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The literature argues that intense political competition may resultin a nation's potential for increased welfare. We theoretically andempirically examine this proposition by linking political competitionto health outcomes in the Indian context. Theoretical analysissuggests that political competitiveness increases the probabilityof having better health outcomes. This analysis also identifiesthat rural areas benefit from more from political competition thanurban areas. In India, the majority of the population (around 70%)resides in rural areas and, therefore, the diversity of ex-ante viewsabout political parties is higher in rural areas compared to urbanareas. In such situations, as competition intensifies, the governmentallocates greater amounts of resources to rural areas to win theelection. Thus, as political competition increases, the probability ofhaving better health outcomes rise in rural areas at a higher rate ascompared to urban areas. Our empirical analysis also exhibits the same. [ABSTRACT FROM AUTHOR]

The dynamics under the joint action of radiation damping and the distant dipolar field in high-field solution magnetic resonance are investigated. Different dynamical regimes during the evolution are identified and their individual features are discussed. In the steady state, the dynamics can be associated with a strange attractor in phase space on which the motion is chaotic. The possibility of the observed chaotic motion being spatiotemporal is examined. [ABSTRACT FROM AUTHOR]

Experimental data indicate that stochastic effects exerted at the level of translation contribute substantially to the variation in abundance of proteins expressed at moderate to high levels. This study analyzes the theoretical consequences of fluctuations in residue-specific elongation rates during translation. A simple analytical framework shows that rate variation during elongation gives rise to protein production rates that consist of sums of products of random variables. Simulations show that because the contribution to total variation of products of random variables greatly exceeds that of sums of random variables, the overall distribution exhibits approximately log-normal behavior. Empirical fits of the data can be satisfied by either sums of log-normal distributions, or sums of log-normal and log-logistic distributions. Elongation rate stochastic variation offers an accounting for a major component of biological variation. The analysis provided here highlights a probability distribution that is a natural extension of the Poisson and has broad applicability to many types of multiplicative noise processes. [ABSTRACT FROM AUTHOR]

The article offers information on Staphylococcus aureus, an infectious agent that was first identified in 1880 by Alexander Ogston, a surgeon from the University of Aberdeen in Scotland. Treatment options for this infection was, for decades, limited to topical application of carbolic acid. In 1940s penicillin was introduced as an effective therapy, but then methicillin-resistant Staphylococcus aureus soon appeared. In recent years, new strains of S. aureus have been recognized.

Cholera toxin (CT) elicits a mucosal immune response in mice when used as a vaccine adjuvant. The mechanisms by which CT exerts its adjuvant effects are incompletely understood. We show that protection against inhalation anthrax by an irradiated spore vaccine depends on CT-mediated induction of IL-17-producing CD4 Th17 cells. Furthermore, IL-17 is involved in the induction of serum and mucosal antibody responses by CT. Thi7 cells induced by CT have a unique cytokine profile compared with those induced by lL-6 and TGF-β, and their induction by CT requires cAMP-dependent secretion of lL-1β and β-calcitonin gene-related peptide by dendritic cells. These findings demonstrate that Th17 cells mediate mucosal adjuvant effects of CT and identify previously unexplored pathways involved in Th17 induction thatcould be targeted for development of unique mucosal adjuvants. [ABSTRACT FROM AUTHOR]

Summary: We evaluated γ-irradiated Listeria monocytogenes as a killed bacterial vaccine, testing the hypothesis that irradiation preserves antigenic and adjuvant structures destroyed by traditional heat or chemical inactivation. Irradiated Listeria monocytogenes (LM), unlike heat-killed LM, efficiently activated dendritic cells via Toll-like receptors and induced protective T cell responses in mice. Like live LM, irradiated LM induced Toll-like-receptor-independent T cell priming. Cross-presentation of irradiated listerial antigens to CD8+ T cells involved TAP- and proteasome-dependent cytosolic antigen processing. These results establish that killed LM can induce protective T cell responses, previously thought to require live infection. γ-irradiation may be potentially applied to numerous bacterial vaccine candidates, and irradiated bacteria could serve as a vaccine platform for recombinant antigens derived from other pathogens, allergens, or tumors. [Copyright &y& Elsevier]

