-based chemiluminescence (CL) microarray analysis platform. The aim was to reuse rAg microarray chips in order to reduce the screening effort and costs. An antibody capturing format was used to detect antibodies against zoonotic pathogens in sera of slaughtered pigs. Different denaturation and reactivation buffers were tested. Acidic glycine-SDS buffer (pH 2.5) and 8 M guanidinium hydrochloride showed the best results in respect of denaturation efficiencies. The highest CL signals after regeneration were achieved with a carbonate buffer containing 10 mM DTT and 0.1% BSA for reactivation. Antibodies against Yersinia spp. and hepatitis E virus (HEV) were detected in swine sera on one immunochip over 4 days and 25 measurement cycles. Each cycle took 10 min for detection and regeneration. By using the rAg microarray chip, a fast and automated screening of antibodies against pathogens in sera of slaughtered pigs would be possible for zoonosis monitoring.

Bayesian analysis was used to estimate the pig's and herd's true prevalence of enteropathogenic Yersinia in serum samples collected from Finnish pig farms. The sensitivity and specificity of the diagnostic test were also estimated for the commercially available ELISA which is used for antibody detection against enteropathogenic Yersinia. The Bayesian analysis was performed in two steps; the first step estimated the prior true prevalence of enteropathogenic Yersinia with data obtained from a systematic review of the literature. In the second step, data of the apparent prevalence (cross-sectional study data), prior true prevalence (first step), and estimated sensitivity and specificity of the diagnostic methods were used for building the Bayesian model. The true prevalence of Yersinia in slaughter-age pigs was 67.5% (95% PI 63.2-70.9). The true prevalence of Yersinia in sows was 74.0% (95% PI 57.3-82.4). The estimates of sensitivity and specificity values of the ELISA were 79.5% and 96.9%.

Background: The aim of this study was to determine antibody titres against Campylobacter, Salmonella, and Yersinia in a population-based cohort of pregnant women in Denmark in order to evaluate adverse pregnancy outcomes (miscarriage, preterm birth, and small for gestational age) in relation to occupational exposure to animals in women exposed to food producing animals., Methods: We used data and blood samples from the Danish National Birth Cohort. Serum samples collected during the first trimester from 192 pregnant women who were occupationally exposed to domestic animals and 188 randomly selected unexposed pregnant women were analysed for IgG, IgM, and IgA antibodies against Campylobacter, Salmonella, and Yersinia. Pregnancy outcomes of interest were identified through the Danish National Patient Register., Results: Women with occupational exposure to animals had significantly higher IgG antibody concentrations against Campylobacter, Salmonella, and Yersinia, whereas they had lower concentrations of IgM and IgA antibodies., Conclusions: Serological markers were not identified as risk factors for adverse pregnancy outcomes, with the exception of elevated concentrations of Salmonella antibodies, which were found to be associated with an increased risk of preterm birth.

Deciphering the principles how pathogenic bacteria adapt their metabolism to a specific host microenvironment is critical for understanding bacterial pathogenesis. The enteric pathogenic Yersinia species Yersinia pseudotuberculosis and Yersinia enterocolitica and the causative agent of plague, Yersinia pestis, are able to survive in a large variety of environmental reservoirs (e.g., soil, plants, insects) as well as warm-blooded animals (e.g., rodents, pigs, humans) with a particular preference for lymphatic tissues. In order to manage rapidly changing environmental conditions and interbacterial competition, Yersinia senses the nutritional composition during the course of an infection by special molecular devices, integrates this information and adapts its metabolism accordingly. In addition, nutrient availability has an impact on expression of virulence genes in response to C-sources, demonstrating a tight link between the pathogenicity of yersiniae and utilization of nutrients. Recent studies revealed that global regulatory factors such as the cAMP receptor protein (Crp) and the carbon storage regulator (Csr) system are part of a large network of transcriptional and posttranscriptional control strategies adjusting metabolic changes and virulence in response to temperature, ion and nutrient availability. Gained knowledge about the specific metabolic requirements and the correlation between metabolic and virulence gene expression that enable efficient host colonization led to the identification of new potential antimicrobial targets.

