Highlights • In addition to its regulation by cytokines, NOS2 is modulated by micromilieu factors. • NOS2-derived NO controls pathogens by restricting their access to micronutrients. • NOS2 is ...expressed and functional in specific T cell subsets. • NOS2-positive mesenchymal stem cells and lymphatic stromal cells suppress T cells.
•Macrophages serve as replicative niche, antimicrobial effectors or immunoregulators.•Functional diversity results from cytokines, micromilieu factors and metabolites.•Micro milieu factors include ...hypoxia, tonicity and amino acid availability.•Leishmania reprogram the transcription, translation and metabolism of macrophages.
Leishmania are protozoan parasites that predominantly reside in myeloid cells within their mammalian hosts. Monocytes and macrophages play a central role in the pathogenesis of all forms of leishmaniasis, including cutaneous and visceral leishmaniasis. The present review will highlight the diverse roles of macrophages in leishmaniasis as initial replicative niche, antimicrobial effectors, immunoregulators and as safe hideaway for parasites persisting after clinical cure. These multiplex activities are either ascribed to defined subpopulations of macrophages (e.g., Ly6ChighCCR2+ inflammatory monocytes/monocyte-derived dendritic cells) or result from different activation statuses of tissue macrophages (e.g., macrophages carrying markers of of classical M1 or alternative activation M2). The latter are shaped by immune- and stromal cell-derived cytokines (e.g., IFN-γ, IL-4, IL-10, TGF-β), micro milieu factors (e.g., hypoxia, tonicity, amino acid availability), host cell-derived enzymes, secretory products and metabolites (e.g., heme oxygenase-1, arginase 1, indoleamine 2,3-dioxygenase, NOS2/NO, NOX2/ROS, lipids) as well as by parasite products (e.g., leishmanolysin/gp63, lipophosphoglycan). Exciting avenues of current research address the transcriptional, epigenetic and translational reprogramming of macrophages in a Leishmania species- and tissue context-dependent manner.
Routine vaccination of elderly people against pneumococcal diseases is recommended in many countries. National guidelines differ, recommending either the 23-valent polysaccharide vaccine (PPV23), the ...13-valent conjugate vaccine (PCV13) or both. Considering the ongoing debate on the effectiveness of PPV23, we performed a systematic literature review and meta-analysis of the vaccine efficacy/effectiveness (VE) of PPV23 against invasive pneumococcal disease (IPD) and pneumococcal pneumonia in adults aged ≥60 years living in industrialized countries.
We searched for pertinent clinical trials and observational studies in databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. We assessed the risk of bias of individual studies using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. We rated the overall quality of the evidence by GRADE criteria. We performed meta-analyses of studies grouped by outcome and study design using random-effects models. We applied a sensitivity analysis excluding studies with high risk of bias.
We identified 17 eligible studies. Pooled VE against IPD (by any serotype) was 73% (95%CI: 10-92%) in four clinical trials, 45% (95%CI: 15-65%) in three cohort studies, and 59% (95%CI: 35-74%) in three case-control studies. After excluding studies with high risk of bias, pooled VE against pneumococcal pneumonia (by any serotype) was 64% (95%CI: 35-80%) in two clinical trials and 48% (95%CI: 25-63%) in two cohort studies. Higher VE estimates in trials (follow-up ~2.5 years) than in observational studies (follow-up ~5 years) may indicate waning protection. Unlike previous meta-analyses, we excluded two trials with high risk of bias regarding the outcome pneumococcal pneumonia, because diagnosis was based on serologic methods with insufficient specificity.
Our meta-analysis revealed significant VE of PPV23 against both IPD and pneumococcal pneumonia by any serotype in the elderly, comparable to the efficacy of PCV13 against vaccine-serotype disease in a recent clinical trial in elderly people. Due to its broader serotype coverage and the decrease of PCV13 serotypes among adults resulting from routine infant immunization with PCV13, PPV23 continues to play an important role for protecting adults against IPD and pneumococcal pneumonia.
The kinetoplastid protozoan parasites belonging to the genus
are the causative agents of different clinical forms of leishmaniasis, a vector-borne infectious disease with worldwide prevalence. The ...protective host immune response against
parasites relies on myeloid cells such as dendritic cells and macrophages in which upon stimulation by cytokines (e.g., interferon-γ) a complex network of signaling pathways is switched on leading to strong antimicrobial activities directed against the intracellular parasite stage. The regulation of these pathways classically depends on post-translational modifications of proteins, with phosphorylation events playing a cardinal role.
parasites deactivate their phagocytic host cells by inducing specific mammalian phosphatases that are capable to impede signaling. On the other hand, there is now also evidence that
spp. themselves express phosphatases that might target host cell molecules and thereby facilitate the intracellular survival of the parasite. This review will present an overview on the modulation of host phosphatases by
parasites as well as on the known families of
phosphatases and their possible function as virulence factors. A more detailed understanding of the role of phosphatases in
-host cell interactions might open new avenues for the treatment of non-healing, progressive forms of leishmaniasis.
During the past 15 years, nitric oxide (NO) and NO synthases have become an important research topic in cellular and molecular biology. NO is produced by many if not all mammalian cells and fulfils a ...broad spectrum of signaling functions in physiological and pathophysiological processes. In this review, recent advances in our understanding of the mechanisms by which NO regulates the expression of eukaryotic genes will be summarized. The currently available data illustrate that NO has multiple molecular targets: it can not only directly influence the activity of transcription factors but also modulates upstream signaling cascades, mRNA stability and translation, as well as the processing of the primary gene products.