We study a driven quasiperiodic skew-product dynamical mapping in which orbits with all Lyapunov exponents equal to zero lie on fractal attractors. These form a special category of strange nonchaotic attractors (SNAs), and we describe the scenario for their formation as well as methods for their characterization. [ABSTRACT FROM AUTHOR]

Cross-presentation is the pathway by which exogenous antigens are routed for presentation on MHC class I for activation of CD8+ T cells. This pathway is important for the development of CD8+ cytotoxic T lymphocyte responses against tumors and infectious pathogens that do not directly infect APC. We review studies showing that certain Toll-like receptors mediate cross-presentation by dendritic cells, initiating cytosolic processing of antigen after inducing dendritic cell maturation. The implications of these studies for understanding CD8+ T cell activation and implementing novel vaccine strategies is considered. [ABSTRACT FROM AUTHOR]

Conjugation of protein antigen with immunostimulatory oligonucleotides creates a potent immunogen. Physical linking of oligonucleotides to antigen enhances antigen uptake and targets the adjuvant properties of the oligonucleotides to the antigen-presenting cell. In addition, the conjugated oligonucleotides appear to have improved immunostimulatory abilities compared to free oligonucleotides, presumably due to enhanced activation of Toll-like receptor 9. Immunization with these conjugate preparations elicits antigen-specific antibody responses, a T-helper cell 1-biased cytokine profile from CD4 T cells, and CD8 cytotoxic T-lymphocyte activity that is CD4 independent. The humoral and cellular immune responses induced by these conjugates suggest they can be used to create effective vaccines against infectious pathogens and tumors and to beneficially modulate allergic responses. Indeed, recent clinical trial data show symptom relief and immunomodulation of the allergic response in patients with allergic rhinitis. This review considers the mechanisms of action of antigen–oligonucleotide conjugates and discusses available data regarding their use for the prevention and treatment of infectious, oncologic, and allergic diseases. [ABSTRACT FROM AUTHOR]

In intermittent dynamical systems, the distributions of local Lyapunov exponents are markedly non-Gaussian and tend to be asymmetric and fat-tailed. A comparative analysis of the different time-scales in intermittency provides a heuristic explanation for the origin of the exponential tails, for which we also obtain an analytic expression deriving from a more quantitative theory. Application is made to several examples of discrete dynamical systems displaying intermittent dynamics. [ABSTRACT FROM AUTHOR]

In-spite of being the largest democracy in the world, Indian states are spending only around 1% of net state domestic product on public healthcare which is way lower than the world average. This low level of public healthcare spending resulted in a high out of pocket healthcare spending and poor health outcome in India. But democratically elected governments are responsible for spending significant amount of their budget on healthcare for the benefit of the masses. It is generally believed that, in a democracy, political competition drives the elected government to spend more on healthcare, education, infrastructure, etc. for the welfare of the citizens. This is especially true in developing countries, like India, where a significant section of population is poor. We empirically argue that intense political competition forces the incumbent government to spend more on public healthcare in order to win the election. Empirical analysis is done by creating a state level panel of 16 major Indian states, covering a span of two decades (1991–2011). • Political competition increases the public healthcare expenditure in India. • Higher level of electoral turnout compels government to spend more on healthcare. • Political Decentralization increases public healthcare expenditure in India. • Poor healthcare condition leads to high public healthcare spending. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. However, host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20, and -24 signal through STAT3-dependent type I and type II IL-20 receptors and have been associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We hypothesized these cytokines may play a role in S. aureus skin infections. We show here that this family of cytokines promotes cutaneous S. aureus infection in mice by STAT3-dependent mechanisms that down-regulate IL-1 beta- and IL-17A-dependent inflammatory pathways required for control of infection. Inhibition of IL-1 beta by these cytokines was consistent with their demonstrated rapid inactivating sumoylation of C/EBP beta, a transcriptional activator of IL-1 beta. Similar effects of these cytokines were seen in human keratinocytes after S. aureus exposure, and antibody blockade of IL-20 receptor signaling improved infectious outcomes in mice. Our findings identify an immunosuppressive role for these cytokines during infection that may be therapeutically targeted to alter infectious susceptibility. [ABSTRACT FROM AUTHOR]