Like other pathogenic bacteria, Yersinia and Aeromonas species have been continuously co-evolving with their respective hosts. Although the former is a bonafide human pathogen, the latter has gained notararity as an emerging disease-causing agent. In response to immune cell challenges, bacterial pathogens have developed diverse mechanism(s) enabling their survival, and, at times, dominance over various host immune defense systems. The bacterial type three secretion system (T3SS) is evolutionarily derived from flagellar subunits and serves as a vehicle by which microbes can directly inject/translocate anti-host factors/effector proteins into targeted host immune cells. A large number of Gram-negative bacterial pathogens possess a T3SS empowering them to disrupt host cell signaling, actin cytoskeleton re-arrangements, and even to induce host-cell apoptotic and pyroptotic pathways. All pathogenic yersiniae and most Aeromonas species possess a T3SS, but they also possess T2- and T6-secreted toxins/effector proteins. This review will focus on the mechanisms by which the T3SS effectors Yersinia outer membrane protein J (YopJ) and an Aeromonas hydrophila AexU protein, isolated from the diarrheal isolate SSU, mollify host immune system defenses. Additionally, the mechanisms that are associated with host cell apoptosis/pyroptosis by Aeromonas T2SS secreted Act, a cytotoxic enterotoxin, and Hemolysin co-regulated protein (Hcp), an A. hydrophila T6SS effector, will also be discussed.

The research on fast screening methods for antibodies against zoonotic pathogens in slaughter animals is important for food safety in farming and meat-processing industries. As a proof-of-concept study, antibodies against the emerging zoonotic pathogen hepatitis E virus (HEV) and enteropathogenic Yersinia spp. were analyzed in parallel using immobilized recombinant antigens (rAgs) of HEV genotypes 1 and 3 and Yersinia outer protein D (YopD) on a flow-through chemiluminescence immunochip. These rAgs are usually part of commercially available line immunoassays (LIAs) used for human diagnostics. In this study, sera from slaughtered pigs were tested on the microarray analysis platform MCR 3 to detect anti-HEV and anti-Yersinia IgG. The new method was characterized regarding signal reproducibility and specificity. The analytical performance was compared with in-house enzyme-linked immunosorbent assay (ELISA) and a LIA based on recomLine HEV (Mikrogen) or the ELISA test kit pigtype Yersinia Ab (Qiagen), respectively. The immunochip revealed the highest analytical sensitivity and was processed in 9 min automatically on the MCR 3. A comparative screening of swine serum samples from Bavarian slaughterhouses regarding anti-HEV and anti-Yersinia IgG seroprevalence was conducted. By using the LIA, 78% of the sera were tested positive for HEV antibodies. The immunochip and the ELISA identified anti-HEV IgG in 96% and 93% of the tested samples using the O2C-gt1 and O2C-gt3 rAg, respectively. The screening for anti-Yersinia IgG resulted in 86% positive findings using the immunochip and 57% and 48% for the ELISA methods, respectively, indicating a higher detection capability of the new method. Serum samples of slaughtered pigs could be analyzed faster and in an automated way on the microarray analysis platform MCR 3 which shows the great potential of the new immunochip assay format for multiplexed serum screening purposes.

In addition to its well-known pro-inflammatory effects, tumor necrosis factor (TNF) displays anti-inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (T(reg)) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4(+)CD25(+)FoxP3(+) T(reg) cells in the ReA animal model. The number of T(reg) cells as well as the FoxP3 mRNA expression and interleukin (IL)-10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55(-/-) mice vs wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of T(reg) cell in TNFRp55(-/-) was similar to WT mice. To explore the in vivo function of T(reg) cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4(+) T cells from TNFRp55-deficient mice of day 21, into naïve WT or TNFRp55(-/-) mice. When knockout mice were used as recipients we observed higher delayed-type hypersensitivity (DTH) responses and joint inflammation after heat-killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL-17, interferon (IFN)-γ, IL-6, transforming growth factor (TGF)-β1 and IL-12/23p40 and lower IL-10 levels in RLN of paws challenged with HKY in TNFRp55(-/-) recipient mice. In addition, we found that CD4(+) T cells from TNFRp55(-/-) mice controlled antigen-specific IL-12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of T(reg) cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.

