Repertoire of Escherichia coli agonists sensed by innate immunity receptors of the bovine udder and mammary epithelial cells

Escherichia coli is a frequent cause of clinical mastitis in dairy cows. It has been shown that a prompt response of the mammary gland after E. coli entry into the lumen of the gland is required to control the infection, which means that the early detection of bacteria is of prime importance. Yet, apart from lipopolysaccharide (LPS), little is known of the bacterial components which are detected by the mammary innate immune system. We investigated the repertoire of potential bacterial agonists sensed by the udder and bovine mammary epithelial cells (bMEC) during E. coli mastitis by using purified or synthetic molecular surrogates of bacterial agonists of identified pattern-recognition receptors (PRRs). The production of CXCL8 and the influx of leucocytes in milk were the readouts of reactivity of stimulated cultured bMEC and challenged udders, respectively. Quantitative PCR revealed that bMEC in culture expressed the nucleotide oligomerization domain receptors NOD1 and NOD2, along with the Toll-like receptors TLR1, TLR2, TLR4, and TLR6, but hardly TLR5. In line with expression data, bMEC proved to react to the cognate agonists C12-iE-DAP (NOD1), Pam3CSK4 (TLR1/2), Pam2CSK4 (TLR2/6), pure LPS (TLR4), but not to flagellin (TLR5). As the udder reactivity to NOD1 and TLR5 agonists has never been reported, we tested whether the mammary gland reacted to intramammary infusion of C12-iE-DAP or flagellin. The udder reacted to C12-iE-DAP, but not to flagellin, in line with the reactivity of bMEC. These results extend our knowledge of the reactivity of the bovine mammary gland to bacterial agonists of the innate immune system, and suggest that E. coli can be recognized by several PRRs including NOD1, but unexpectedly not by TLR5. The way the mammary gland senses E. coli is likely to shape the innate immune response and finally the outcome of E. coli mastitis

Investigating the contribution of IL-17A and IL-17F to the host response during Escherichia coli mastitis

Mastitis remains a major disease of cattle with a strong impact on the dairy industry. There is a growing interest in understanding how cell mediated immunity contributes to the defence of the mammary gland against invading mastitis causing bacteria. Cytokines belonging to the IL-17 family, and the cells that produce them, have been described as important modulators of the innate immunity, in particular that of epithelial cells. We report here that expression of IL-17A and IL-17F genes, encoding two members of the IL-17 family, are induced in udder tissues of cows experimentally infected with Escherichia coli. The impact of IL-17A on the innate response of bovine mammary epithelial cells was investigated using a newly isolated cell line, the PS cell line. We first showed that PS cells, similar to primary bovine mammary epithelial cells, were able to respond to agonists of TLR2 and to LPS, provided CD14 was added to the culture medium. We then showed that secretion of CXCL8 and transcription of innate immunity related-genes by PS cells were increased by IL-17A, in particular when these cells were stimulated with live E. coli bacteria. Together with data from the literature, these results support the hypothesis that IL-17A and IL-17 F could play an important role in mediating of host-pathogen interactions during mastitis

Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease

From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria

Evaluation of a knowledge translation strategy to improve policymaking and practices in health promotion and disease prevention setting in French regions: TC-REG, a realist study

OBJECTIVE: This paper presents the results of a realist evaluation of a knowledge translation (KT) intervention implemented in the field of health promotion and disease prevention at the local level in France. DESIGN: Realist evaluation study. SETTING: The target population comprised decision-makers and field professionals working in prevention and public health services operating in regions of France (ie, ARS (Agence Régionale de Santé: regional health agency), IREPS (Instance Régionale d'Education et de Promotion de la Santé pour tous: regional organisation for health promotion and education) and their partners). PARTICIPANTS: This evaluation was based on data collected from 2 seminars, 82 interviews, 18 observations and 4 focus groups over 18 months. INTERVENTION: The TC-REG intervention aimed to increase the use of evidence in cancer prevention, health promotion and disease prevention across four geographical regions in France. The intervention combined various activities: Supporting access to and adaptation of usable evidence, strengthening professionals' skills in analysing, adopting and using policy briefs, and facilitating the use of evidence in organisations and processes. RESULTS: The collected data was used to define favourable/unfavourable contexts for the use of scientific data and mechanisms to be activated to encourage the use of scientific knowledge. From these raw results eight final refined middle-range theories were defined. Organised around the mechanisms to be activated, these middle-range theories illustrate how to activate knowledge and under what conditions. These analyses provided a basis for the production of seven operational and contextualised recommendations to develop KT to inform regional policymaking regarding health promotion and disease prevention. CONCLUSION: The results obtained from the analyses led us to formulate two perspectives of an operational nature for the benefit of those involved in prevention and health promotion

Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria

FcεR1-expressing neutrophils accumulate in the brain of mice infected with Plasmodium berghei (PbANKA) and promote the development of experimental cerebral malaria

Molecular biology of histidine decarboxylase and prostaglandin receptors

Histamine and prostaglandins (PGs) play a variety of physiological roles as autacoids, which function in the vicinity of their sources and maintain local homeostasis in the body. They stimulate target cells by acting on their specific receptors, which are coupled to trimeric G proteins. For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses. We cloned the cDNAs for mouse l-histidine decarboxylase (HDC) and 6 mouse prostanoid receptors (4 PGE2 receptors, PGF receptor, and PGI receptor). We then characterized the expression patterns and functions of these genes. Furthermore, we established gene-targeted mouse strains for HDC and PG receptors to explore the novel pathophysiological roles of histamine and PGs. We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors

Int J Environ Res Public Health

This scoping study aims to explore the relationships between urban green spaces (UGSs) and the onset, remission and recovery of cancer. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (protocol published in 2018). Eligibility criteria for papers were: (1) to be concerned with UGSs, (2) reporting effects of UGSs on cancer-related outcomes including direct or indirect measures, (3) reporting randomized controlled trials, prospective cohort studies, case studies, observational studies, non-comparative studies, (4) in English or French. The search covered primary studies in the published and unpublished (grey) literatures searching by hand and electronic databases (MEDLINE, Green File, Cumulative Index to Nursing and Allied Health Literature and ScienceDirect). Among 1703 records screened by two reviewers independently, 29 were included for qualitative synthesis. We classify the cancers concerned and the effects reported i.e., protective effect, risk or without association. The most investigated cancers are bladder, breast and lung cancer. Our study also identified contributing factors and their mediating effects between UGSs and cancer. Even though the strength of the evidence of the associations between UGSs and cancer is still weak due to the low number of studies and their design, results highlight the wide variety of possible mediating factors between the use of green spaces and cancer occurrence, remission and/or prevention. Knowledge gaps and future research perspectives should be oriented to qualitative research on protective factors with an attention to equity in UGS access and use

Streptococcus uberis strains isolated from the bovine mammary gland evade immune recognition by mammary epithelial cells, but not of macrophages

Streptococcus uberis is frequently isolated from the mammary gland of dairy cattle. Infection with some strains can induce mild subclinical inflammation whilst others induce severe inflammation and clinical mastitis. We compared here the inflammatory response of primary cultures of bovine mammary epithelial cells (pbMEC) towards S. uberis strains collected from clinical or subclinical cases (seven strains each) of mastitis with the strong response elicited by Escherichia coli. Neither heat inactivated nor live S. uberis induced the expression of 10 key immune genes (including TNF, IL1B, IL6). The widely used virulent strain 0140J and the avirulent strain, EF20 elicited similar responses; as did mutants defective in capsule (hasA) or biofilm formation (sub0538 and sub0539). Streptococcus uberis failed to activate NF-κB in pbMEC or TLR2 in HEK293 cells, indicating that S. uberis particles did not induce any TLR-signaling in MEC. However, preparations of lipoteichoic acid (LTA) from two strains strongly induced immune gene expression and activated NF-κB in pbMEC, without the involvement of TLR2. The immune-stimulatory LTA must be arranged in the intact S. uberis such that it is unrecognizable by the relevant pathogen receptors of the MEC. The absence of immune recognition is specific for MEC, since the same S. uberis preparations strongly induced immune gene expression and NF-κB activity in the murine macrophage model cell RAW264.7. Hence, the sluggish immune response of MEC and not of professional immune cells to this pathogen may aid establishment of the often encountered belated and subclinical phenotype of S. uberis mastitis