Neutrophils possess multiple antimicrobial mechanisms that are critical for protection of the host against infection with extracellular microbes, such as the bacterial pathogen Staphylococcus aureus. Recruitment and activation of neutrophils at sites of infection are driven by cytokine and chemokine signals that directly target neutrophils via specific cell surface receptors. The IL-20 subfamily of cytokines has been reported to act at epithelial sites and contribute to psoriasis, wound healing, and antiinflammatory effects during S. aureus infection. However, the ability of these cytokines to directly affect neutrophil function remains incompletely understood. In this article, we show that human neutrophils altered their expression of IL-20R chains upon migration and activation in vivo and in vitro. Such activation of neutrophils under conditions mimicking infection with S. aureus conferred responsiveness to IL-20 that manifested as modification of actin polymerization and inhibition of a broad range of actindependent functions, including phagocytosis, granule exocytosis, and migration. Consistent with the previously described homeostatic and anti-inflammatory properties of IL-20 on epithelial cells, the current study provides evidence that IL-20 directly targets and inhibits key inflammatory functions of neutrophils during infection with S. aureus. [ABSTRACT FROM AUTHOR]

Interleukin (IL) 17-secreting CD4+ helper T cells (Th17 cells) are essential for host defense at mucosal surfaces, and Th17 cell dysregulation can result in autoimmunity. Exposure to microbial products, such as bacterial LPS, can affect the ability of dendritic cells (DCs) to polarize Th17 cells. Acyloxyacyl hydrolase (AOAH) is a mammalian enzyme expressed by antigen (Ag)-presenting cells that deacylates and thereby inactivates LPS in host tissues. We hypothesized that inactivation of intestinal microbiota-derived LPS by AOAH influences the ability of DCs to polarize and generate Th17 effector cells. We found that LPS-containing Gram-negative microbiota augmented the differentiation of Ag-specific Th17 cells, and identified a colonic DC subset (CD103+CD11b+ALDH−) displaying a unique capacity to both express AOAH and polarize Th17 cells. Compared with WT, these Aoah−/− colonic DCs produce less IL-6, resulting in diminished Ag-specific Th17 polarization and increased regulatory T-cell induction in vitro. Oral administration of LPS led to reduced IL-6 production from CD103+CD11b+ALDH− colonic DCs in Aoah−/− mice compared with Aoah+/+ mice, resulting in an abrogated Ag-specific Th17 response in the colon after mucosal immunization that could be rescued by systemic delivery of recombinant IL-6. These data identify the ability of AOAH to modulate microbiota signals that drive Th17 polarization and influence mucosal T-cell immunity, and suggest that host pathways to handle microbiota-derived products may be targeted to modulate Th17 responses in the context of inflammatory disorders or infection at mucosal surfaces. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection is characterized by infiltration of cells of the immune system, including dendritic cells, into the gastric mucosa. During chronic inflammation with Helicobacter pylori infection, a variety of cytokines are secreted into the mucosa, including interleukin-1β (IL-1β). The role of IL-1 in H. pylori infection was investigated using bone-marrow-derived dendritic cells from wild-type and IL-1 receptor-deficient (IL-1R−/−) mice. Dendritic cells were incubated with H. pylori at a multiplicity of infection of 10 and 100, and cytokine production evaluated. Helicobacter pylori SS1, H. pylori SD4, and an isogenic cagE mutant of SD4 stimulated IL-12, IL-6, IL-1β, IL-10, and tumor necrosis factor-alpha at comparable levels in dendritic cells from both wild-type and IL-1R−/− mice. IL-10 production required the higher inoculum, while IL-12 was decreased at this bacterial load. Pretreatment of dendritic cells with an antibody to IL-10 resulted in an increased production of IL-12, confirming the down-regulation of IL-12 by IL-10. cagE was required for maximum stimulation of IL-12 by H. pylori. We speculate that the down-regulation of IL-12 by IL-10 at the higher multiplicity of infection represents the modulation of the host inflammatory response in vivo by H. pylori when the bacterial load is high, allowing for persistent colonization of the gastric mucosa. [ABSTRACT FROM AUTHOR]