Cell death plays a central role in host-pathogen interactions, as it can eliminate the pathogen's replicative niche and provide pro-inflammatory signals necessary for an effective immune response; conversely, cell death can allow pathogens to eliminate immune cells and evade anti-microbial effector mechanisms. In response to developmental signals or cell-intrinsic stresses, the executioner caspases-3 and -7 mediate apoptotic cell death, which is generally viewed as immunologically silent or immunosuppressive. A proinflammatory form of cell death that requires caspase-1, termed pyroptosis, is activated in response to microbial products within the host cytosol or disruption of cellular membranes by microbial pathogens. Infection by the bacterial pathogen Yersinia has features of both apoptosis and pyroptosis. Cell death and caspase-1 processing in Yersinia-infected cells occur in response to inhibition of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ. However, the molecular basis of YopJ-induced cell death, and the role of different death pathways in anti-Yersinia immune responses remain enigmatic. Here, we discuss the role that cell death may play in inducing specific pro-inflammatory signals that shape innate and adaptive immune responses against Yersinia infection.

Brucella has a great impact on health and economy in Syria, thus much effort is being placed on the development of diagnostics and vaccines. In this context, a wide Nanobody "immune" library was previously established, from which several Brucella-specific binders were isolated. One of these camel genetically engineered heavy-chain antibody fragments was referred to as NbBruc02. The precise antigen of NbBruc02 was presumed to be, according to proteomic approaches, the Brucella heat shock protein of 60 kDa (HSP-60). HSP-60, or alternatively named GroEL, is an interesting Brucella immunodominant antigen with important roles in the parasite life cycle, mainly adhesion and penetration during the infection of macrophages. In the present work, the capacity of NbBruc02 to filtrate the native GroEL from Brucella total extract was tested by immunochromatography approach. The interaction between NbBruc02 and its antigen was further confirmed using recombinant GroEL from Brucella. Interestingly, NbBruc02 was able to immunodetect the native as well as the denatured forms of the rGroEL in ELISA and immunoblotting, respectively. In agreement with previously reported data, NbBruc02 was able only to detect the denatured Yersinia rGroEL. Using surface plasmon resonance (SPR) biosensor, NbBruc02 showed a strong interaction, with nanomolar affinity (K (D) = ~10(-8) M), with the native rGroEL of Brucella and not of Yersinia. Because the casual conformational changes in the GroEL 3D structure make the base of its function, NbBruc02 by its ability to recognize a "conformational epitope," could open wide perspectives to study the role of GroEL in Brucella physiology.

In eukaryotic cells, there are two well characterized pathways that regulate translation initiation in response to stress, and each have been shown to be targeted by various viruses. We recently showed in a yeast-based model that the bacterial virulence factor YopJ disrupts one of these pathways, which is centered on the α-subunit of the translation factor eIF2. Here, we show in mammalian cells that induction of the eIF2 signaling pathway occurs following infection with bacterial pathogens and that, consistent with our yeast-based findings, YopJ reduces eIF2 signaling in response to endoplasmic reticulum stress, heavy metal toxicity, dsRNA, and bacterial infection. We demonstrate that the well documented activities of YopJ, inhibition of NF-κB activation and proinflammatory cytokine expression, are both dependent on an intact eIF2 signaling pathway. Unexpectedly, we found that cells with defective eIF2 signaling were more susceptible to bacterial invasion. This was true for pathogenic Yersinia, a facultative intracellular pathogen, as well as for the intracellular pathogens Listeria monocytogenes and Chlamydia trachomatis. Collectively, our data indicate that the highly conserved eIF2 signaling pathway, which is vitally important for antiviral responses, plays a variety of heretofore unrecognized roles in antibacterial responses.