Infants < 3 months of age are at highest risk for developing severe complications after pertussis. The majority of pregnant women has low concentrations of pertussis-specific antibodies and thus ...newborns are insufficiently protected by maternally transferred antibodies. Acellular pertussis vaccination during pregnancy was recently implemented in various countries. Here, we assessed the evidence for safety and effectiveness of pertussis vaccination during pregnancy.
We searched Medline, Embase, and ClinicalTrials.gov from January 1st 2010 to January 10th 2019. We assessed risk of bias (ROB) using the Cochrane ROB tool and ROBINS-I. We evaluated the quality of evidence using the GRADE approach.
We identified 1273 articles and included 22 studies (14 for safety; 8 for effectiveness), comprising 1.4 million pregnant women in safety studies and 855,546 mother-infant-pairs in effectiveness studies. No significant differences between vaccinated and unvaccinated women and their infants were observed for safety outcomes with the exception of fever and chorioamnionitis. Compared to no vaccination, three studies showed a significantly increased relative risk for the presence of the ICD-9 code for chorioamnionitis in electronic patient data after pertussis vaccination. However, no study reported an increased risk for clinical sequelae of chorioamnionitis after vaccination during pregnancy, such as preterm birth or neonatal intensive care unit admission. Vaccine effectiveness against pertussis in infants of immunized mothers ranged from 69 to 91% for pertussis prevention, from 91 to 94% for prevention of hospitalization and was 95% for prevention of death due to pertussis. Risk of bias was serious to critical for safety outcomes and moderate to serious for effectiveness outcomes. GRADE evidence quality was moderate to very low, depending on outcome.
Although an increased risk for a diagnosis of fever and chorioamnionitis was detected in pregnant women after pertussis vaccination, there was no association with a higher frequency of clinically relevant sequelae. Vaccine effectiveness for prevention of infant pertussis, hospitalization and death is high. Pertussis vaccination during pregnancy has an overall positive benefit-risk ratio. In view of the overall quality of available evidence ongoing surveillance of chorioamnionitis and its potential sequelae is recommended when pertussis vaccination in pregnancy is implemented.
PROSPERO CRD42018087814, CRD42018090357.
In memoriam Martin Röllinghoff (1941–2022) Bogdan, Christian
European journal of immunology,
January 2024, 2024-Jan, 2024-01-00, 20240101, Letnik:
54, Številka:
1
Journal Article
Type I interferons (IFN-α and IFN-β) were originally described as potent antiviral substances, which are produced upon infection of animal cells with viruses. Despite a large body of literature that ...has accumulated during the past 25 years, their regulatory function in the immune system is still much less appreciated. Recent studies have highlighted the production of type I IFNs, their function in the immune response to infectious agents and the target cells of these interferons. Type I IFNs clearly affect the release of proinflammatory cytokines or nitric oxide by dendritic cells and macrophages, the capacity of type II interferon (IFN-γ) to activate phagocytes, the differentiation of T helper cells and the innate control of non-viral pathogens.
Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na+ concentrations is unknown. We found that Na+ accumulated at the site of ...bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na+ storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na+ content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection.
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•Na+ accumulates at site of bacterial skin infections in humans and in mice•Salt boosts classical macrophage (MΦ) activation and wards off infection•Salt increases NOS2 activity in MΦ via p38/MAPK and NFAT5 signaling•High-salt diet promotes skin Na+ storage and ameliorates cutaneous leishmaniasis
Jantsch et al. show that Na+ accumulates in infected skin in humans and mice and creates a hypertonic microenvironment increasing NO production in macrophages to facilitate pathogen removal. High-salt diet promotes skin Na+ accumulation, which boosts macrophage activation and helps resolve bacterial infection.
To allow an efficient protection against viruses like the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), it is important to avoid their spreading by using filtering face pieces ...(FFP), which are categorized by different standards according to their filtration efficiency. In this study, we subjected six brands of FFP2 standard masks to three different conditions and subsequently analysed them for their filtration performance to evaluate potentials for reusability. The conditions comprised changes of temperature and air humidity, an exposure to isopropyl alcohol (IPA) and an autoclave sterilization. While four of six masks consisted of electrostatically treated melt blown non-wovens, two masks were fabricated using a nanofibrous multilayer system. Due to the absence of prior electrostatic treatment, the nano-masks did not show a significant change in filtration efficiency when discharged by IPA, unlike the melt blown nonwoven masks showing a significant decrease of filtration efficiency down to around 50% at a particle size of 0.3 μm. However, most melt blown masks maintained a sufficient filtration efficiency after all other treatments with even better results than the nanofibrous masks. This was particularly the case for the capacity to filter smallest particles/droplets with a size of around 0.1 μm, which is below the range of typical filtering standards and important for the retention of virally contaminated nano-aerosols or unattached viruses. After temperature/humidity variation and autoclave sterilization, melt blown masks were able to retain a filtration efficiency up to over 90% at 0.1 μm contrary to nano-masks showing a decrease down to around 70%. Based on their better filtration performance, lower price and potential reusability, we conclude that electret melt blown masks are the preferable type of FFP2 masks.
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