Abstract: Coccidioides immitis is endemic in the soil of the desert Southwest. It causes a respiratory infection that is usually mild, but can last months and may disseminate beyond the lung. Disseminated infections can be fatal or require life-long therapy. Development of an effective vaccine may be a successful method of preventing serious disease. In this paper, we show that immunostimulatory-oligodeoxynucleotides (ISS-ODN) are an effective adjuvant for a recombinant coccidioidal protein known as antigen 2/proline rich antigen. Protective immunity induced by this ISS-ODN-based vaccine requires IL-12, interferon-γ and MHC Class II-restricted T-cells. Cytotoxic CD8 T-cells are not required. This study elucidates the mechanisms needed to elicit successful immunity against coccidioidomycosis, and holds promise for development of an effective coccidioidal vaccine against coccidioidomycosis. [Copyright &y& Elsevier]

Abstract: Immunostimulatory DNA sequences and their synthetic oligonucleotide analogs (CpG-ODN) activate innate immunity and can stimulate antibacterial effects against numerous intracellular pathogens. While it has been shown previously that CpG-ODN inhibit growth of Mycobacterium avium in murine and human macrophages, we now report that Mycobacterium tuberculosis growth can be inhibited by CpG-ODN treatment of human monocyte-derived macrophages (hMDM). This inhibitory effect was reversed by IFN-γ, which has been shown repeatedly to enhance the growth of virulent M. tuberculosis in cultured hMDM. The antibacterial effect of CpG-ODN in human macrophages was specific for M. tuberculosis when compared to other intracellular pathogens including Listeria monocytogenes and Salmonella enterica serovar Dublin. These data indicate that CpG-ODN can improve the ability of hMDM to contain growth of virulent M. tuberculosis. [Copyright &y& Elsevier]

Immunostimulatory DNA sequences and their synthetic oligonucleotide analogs (CpG-ODN) activate innate immunity and can stimulate antibacterial effects against numerous intracellular pathogens. While it has been shown previously that CpG-ODN inhibit growth of Mycobacterium avium in murine and human macrophages, we now report that Mycobacterium tuberculosis growth can be inhibited by CpG-ODN treatment of human monocyte-derived macrophages (hMDM). This inhibitory effect was reversed by IFN-c, which has been shown repeatedly to enhance the growth of virulent M. tuberculosis in cultured hMDM. The antibacterial effect of CpG-ODN in human macrophages was specific for M. tuberculosis when compared to other intracellular pathogens including Listeria monocytogenes and Salmonella enterica serovar Dublin. These data indicate that CpG-ODN can improve the ability of hMDM to contain growth of virulent M. tuberculosis. [ABSTRACT FROM AUTHOR]