Background: Rapid detection and therapeutic intervention for infectious and emerging diseases is a major scientific goal in biodefense and public health. Toward this end, cytokine profiles in human blood were investigated using a human whole blood ex vivo exposure model, called WEEM., Results: Samples of whole blood from healthy volunteers were incubated with seven pathogens including Yersinia pseudotuberculosis, Yersinia enterocolitica, Bacillus anthracis, and multiple strains of Yersinia pestis, and multiplexed protein expression profiling was conducted on supernatants of these cultures with an antibody array to detect 30 cytokines simultaneously. Levels of 8 cytokines, IL-1α, IL-1β, IL-6, IL-8, IL-10, IP-10, MCP-1 and TNFα, were significantly up-regulated in plasma after bacterial exposures of 4 hours. Statistical clustering was applied to group the pathogens based on the host response protein expression profiles. The nearest phylogenetic neighbors clustered more closely than the more distant pathogens, and all seven pathogens were clearly differentiated from the unexposed control. In addition, the Y. pestis and Yersinia near neighbors were differentiated from the B. anthracis strains., Conclusions: Cluster analysis, based on host response cytokine profiles, indicates that distinct patterns of immunomodulatory proteins are induced by the different pathogen exposures and these patterns may enable further development into biomarkers for diagnosing pathogen exposure.

Intestinal antigen encounter leads to recirculation of antigen-specific plasmablasts via lymphatics and blood back to the intestine. Investigating these gut-originating cells in blood provides a less invasive tool for studying intestinal immune responses, with the limitation that the cells disappear from the circulation in two weeks. No data exist on situations where pathogens persist in the intestine. Patients with Salmonella, Yersinia, or Campylobacter gastroenteritis and volunteers receiving an oral typhoid vaccine were assayed for plasmablasts specific to each subject's own pathogen/antigen weekly until the response faded. In vaccinees, plasmablasts disappeared in two weeks. In gastroenteritis, the response faded 2-3 and 3-7 weeks after the last positive Salmonella or Yersinia stool culture. Even in symptomless patients, pathogens persisting in the intestine keep seeding plasmablasts into the circulation. Assaying these cells might offer a powerful tool for research into diseases in which persisting microbes have a potential pathogenetic significance.

Recent epidemiological evidence has demonstrated that pork is an important source of yersiniosis in humans. Identifying risk factors and potential interventions in swine production that may decrease the risk of pork production contamination during harvest and processing is an important step before controlling Yersinia spp. Therefore, management strategies and production processes that might be associated with fattening pigs testing seropositive for pathogenic Yersinia spp. were investigated in 80 fattening pig farms. Although >70 farm characteristics were included in the risk assessment, there were only a few that seemed to be connected with serological prevalence: housing on a fully slatted floor and the use of municipal water were observed more often in herds with low serological Yersinia prevalence, whereas recurring health problems and a low daily weight gain compared with the mean of the herds included in the study were found in herds with a high prevalence. Besides, the Yersinia prevalence seemed to be inversely proportional to the herds' serological Salmonella status collected in accordance with German legislation. Additionally, the development of the serological Yersinia status of selected herds was assessed over a period of a year to gain knowledge of the dynamics of Yersinia infections in fattening pig herds. Three out of four serological negative herds maintained a low level of Yersinia prevalence, whereas one herd shifted between negative status and a prevalence of 100%. The reason for these considerable fluctuations could not be explained, and there was no direct association with the analyzed risk factors. Further research should be carried out to prove the given risk factors, especially the possible relation to the Salmonella prevalence before implementing a combined zoonoses surveillance and control program.

The lipopolysaccharide (LPS) of strains representing various serotypes of Yersinia enterocolitica and Y. enterocolitica-like bacteria was studied by deoxycholate-PAGE and silver staining analysis. Four main types of LPS were detected based on the O-polysaccharide (O-PS): (i) LPS with homopolymeric O-PS, (ii) LPS with ladder-forming heteropolymeric O-PS, (iii) LPS with single-length O-PS, and (iv) semi-rough LPS without O-PS. Within the first three types, several subvariants were detected. Selected serotypes representing all above LPS types are sensitive to bacteriophage φR1-37 indicating that they share the phage receptor, a hexasaccharide called outer core in Y. enterocolitica O:3. Whereas phage φR1-37-resistant mutants of homopolymeric O-PS have lost only the outer core, those of ladder-forming or single-length O-PS have lost also the O-PS suggesting that in the latter ones the outer core is bridging between O-PS and lipid A-core. This work forms a basis of further structural, biochemical and genetic studies of these LPSs.

