Mannose-Binding Lectin Regulates Host Resistance and Pathology during Experimental Infection with Trypanosoma cruzi

Mannose-binding lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas’ disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. In this study we employed MBL−/− mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas’ disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL−/− mice compared to WT controls. This was associated with reduced systemic levels of IL-12/23p40 in MBL−/− mice. Importantly, MBL−/− mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen

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MyD88 signalling in myeloid cells is sufficient to prevent chronic mycobacterial infection

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis that is responsible for almost 1.5 million deaths per year. Sensing of mycobacteria by the host's immune system relies on different families of receptors present on innate immune cells. Amongst them, several members of the TLR family are involved in the activation of immune cells by mycobacteria, yet the in vivo contribution of individual TLRs to the protective immune response remains controversial. On the contrary, MyD88, the adaptor molecule for most TLRs, plays a non-redundant role in the protection against tuberculosis and mice with a complete germline deletion of MyD88 succumb very early to infection. MyD88 is expressed in both immune and non-immune cells, but it is not clear whether control of mycobacteria requires ubiquitous or cell-type specific MyD88 expression. Therefore, using novel conditional switch-on mouse models, we aimed to investigate the importance of MyD88 signalling in DCs and macrophages for the induction of protective effector mechanisms against mycobacterial infection. We conclude that specific reactivation of MyD88 signalling in CD11c- or lysozyme M-expressing myeloid cells during Mycobacterium bovis Bacille Calmette-Guerin infection is sufficient to restore systemic and local inflammatory cytokine production and to control pathogen burden.Fil: Berod, Luciana. Helmholtz Centre for Infection Research; Alemania. Medical School Hanover; AlemaniaFil: Stüve, Philipp. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Swallow, Maxine. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Arnold Schrauf, Catharina. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Kruse, Friederike. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Gentilini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Helmholtz Centre for Infection Research; Alemania. Medical School Hanover; AlemaniaFil: Freitag, Jenny. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Holzmann, Bernhard. Universitat Technical Zu Munich; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Sparwasser, Tim. Medical School Hanover; Alemania. Helmholtz Centre for Infection Research; Alemani

Interferons in immunity to chlamydia pneumoniae

The cytokine IFN-gamma is the architect behind an amazing immunological program of host resistance to intracellular bacterial and protozoan infections. IFN-gamma activates macrophages, making them into inhospitable habitats for parasites attempting to grow inside them. The family of obligate intracellular Gram-negative bacteria Chlamydia is an example of such pathogens. The overall aim of this thesis was to unravel resistance to infection with the human respiratory pathogen C. pneumoniae. Specific focus was placed on innate immune responses to C. pneumoniae and the regulation and role of IFN-gamma in the outcome of infection. An experimental mouse model of lung infection and a macrophage model of in vitro infection were used for this purpose. A protective role for infection-induced IFN-gamma in restricting C. pneumoniae growth in vivo was observed, though IFN-gamma was not required for resolution of infection. IL-12 and/or IL-23 was a necessary but not an absolute requirement for expression of IFN-gamma. IFN-gamma-dependent protection was in part mediated by iNOS expression. TNF-alpha, known to be synergistic with IFN-gamma, was not required for restricting Chlamydial growth. Innate immune cells in the lung constituted an important source of IFN-gamma and were essential for restricting C. pneumoniae growth and for containment of bacteria in the lungs. However, NK cells were not implicated in such protective IFN-gamma release. On the other hand, lung macrophages isolated from C.pneumoniae-infected mice expressed IFN-gamma. Moreover, bone marrow-derived macrophages (BMMphi) conferred upon transfer to RAG-1-/-/IFN-gamma-/-mice, enhanced resistance to C. pneumoniae infection via their ability to release IFN-gamma. Innate IFN-gamma was however not required for protection conferred by CD4+ or CD8+ T cells. Innate and T cell-derived IFN-gamma are also non-redundant (complementary) in protesting mice against C. pneumoniae. C. pneumoniae-infected BMMphi also expressed IFN-gamma in vitro. Such IFN-gamma release was IL-12independent but required instead IFN-alpha/beta and restricted Chlamydial growth. IFN-alpha/beta, and not IFNgamma, was required for iNOS-mediated protection in BMMphi. The molecular details of BMMphi-derived IFNgamma expression revealed a TLR4-MyD88-dependent pathway of IFN-alpha and IFN-gamma induction. Also surprising was the presente of a TLR4- and MyD88-independent, infection-induced NF-kappaB activation and proinflammatory cytokine expression. Phosphorylation of STAT1 during infection was IFN-alpha/beta-dependent, and necessary for increased IFN-gamma expression and for restricting Chlamydial growth. Expression of IFN-gamma and restriction of C. pneumoniae growth also required NF-kappaB activation, but such activation was independent of IFN-alpha/beta, revealing a dual pathway of C.pneumoniae-induced IFN-gamma expression in BMMphi: a TLR4-MyD88-IFNalpha/beta-STAT1 -dependent pathway, and a TLR4-independent pathway leading to NF-kappaB activation. IFN-alpha/beta was also protective in vivo by cooperating with IFN-gamma for activation of STAT1, which was required for restricting Chlamydial growth. Different from the in vitro situation, IFN-gamma was sufficient on its own for this effect and did not require IFN-alpha/beta for its expression. In summary, IFN-gamma is important for restricting C. pneumoniae growth. Innate IFN-gamma is protective both in lungs and in BMMphi. IFN-alpha/beta are pivotal in regulating protective responses in BMMphi, including IFNgamma release, but are dispensable for IFN-gamma expression and protection in vivo. This discrepancy may be a qualitative feature in C. pneumoniae pattern recognition by different cell types; lung cells convey the generation of protective, IL-12-driven responses, while IFN-alpha/beta-driven protection in BMMphi is essential