Keratinocytes are the most abundant cell type in the epidermis. They prevent desiccation and provide immunological and barrier defense against potential pathogens such as Staphylococcus aureus and Candida albicans. The study of this first line of immune defense may be hindered by invasive isolation methods and/or improper culture conditions to support stem cell maintenance and other potential mechanisms contributing to long-term subcultivation in vitro. Primary keratinocytes have been successfully isolated from blister roofs induced by negative pressure, which separates the epidermis from the dermis in vivo in human subjects. This method allows collection of pure epidermal cells without dermal contamination in a minimally invasive manner. However, the isolated keratinocytes differentiate and senesce when cultured in vitro beyond five passages. Here, we present evidence that the Rho kinase (ROCK) inhibitor Y-27632 can be used to effectively increase the proliferative capabilities of keratinocytes isolated using the suction blister method, similar to what has been previously reported for primary keratinocytes isolated using alternative methods. We show that the increase in passage number is directly correlated to delayed differentiation, and that cells passaged long term with the inhibitor retain their ability to stratify in organotypic raft cultures and respond to cytokine treatment; additionally, the late passage cells have a heterogeneous mix of differentiated and non-differentiated cells which may be predicted by a ratio of select differentiation markers. The described method presents a minimally invasive procedure for keratinocyte isolation and prolonged culture that allows analysis of keratinocyte function in both healthy volunteers and patients with dermatologic diseases. [ABSTRACT FROM AUTHOR]

Objectives This study measures the prevalence of risk factors among pregnant women and young children aged 12-24 months in a rural community in West Bengal, India. Methods Community health workers (CHWs) enrolled women and children into this 2015 cross-sectional study. Pregnant women were evaluated for underweight, anemia, and abnormal blood pressure. Children were evaluated for underweight, abnormal head and upper arm circumferences, and low scores from the Ages and Stages Questionnaire (ASQ). Data were collected on smartphones and tablets or by paper. Results More than half of the 279 women (59.9%) had a risk factor during pregnancy: 48.7% were anemic, 35.1% had low blood pressure, and 7.5% were underweight. Among the 366 children, 59.3% had a risk factor, including 24.0% with low ASQ scores and 49.7% who had abnormal anthropometric measures. Conclusions for Practice Vulnerable populations, such as pregnant women and young children, needed a greater connection to doctors in this rural community. This study demonstrated the feasibility of CHWs to listen to health concerns and connect underserved populations with health care services. [ABSTRACT FROM AUTHOR]

Background: Community health workers (CHWs) have been placed in many rural areas in India to increase villagers’ connections to basic preventive health care. In this study, we describe how pregnant women and mothers of young children react when CHWs inform them that they, or their child, are at high risk of pregnancy-related complications or early childhood developmental delays, and further screening and health care from a physician is recommended. Methods: In this longitudinal study in rural villages in West Bengal, India, pregnant mothers, as well as mothers of children aged 12–24 months, were screened for high risk complications. They were re-contacted and asked questions regarding how and to what extent did visits by the CHWs improve their household’s overall health behavior, along with details about what additional care, if any, they sought. These responses are presented by different demographic and medical characteristics. Results: Of the 231 pregnant women, all said they had sought additional care in response to the CHW visit, and all stated that feedback from the CHW resulted in improvement to their health behaviors. Most (90%) pregnant women gave birth at an institution. Among the 213 mothers of young children who were followed up, all sought additional care in response to the CHW’s visit. Most (67%) mentioned that they had a significant improvement in their health behaviors following feedback from the CHW, and the rest stated that they had some improvement. Conclusions: With the proper training, CHWs can be partners in health care to improve the health of vulnerable populations, not only in rural areas of India, but also in other developing countries. CHWs can promote positive health outcomes in their villages of residence. [ABSTRACT FROM AUTHOR]

