Therapeutic phages are being employed for vaccination and treatment of cancer and bacterial infections. Their natural immunogenicity triggers intertwined interactions with innate and adaptive immune ...cells that might influence therapy. Phage- and bactierial-derived pathogen-associated molecular patterns released after bacterial lysis have been proposed to stimulate local innate immune responses, which could promote antitumor immunity or bacterial clearance. Conversely, immunogenicity of phages induces phage-specific humoral memory, which can hamper therapeutic success. This review outlines the current knowledge on the different types of immune responses elicited by phages and their potential benefits and adverse side effects, when applied therapeutically. This review further summarizes the knowledge gaps and defines the key immunological questions that need to be addressed regarding the clinical application of antibacterial phage therapy.
Objective
This retrospective surveillance study aimed to follow periodontitis‐associated bacterial profiles and to identify time‐dependent changes in antibiotic susceptibility patterns.
Materials and ...Methods
From 2008 to 2015, bacterial specimen from deep periodontal pockets were collected from a total of 7804 German adults diagnosed with periodontitis. Presence of selected bacteria was confirmed by anaerobic culture and nucleic acid amplification. Antimicrobial susceptibility of clinical isolates was tested by disc diffusion with antibiotics used for the treatment of periodontitis and oral infections. The prevalences of periodontal pathogens were calculated and temporal evolution of antimicrobial susceptibility towards amoxicillin, amoxicillin/clavulanic acid, metronidazole, doxycycline, clindamycin, azithromycin, ciprofloxacin and ampicillin was analysed with logistic regression.
Results
The prevalence of patients harbouring bacteria was 95.9% Fusobacterium nucleatum, 88.0% Tannerella forsythia, 76.4% Treponema denticola, 76.5%, Campylobacter rectus, 76.0% Eikenella corrodens, 75.0% Capnocytophaga spp., 68.2% Porphyromonas gingivalis, 57.7% Peptostreptococcus micros, 43.1% Prevotella intermedia, 30.4% Eubacterium nodatum and 21.5% Aggregatibacter actinomycetemcomitans. In 63.5% of patients, one or more isolates were not susceptible to at least one of the antibiotics tested. The data further revealed a trend towards decreasing susceptibility profiles (p < 0.05) with antibiotic non‐susceptibilities in 37% of patients in 2008 and in 70% in 2015.
Conclusions
The present study confirmed a high prevalence of periodontal pathogens in the subgingival microbiota of German periodontitis patients. The data revealed an incremental increase in isolates displaying resistance to some antibiotics but no relevant change in susceptibility to amoxicillin and metronidazole.
Toll-like receptors (TLR) play a central role in the initiation of the innate immune response to pathogens. Upon recognition of molecular motifs specific for microbial molecules TLR mediate ...pro-inflammatory cytokine secretion and enhance antigen presentation; in B cells they further promote expansion, class switch recombination and immunoglobulin secretion. As a result of their adjuvant properties, TLR ligands have become an integral component of antimicrobial vaccines. In spite of this, little is known of the direct effects of TLR engagement on B-lymphocyte function. The scope of this review is to outline the differences in TLR expression and reactivity in murine and human B-cell subsets and to provide an overview of the currently available literature. We will further discuss the possible roles of TLR in regulating B-cell effector functions and shaping antibody-mediated defence against microbial pathogens in vivo.
Tumor Necrosis Factor Receptor 2 (TNFR2) expression is increasingly being linked to tolerogenic immune reactions and cells with suppressor function including a subset of T‐regulatory cells. ...B‐regulatory cells play an important role in control of T‐cell responses and inflammation. Recently, we described TNFR2 as a marker for IL‐10‐producing B cells, a hallmark of this cell subset. Here, we demonstrate that proliferation of T cells is reduced in the presence of TNFR2 positive human memory B cells generated with TLR9 ligand, while TNFR2‐ and TNFR2+CD27‐ B cells display costimulatory activity. Our data further reveal that IL‐10 secretion is characteristic of IgM+ naïve and memory B cells but suppressive activity is not restricted to IL‐10: (i) the inhibitory effect of TNFR2+ switched memory B cells was comparable to that exerted by TNFR2+ IgM+ memory B cells although IL‐10 secretion levels in the cocultures were lower; (ii) supernatants from TNFR2+ memory B cells failed to suppress T‐cell proliferation. Based on our findings, we propose that formation of Breg is a specific characteristic of human memory B cells undergoing terminal differentiation. Our data further corroborate that TNFR2 represents a viable marker for identification of memory B cells with regulatory function.