The effects of dietary whole cell yeast (Saccharomyces cerevisiae), n-3 HUFA-enriched yeast and treated yeast cells with beta-mercapto-ethanol (2ME) on immunity, growth performance and disease resistance to Yersinia ruckeri were investigated in Oncorhynchus mykiss. During 30 days, juvenile rainbow trout were fed diets supplemented with different forms of yeast at 5 × 10(7) CFU g(-1) or a control diet. After the feeding trial, remaining fish of each treatment were challenged by pathogenic Yersinia ruckeri and kept under observation for 14 days to record clinical signs and daily mortality rate. Yeast supplementation in all treatment groups significantly promoted the growth performance compared to control group. A significantly increase was also observed in immune responses in juvenile fish fed 2ME-treated yeast diet. More ever, the lowest fish mortality was obtained in this treatment group. The present results show that a diet supplemented with 2ME-treated yeast stimulates the immune system and growth of juvenile rainbow trout thus enhancing their resistance against Y. ruckeri., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Multiple antigenic peptides (MAPs), a sequence which include common antigenic epitopes of outer membrane porins (OM) bacteria of the genus Yersinia (Y. pseudotuberculosis, Y. enterocolitica, Y. pestis), pathogenic for humans have been synthesized. After immunization of BALB/c mice the antiserum to the peptide have been obtained. With the help of ELISA we showed that these sera interact with porins isolated from OM pathogenic Yersinia, and MAP interact with antibodies in sera from rabbits immunized with individual porins, and with antibodies in sera of patients with intestinal yersiniosis and pseudotuberculosis.

Bacterial pathogens utilize pore-forming toxins or specialized secretion systems to deliver virulence factors to modulate host cell physiology and promote bacterial replication. Detection of these secretion systems or toxins, or their activities, by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, multiprotein complexes necessary for caspase-1 activation and host defense. Here we demonstrate that caspase-1 activation in response to the Yersinia type III secretion system (T3SS) requires the adaptor ASC and involves both NLRP3 and NLRC4 inflammasomes. Further, we identify a Yersinia type III secreted effector protein, YopK, which interacts with the T3SS translocon to prevent cellular recognition of the T3SS and inflammasome activation. In the absence of YopK, inflammasome sensing of the T3SS promotes bacterial clearance from infected tissues in vivo. These data demonstrate that a class of bacterial proteins interferes with cellular recognition of bacterial secretion systems and contributes to bacterial survival within host tissues., (Copyright 2010 Elsevier Inc. All rights reserved.)

Yersinia species during infection adhere to host immune cells primarily to macrophages and employ its secretary proteins known as Yersinia outer proteins to trigger death in infected cells. In the present study, it is shown that recombinant Yersinia outer protein J (rYopJ) could induce apoptosis in murine peritoneal macrophages in vitro as assessed by morphological features, internucleosomal DNA fragmentation, change in mitochondrial membrane potential (MMP) (Deltapsim), activation of caspases and Annexin V binding. rYopJ-induced cell death was dose and time dependent. Pre-treatment with broad-spectrum caspase inhibitor Z-VAD-FMK, caspase-3 inhibitor Ac-DEVD-CHO and caspase-8 inhibitor Z-IETD-FMK prevented the change in MMP and DNA fragmentation, suggesting caspase-dependent apoptosis of rYopJ-treated macrophages. Blocking the endocytosis by pre-treatment of cells with cytochalasin B did not prevent the rYopJ-induced macrophages apoptosis. The data further suggest that rYopJ-induced apoptosis is mediated by molecules upstream of caspase-8 and relay through mitochondrial pathway involving Bax, Bcl-2, activation of caspase-8 and caspase-3, Bid and polyadenosine diphosphate-ribose polymerase cleavage, cytochrome c release and DNA fragmentation.

The paper presents the results of experiments to elucidate the protection efficiency of secretory antibodies via parenteral and oral inoculation with pathogenic Yersinia in guinea pigs immunized with a polyvalent yersiniasis vaccine designed on the basis of the pseudotuberculosis microbial strain that synthesizes the F1 antigen of a plague microbe. Immunization of guinea pigs with the polyvalent yersiniasis vaccine protects experimental animals against pseudotuberculosis, intestinal yersiniasis, and plague infections.