Multiple candidate vaccines against Staphylococcus aureus infections have failed in clinical trials. Analysis of a recent prematurely halted vaccine trial revealed increased mortality rates among vaccine recipients in whom postsurgical S. aureus infection developed, emphasizing the potential for induction of detrimental immune responses and the need to better understand the requirements for protective immunity against S. aureus. These failures of single-antigen vaccines have prompted ongoing development of multicomponent vaccines to target the multitude of S. aureus virulence factors. In the current study, we used lethally irradiated S. aureus as a model multicomponent vaccine and showed that vaccination of mice decreased survival in a bacteremia challenge model. These deleterious effects were due to a CD4 T-cell-dependent interferon γ response and could be prevented by inhibiting development of this response during vaccination. Our results identify the potential for vaccination to induce pathological immune responses, and they have implications for recent vaccine failures and the design of future staphylococcal vaccines. [ABSTRACT FROM AUTHOR]

Background: Commensal Gram-negative (CGN) microbiota have been identified on human skin by DNA sequencing; however, methods to reliably culture viable Gram-negative skin organisms have not been previously described. Results: Through the use of selective antibiotics and minimal media we developed methods to culture CGN from skin swabs. We identified several previously uncharacterized CGN at the species level by optimizing growth conditions and limiting the inhibitory effects of nutrient shock, temperature, and bacterial competition, factors that may have previously limited CGN isolation from skin cultures. Conclusions: Our protocol will permit future functional studies on the influences of CGN on skin homeostasis and disease. [ABSTRACT FROM AUTHOR]

Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans. [ABSTRACT FROM AUTHOR]

The response to multi-drug resistant bacterial infections must be a global priority. While mounting resistance threatens to create what the World Health Organization has termed a “post-antibiotic era”, the recent discovery that antibiotic use may adversely impact the microbiome adds further urgency to the need for new developmental approaches for anti-pathogen treatments. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, has declared itself a serious threat within the United States and abroad. A potential solution to the problem of antibiotic resistance may not entail looking to the future for completely novel treatments, but instead looking into our history of bacteriophage therapy. This study aimed to test the efficacy, safety, and commercial viability of the use of phages to treat Staphylococcus aureus infections using the commercially available phage SATA-8505. We found that SATA-8505 effectively controls S. aureus growth and reduces bacterial viability both in vitro and in a skin infection mouse model. However, this killing effect was not observed when phage was cultured in the presence of human whole blood. SATA-8505 did not induce inflammatory responses in peripheral blood mononuclear cultures. However, phage did induce IFN gamma production in primary human keratinocyte cultures and induced inflammatory responses in our mouse models, particularly in a mouse model of chronic granulomatous disease. Our findings support the potential efficacy of phage therapy, although regulatory and market factors may limit its wider investigation and use. [ABSTRACT FROM AUTHOR]

The “Western diet” is characterized by increased intake of saturated and omega-6 (n−6) fatty acids with a relative reduction in omega-3 (n−3) consumption. These fatty acids can directly and indirectly modulate the gut microbiome, resulting in altered host immunity. Omega-3 fatty acids can also directly modulate immunity through alterations in the phospholipid membranes of immune cells, inhibition of n−6 induced inflammation, down-regulation of inflammatory transcription factors, and by serving as pre-cursors to anti-inflammatory lipid mediators such as resolvins and protectins. We have previously shown that consumption by breeder mice of diets high in saturated and n−6 fatty acids have inflammatory and immune-modulating effects on offspring that are at least partially driven by vertical transmission of altered gut microbiota. To determine if parental diets high in n−3 fatty acids could also affect offspring microbiome and immunity, we fed breeding mice an n−3-rich diet with 40% calories from fat and measured immune outcomes in their offspring. We found offspring from mice fed diets high in n−3 had altered gut microbiomes and modestly enhanced anti-inflammatory IL-10 from both colonic and splenic tissue. Omega-3 pups were protected during peanut oral allergy challenge with small but measurable alterations in peanut-related serologies. However, n−3 pups displayed a tendency toward worsened responses during E. coli sepsis and had significantly worse outcomes during Staphylococcus aureus skin infection. Our results indicate excess parental n−3 fatty acid intake alters microbiome and immune response in offspring. [ABSTRACT FROM AUTHOR]