T cell‐independent B cell activation via TLR9 induces formation of TNFR2+ memory B cells with suppressive activity. In contrast to TNFR2‐ B cells, TNFR2+ characterizes Breg that limit T‐cell proliferation and subsequently undergo differentiation to antibody‐secreting cells. T‐cell inhibition might serve prevention of de novo responses to cognate antigen.
Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in ...vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, re-thinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro- and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective.
DGfI Study Group Vaccines ‐ Annual Meeting 2022 Wöhrle, Franziska; Kerscher, Bernhard; Cicin‐Sain, Luka ...
European journal of immunology,
March 2022, Letnik:
52, Številka:
3
Journal Article
Blood safety measures used by blood establishments to increase blood component safety can be validated using Transfusion-Relevant Bacterial Reference Strains (TRBRS). Ultra-cold storage conditions ...and manual preparation of the current TRBRS may restrict their practical use. To address this issue, the ISBT Transfusion-Transmitted Infectious Diseases Working Party's Bacterial Subgroup organized an international study to validate TRBRS in a user-friendly, lyophilised format.
Two bacterial strains Klebsiella pneumoniae PEI-B-P-08 and Staphylococcus aureus PEI-B-P-63 were manufactured as lyophilised material. The lyophilised bacteria were distributed to 11 different labs worldwide to assess the robustness for enumeration, identification and determination of growth kinetics in platelet concentrates (PCs).
Production of lyophilised TRBRS had no impact on the growth properties compared with the traditional format. The new format allows a direct low-quantity spiking of approximately 30 bacteria in PCs for transfusion-relevant experiments. In addition, the lyophilised bacteria exhibit long-term stability across a broad temperature range and can even be directly rehydrated in PCs without losing viability. Interlaboratory comparative study demonstrated the robustness of the new format as 100% of spiked PC exhibited growth.
Lyophilised TRBRS provide a user-friendly material for transfusion-related studies. TRBRS in the new format have improved features that may lead to a more frequent use in the quality control of transfusion-related safety measures in the future.
Hepatitis E virus (HEV) infections may be acquired through transfusion of blood components. As transfusion‐transmitted infections mostly affect vulnerable individuals, measures to ensure the supply ...of safe blood components are under discussion. On the basis of the epidemiological situation in Germany, different testing strategy scenarios were investigated through simulation studies. Testing for HEV RNA by nucleic acid amplification technique (NAT) assays with a pool size of 96, and a 95% LoD of 20 IU/ml will result in an 80% reduction in expected HEV transmissions as well as of consequent chronic infections with subsequent severe complications.
Introduction
The most severe side effect in haemophilia A treatment is the development of antifactor VIII antibodies, also called inhibitors. Why inhibitors develop in a proportion of treated ...patients while others are unaffected still remains unanswered. The presence of immunological danger signals, associated with events such as infection or surgery, has been proposed to play a role. Previous studies demonstrated that the presence of the bacterial molecule lipopolysaccharide (LPS) can synergistically increase the activation of human DC and subsequent T cell activation by FVIII.
Aim and Methods
In the present study, we investigated whether a combination of two danger signals can further increase immune cell activation by FVIII. For this, human in vitro differentiated DC that were treated with combinations of danger signals were co‐cultured with autologous primary T cells, and T cell proliferation was analysed.
Results
Interestingly, by combining LPS with a second danger signal, lower LPS concentrations were sufficient to synergistically increase DC and subsequent T cell activation by FVIII. Of note, a combination of LPS and the double‐stranded RNA, polyinosinic‐polycytidylic acid (poly(I:C)), was most potent in increasing FVIII immunogenicity, followed by LPS + R848 (resiquimod). However, a combination of LPS and the bacterial lipopeptide Pam3CysSK4 did not induce increased immune cell activation by FVIII.
Conclusion
Thus, individual combinations of danger signals can increase FVIII product immunogenicity. This should be considered in the treatment routine of haemophilia A patients.
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