Diagnosis of Yersinia infections accompanied by reactive arthritis could be complicated by cross-reaction with other arthritogenic bacteria. The possible cross-reaction between Yersinia antigens and anti-Borrelia antibodies in blood sera of patients with Lyme disease was studied. The occurrence of specific IgA, IgG and IgM antibodies was analyzed in serum samples from 30 patients with Yersinia-triggered reactive arthritis, 30 patients with Lyme disease and five samples from healthy blood donors. For anti-Borrelia IgG antibodies, cross-reaction was detected with YopH, YopB, V-ag, YopD, YopN, YopP and YopE, and for IgA with YopD. For IgM, no cross-reaction was detected. Owing to cross-reactivity with Borrelia, the diagnosis of Yersinia-triggered reactive arthritis should be based on a combination of serological and clinical findings.

Unlabelled: The aim of the study was to assess health hazards in Democratic Republic of Congo on the ground of diseases and traumas incidence among soldiers of Polish Military Contingent served in the stabilization mission EUFOR., Material and Methods: Epidemiological analysis was based on the medical documentation of patients treated from June to December 2006., Results: The main health problem among Polish soldiers were gastrointestinal tract diseases (56,0% of all diseases and traumas), respiratory tract (22,9%) and skin diseases (7,4%). Among them acute diarrheas were dominated (they appeared in case of 98 soldiers in 126 examined population). The laboratory examination of homebound Polish soldiers showed pathological results in case of 81 people. Among them, 44 patients had certified the prevalence of Yersinia antibodies IgM--2 people, and IgG--42 people (Y enterocolica or Y pseudotuberculosis). Bacteriological examination of stool in direction of Yersinia spp. was negative., Conclusion: Laboratory examination of Yersinia antibodies before departure of Polish soldiers to Congo was not performed, so it is impossible to certify if infection of yersiniasis appeared in Poland or during military mission abroad. Among any homebound soldiers of Polish Military Contingent contagious or parasitic disease was recorded.

The pathogenic bacteria Yersinia spp. contain a virulence plasmid that encodes a type III secretion system and effectors. During infection, four of the effectors target the actin cytoskeleton, crippling the phagocytic machinery in the infected cell. The remaining two effectors dampen the innate immune response by targeting important signalling pathways. Although the biochemical activity for each of these effectors is known, the mechanisms involved in their ordered secretion and delivery remain elusive.

Protection of rainbow trout fry following bath vaccination with a bacterin of Y. ruckeri O1, the bacterial pathogen causing enteric red mouth disease (ERM), was investigated at 5, 15 and 25 degrees C. Rainbow trout fry were acclimatised for 8 weeks at the three temperatures before vaccination. They were subsequently challenged with Y. ruckeri 4 and 8 weeks post-vaccination which demonstrated a significant protection of vaccinated fish kept at 15 degrees C. No protective effect of vaccination in rainbow trout reared at 5 and 25 degrees C could be recorded. Spleen tissue was sampled from vaccinated and control fish at 0, 8, 24 and 72 h post-vaccination in order to analyse gene transcript profiles using quantitative real-time RT-PCR (q-PCR). Gene expression in fish vaccinated at 15 degrees C (the protected fish) was up-regulated with regard to the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-6 and the anti-inflammatory cytokines IL-10 and TGF-beta, the cell receptors TcR, CD8alpha, CD4, C5aR and the teleost specific immunoglobulin IgT. Passive immunisation using transfer of plasma from vaccinated fish to naïve fish conferred no protection. This indicates that humoral factors such as Ig and complement are less important in the protection induced by bath vaccination. Expression of cellular factors such as CD8alpha was significantly increased in the protected trout and this suggests that cellular factors including cytotoxic T-cells could play a role in immunity against Y. ruckeri.

Attenuated enteropathogenic Yersinia strains are attractive candidates for the development of oral live carrier vaccines. Yersiniae colonize the small intestine and invade lymphoid tissue of the terminal ileum where they replicate extracellularly. Yersiniae can be engineered to secrete or translocate heterologous antigens into the cytosol of antigen-presenting cells by their type 3 secretion system (T3SS). This results in the induction of both cellular and humoral immune responses to heterologous antigens of viral, bacterial and parasitic origin. In this review, we summarize the progress in developing Yersinia-based vaccine carrier strains by mutating the T3SS effector proteins of Yersinia called Yops (Yersinia outer proteins) to both attenuate the strains and to modulate the T-cell response.