Mechanisms underlying modern increases in prevalence of human inflammatory diseases remain unclear. The hygiene hypothesis postulates that decreased microbial exposure has, in part, driven this immune dysregulation. However, dietary fatty acids also influence immunity, partially through modulation of responses to microbes. Prior reports have described the direct effects of high-fat diets on the gut microbiome and inflammation, and some have additionally shown metabolic consequences for offspring. Our study sought to expand on these previous observations to identify the effects of parental diet on offspring immunity using mouse models to provide insights into challenging aspects of human health. To test the hypothesis that parental dietary fat consumption during gestation and lactation influences offspring immunity, we compared pups of mice fed either a Western diet (WD) fatty acid profile or a standard low-fat diet. All pups were weaned onto the control diet to specifically test the effects of early developmental fat exposure on immune development. Pups from WD breeders were not obese or diabetic, but still had worse outcomes in models of infection, autoimmunity, and allergic sensitization. They had heightened colonic inflammatory responses, with increased circulating bacterial LPS and muted systemic LPS responsiveness. These deleterious impacts of the WD were associated with alterations of the offspring gut microbiome. These results indicate that parental fat consumption can leave a "lard legacy" impacting offspring immunity and suggest inheritable microbiota may contribute to the modern patterns of human health and disease. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1β- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection. [ABSTRACT FROM AUTHOR]

Summary: T helper 17 (Th17) cells play an important role in mucosal host defense through production of the signature cytokines IL-17 and IL-22. Prostaglandin E2 (PGE2) has been shown to enhance IL-17 production by mature Th17 cells. However, when present during Th17 cell differentiation, we found that PGE2 inhibited the transcription factor IRF4 and suppressed production of IL-17 but not IL-22. We show that IRF4 was required for IL-17 expression but inhibited IL-22 expression, highlighting the potential for discordant regulation of these two cytokines in Th17 cells. The pathogenic fungus Cryptococcus neoformans produces PGE2, and we found that it uses PGE2- and IRF4-dependent mechanisms to specifically inhibit induction of IL-17 during Th17 cell differentiation. Blockade of host PGE2 during infection led to increased IL-17 production from CD4+ T cells and increased survival of mice. These findings suggest that host- or pathogen-derived PGE2 can act directly on Th17 cells during differentiation to inhibit IL-17-dependent antimicrobial responses. [Copyright &y& Elsevier]

TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10-/-Tlr4-/- mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10-/- and Il10-/-Tlr9-/- mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10-/-Tlr4-/- CD4+ T cells into Rag1-/- recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10-/- CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses. [ABSTRACT FROM AUTHOR]

Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Spores of Bacillus subtilis are encased in a protein coat composed of ∼80 different proteins. Recently, we reconstituted the basement layer of the coat, composed of two structural proteins (SpoVM and SpoIVA) around spore-sized silica beads encased in a lipid bilayer, to create synthetic spore-like particles termed 'SSHELs'. We demonstrated that SSHELs could display thousands of copies of proteins and small molecules of interest covalently linked to SpoIVA. In this study, we investigated the efficacy of SSHELs in delivering vaccines. We show that intramuscular vaccination of mice with undecorated one micron-diameter SSHELs elicited an antibody response against SpoIVA. We further demonstrate that SSHELs covalently modified with a catalytically inactivated staphylococcal alpha toxin variant (HlaH35L), without an adjuvant, resulted in improved protection against Staphylococcus aureus infection in a bacteremia model as compared to vaccination with the antigen alone. Although vaccination with either HlaH35L or HlaH35L conjugated to SSHELs similarly elicited the production of neutralizing antibodies to Hla, we found that a subset of memory T cells was differentially activated when the antigen was delivered on SSHELs. We propose that the particulate nature of SSHELs elicits a more robust immune response to the vaccine that results in superior protection against subsequent S. aureus infection. [ABSTRACT FROM AUTHOR]