Barnesykepleieres kompetanseutvikling i klinisk praksis

Bakgrunn: I 2023 var det 360 218 barn som var i kontakt med de 22 somatiske barneavdelingene som finnes i Norge. Her behandles barn fra 0 til 18 år med et bredt spekter av sykdoms- og skadetilstander. På grunn av barns umodenhet gjennom vekst og utvikling, trenger sykepleiere spesifikk kompetanse i møte med syke og skadde barn. Denne kompetansen oppøves både under barnesykepleierutdanningen og i klinisk praksis etter utdanningen. Majoriteten av ansatte ved barneavdelinger er sykepleiere uten barnesykepleierutdanning. Økte krav til pasientsikkerhet og avanserte behandlingsmetoder krever sykepleiefaglig spesialkompetanse, og nasjonale anbefalinger går derfor ut på å øke innsatsen på kompetanseutvikling. Derfor har vi utforsket barnesykepleieres erfaringer med egen kompetanseutvikling. Problemstilling: Hvilke erfaringer har barnesykepleiere med kompetanseutvikling på en barneavdeling etter endt utdanning? Metode: Kvalitativ studie der vi utførte tre semistrukturerte intervju av barnesykepleiere i klinisk arbeid ved barneavdelinger. Analysemetoden som er brukt er refleksiv tematiske analyse. Funn: Funnene presenteres gjennom fire hovedtemaer: 1) Barnesykepleierutdanningen gir god barnesykepleiefaglig basiskompetanse, 2) arbeidsoppgaver og ansvar i barneavdelinger gir kompetanseutvikling, 3) utfordringer knyttet til kompetanseutvikling i klinisk praksis og 4) faglig engasjement fremmer kompetanseutvikling. Funnene viser at barnesykepleierutdanningen gir bred basiskunnskap, men at det er behov for kompetanseutvikling i klinisk praksis for å videreutvikle dybdekunnskap. Konklusjon: Barnesykepleieres kompetanseutvikling bør bygge på den individuelle faktiske oppnådde kompetansen under utdanning, og rettes mot fagspesifikke områder i respektiv avdeling. Faglig engasjement og samarbeid fremmer kompetanseutvikling, og bør anerkjennes og fremmes som viktige faktorer for kompetanseutvikling, både individuelt og kollektivt. Nøkkelord: Barnesykepleiere, erfaringer, kompetanseutvikling og klinisk praksisBackground: In 2023, there were 360,218 children who were in contact with the 22 somatic children's wards in Norway. Here, children from 0 to 18 years of age are treated with a wide range of illnesses and injuries. Due to children's immaturity through growth and development, nurses need specific competence when dealing with sick and injured children. This competence is practiced both during the pediatric nurse education and in clinical practice after the education. The majority of employees in pediatric wards are nurses without pediatric nurse education. Increased requirements for patient safety and advanced treatment methods require specialist nursing competence, and national recommendations therefore aim to increase the effort on competence development. Therefore, we have explored pediatric nurses' experiences with their own competence development. Research question: How do pediatric nurses experience competence development in a children's ward after completing their education? Method: Qualitative study performed through three semi-structured interviews of pediatric nurses from work in a general pediatric ward. The analysis method used is reflexive thematic analysis. Results: The results are presented through four main themes: 1) The pediatric nurse education provides good basic competence in pediatric nursing, 2) work tasks and responsibility in pediatric wards provide competence development, 3) challenges related to competence development in clinical practice and 4) engagement promotes development of competence. The results show that the pediatric nurse education provides broad basic knowledge, but there is a need for competence development in clinical practice, to develop in depth knowledge. Conclusion: Further competence development should be based on the actual acquired clinical competence, during specialization, and be adjusted to the subject fields in the respective ward. Professional engagement and teamwork promote competence development and should be recognized and encouraged as important qualities in developmental work both individually and collectively. Keywords: Pediatric nurse, experience, competence development and clinical practic