The presence of the specific antibodies for some enterobacteria--Yersinia, Salmonella and Shigella was investigated in patients hospitalized in the period 2000-2007 with reactive arthritis and other rheumatoid diseases. The antibacterial antibodies in the diagnosis titres were found in 172 out of 1102 (15.6%) patients. Increased antibodies levels to Yersinia were detected in the sera from 113 (65.7%) of the 172 patients, for Shigella in 47 (27.3%) and for Salmonella in 12 (7.0%) cases. From all serologically positive patients 126 (73.2 %) had clinical diagnosis of reactive arthritis and 46 (26.7%) other rheumatoid diseases (ankylosing spondilytis, Reiter's syndrome, sacroilitis). The most serologically positive cases (63.9%) were of middle-age (30-50 years). There were no significant differences between sexes among serologically positive cases.

Microbial pathogens have developed various stratagems for modulating and/or circumventing the host's innate and adaptive immunity. Hence, certain virulence factors can be viewed as potential therapeutic agents for human immunopathological diseases. This is the case for virulence plasmid-encoded proteins from pathogenic Yersiniae that inhibit the host's inflammatory response by interfering with various cellular signaling pathways.

Low temperatures as well as encounters with host phagocytes are two stresses that have been relatively well studied in many species of bacteria. The exoribonuclease polynucleotide phosphorylase (PNPase) has previously been shown to be required by several species of bacteria, including Yersinia, for low-temperature growth. We have shown that PNPase also enhances the ability of Yersinia to withstand the killing activities of murine macrophages. We have gone on to show that PNPase is required for the optimal functioning of Yersinia's type three secretion system (T3SS), an organelle that injects effector proteins directly into host cells. Surprisingly, the PNPase-mediated effect on T3SS activity is independent of PNPase's ribonuclease activity and instead requires only its S1 RNA-binding domain. In stark contrast, the catalytic activity of PNPase is strictly required for enhanced growth at low temperature. Preliminary experiments suggest that the RNA-binding interface of the S1 domain is critical for its T3SS-enhancing activity. Our findings indicate that PNPase plays versatile roles in promoting Yersinia's survival in response to stressful conditions.

This review is based on the opening lecture I was honored to give during the 9th International Symposium on Yersinia in Lexington, Kentucky in October 2006. I present some topics that have been close to my interest during the past 25 years with some historical anecdotes. For example, how detection of intervening sequences in Yersinia enterocolitica rDNA genes resulted in development of microbial diagnostic applications. How the adhesin YadA was detected and named and what do we know of its function now? What was the first pseudogene sequenced in Yersinia pestis? I will also discuss Yersinia lipopolysaccharide, bacteriophages and serum resistance mechanisms which we have worked on lately.

Rabbit IgG raised against whole cells of Yersinia enterocolitica O:3, O:9 and against a group of pathogenic Y. enterocolitica strains (serotypes O:3, O:5,27, O:8. and O:9) were prepared. The antibody limiting titers were within the range of 1:9.5 x 10(4)-1:7.5 x 10(5). The immunoblotting analysis of Yersinia lipopolysacchides separated by SDS-PAGE showed that IgG against the single serotype O:3 interacted with high-molar-mass LPS of O:3 whereas other antibodies were bound to low-molar-mass LPS of serotypes O:3, O:5,27, O:9 and strain Y. enterocolitica (CNCTC Y 2/68). IgG against the group of pathogenic serotypes also weakly interacted with low-molar-mass LPS of serotypes O:5, O:6,30, and O:10. The cross-reactivity of the antibodies with Y. pseudotuberculosis Ia and/or Y. rohdei b, d, e, f, i, which was observed by means of dot-blotting procedure using the whole bacterial cells as an antigen, was shown not to be caused by LPS of these bacteria. The prepared antibodies were used in the development of indirect competitive ELISA. At the optimum concentration of the immunoreactants the detection limits were within the range of 3-7 x 10(6) colony-forming units per mL.

Objective: In reactive arthritis (ReA), a bacteria-specific T cell response to the triggering microbe is detected in synovial fluid. So far, direct characterization of bacteria-specific T cells and identification of the immunodominant fine specificities remain difficult due to the lack of appropriate techniques. The aim of the present study was to directly determine the fine specificity of CD4+ T cells specific to ReA-associated bacteria-derived protein., Methods: In 2 patients with Yersinia-induced ReA, live Yersinia Hsp60-specific CD4+ T cells were directly isolated from synovial fluid after stimulation with Yersinia-derived protein Hsp60 using a cytometric cytokine secretion assay. Generated short-term T cell lines were then tested in vitro for their peptide epitope specificity. Also, direct cross-reactivity of one line with Chlamydia- and human-derived Hsp60 was assessed., Results: Generated short-term CD4+ T cell lines were highly antigen-specific and revealed single immunodominant peptide epitopes that were confirmed by direct testing with single peptides in both peripheral blood and synovial fluid cells. Yersinia Hsp60-specific T cells of one patient cross-reacted directly with human Hsp60., Conclusion: Our results demonstrate the feasibility of direct assessment of live, potentially pathogenic, antigen-specific interferon-gamma+ CD4+ T cells taken from inflammatory lesions of patients with rheumatic diseases such as ReA. This might have implications not only regarding pathogenesis, but also in the design of new immunotherapies.

Understanding of the aetiological basis of thyroid autoimmunity may be gained by studying the early stages of the disease process. We aimed to (1) investigate the relationship between thyroid antibody status and Yersinia enterocolitica (YE) infection in euthyroid subjects and (2) explore the relative importance of genetic and environmental risk factors in the acquisition of YE infection. The association between thyroid antibody status and YE infection was explored using a case-control design. Furthermore, thyroid antibody-positive twins were compared with their thyroid antibody-negative co-twin. In 468 twins, IgA and IgG antibodies to virulence-associated outer-membrane proteins (YOPs) of YE were measured. Of these, 147 were thyroid antibody-positive (cases). A total of 147 age- and gender-matched twins were chosen as controls. The prevalence of YOP antibodies was lower among thyroid antibody-positive individuals than among controls. Yersinia infection was not associated with a positive thyroid antibody status: the odds ratio (with 95% CI) for YOP IgA-ab was 0.66 (0.42-1.05), P = 0.078 and for YOP IgG-ab it was 0.95 (0.60-1.50), P = 0.816. Within discordant twin pairs, the thyroid antibody-positive twin did not have an increased risk of Yersinia infection compared to the thyroid antibody-negative co-twin [odds ratio: YOP IgA-Ab: 0.94 (0.49-1.83), P = 0.866, and YOP IgG-Ab: 1.35 (0.72-2.53), P = 0.345]; 41% (95% CI 10-67% of the liability of being YOP antibody-positive was due to genetic effects. In conclusion, Yersinia infection does not confer an increased risk of thyroid antibodies. The genetic contribution in the acquisition of Yersinia infection is modest.

The data on the structure and biological activity of the lipopolysaccharide (LPS) of Yersinia as an important virulence factor are analyzed. The biological effects of LPS are characterized by dose dependence: small doses stimulate the intensity of phagocytosis, while large doses decrease phagocytic activity and produce cytotoxic effect. Yersinia LPS plays an important role in the development of such consequences of yersiniosis as reactive arthritis, erythema nodosum, Reiter's syndrome. Yersinia LPS is a widespread component for the diagnostics of yersiniosis and pseudotuberculosis.

In contrast to Salmonella and Shigella, enteropathogenic Yersinia species are extracellular multiplying Gram-negative bacteria. This life style requires a sophisticated anti-host strategy, which is implemented by the Yersinia virulence plasmid. This plasmid encodes the type 3 secretion system (injectisome), at least six microinjected anti-host effector proteins, a trimeric coiled coil outer membrane protein (Yersinia adhesin) with cell adhesin and protective functions against complement and defensins, and the released V antigen, which has Toll-like receptor 2 agonist activity.