Mechanisms Of Protective Immunity Research Articles

Comparative transcriptome analysis reveals the different responding mechanisms of ovary and hepatopancreas following polyI:C challenge in Macrobrachium nipponense

The ovary in mammals has developed specialized mechanisms for protection against pathogen infections; however, the understanding of the innate immune system in the ovary of crustaceans is still limited. To elucidate the ovary's defense mechanisms in response to viral challenges, we subjected oriental river prawns (Macrobrachium nipponense) to poly I:C, a double-stranded RNA analog that emulates viral dsRNA, and analyzed the ovary's transcriptome profiles. Concurrently, RNA-seq analysis was performed on the hepatopancreas, a well-recognized immune-related tissue, following poly I:C challenge to investigate the distinct response mechanisms of the ovary and hepatopancreas and to gain a comprehensive understanding of the immune responses in both tissues. The results indicate that 1368 genes are differentially expressed in the ovary, with 903 genes upregulated and 465 genes downregulated. Subsequent analysis reveals that these differentially expressed genes (DEGs) include numerous genes associated with innate immunity, such as members of the C-type lectin, fibrinogen-related protein (Frep), Toll-like receptor, and NOD-like receptor (NLR) gene families, as well as acid phosphatase, scavenger receptor, crustin, Down syndrome cell adhesion molecule (Dscam), hemocyanin, and lipopolysaccharide and beta-1,3-glucan binding protein (LGBP). Furthermore, the DEGs include several genes related to ovary development, such as sox8, vitellogenin, progranulin, cyclin-dependent kinase, ecdysone receptor, frizzled, and members of the Fox gene family. In the hepatopancreas, a total of 729 DEGs were identified. Comparison of the DEGs in both tissues indicates that only 91 genes are common to both groups, highlighting significant tissue-specific responses to poly I:C stimulation. This study aims to enhance our understanding of the immune protective mechanisms employed by the ovary in response to pathogen exposure and establishes a foundation for investigating ovarian reproductive immunity in crustaceans.

Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

Gonococci – Pathogens of Growing Importance. Part 2. Virulence Factors, Antimicrobial Resistance and Vaccine Development

Abstract Neisseria gonorrhoeae (gonococcus) is a human pathogen, the aetiological agent of gonorrhoea, which is the second most common bacterial sexually transmitted disease (STD) in the world. The structure of N. gonorrhoeae cell wall is typical of Gram-negative bacteria, poses variable antigens porin B (PorB), and opacity-associated proteins (Opa proteins), lipooligosaccharide (LOS) and type IV pili (TFP) playing an essential role in pathogenesis. In addition to adhesins, gonococcus presents other virulence factors such as reducing modifiable protein (Rmp), iron transporters, membrane pumps, and IgA peptidase. The pathogen produces outer membrane vesicles (OMVs), releases peptidoglycan (PG) fragments and is well adapted to develop infection in diverse niches of the female and male reproductive tracts. The characteristic genotypic trait of N. gonorrhoeae is the state of natural competence, which allows DNA uptake from the environment. The antigenic and phase variability is essential to gonococcal defence against the human immune system. Because of the increasing antimicrobial resistance (AMR) of N. gonorrhoeae and the high incidence rate of gonococcal infections, developing an antigonococcal vaccine has become an urgent need. Vaccine development difficulties are mainly due to the gonococcal ability of immune evasion, the lack of an animal model, and the limited understanding of protective immune response mechanisms.

Defining the balance between optimal immunity and immunopathology in influenza virus infection.

Influenza A viruses remain a global threat to human health, with continued pandemic potential. In this Review, we discuss our current understanding of the optimal immune responses that drive recovery from influenza virus infection, highlighting the fine balance between protective immune mechanisms and detrimental immunopathology. We describe the contribution of innate and adaptive immune cells, inflammatory modulators and antibodies to influenza virus-specific immunity, inflammation and immunopathology. We highlight recent human influenza virus challenge studies that advance our understanding of susceptibility to influenza and determinants of symptomatic disease. We also describe studies of influenza virus-specific immunity in high-risk groups following infection and vaccination that inform the design of future vaccines to promote optimal antiviral immunity, particularly in vulnerable populations. Finally, we draw on lessons from the COVID-19 pandemic to refocus our attention to the ever-changing, highly mutable influenza A virus, predicted to cause future global pandemics.

HYPERTENSION RELATED NETOSIS IS STRONGLY DEPENDENT ON NIGHTTIME BLOOD PRESSURE IN A COHORT OF NEWLY DIAGNOSED, TREATMENT NAÏVE HYPERTENSIVE PATIENTS

Objective: Over the last years, accumulating evidence has highlighted the key role of immunity in the inflammatory environment of essential hypertension (EH). Neutrophil extracellular traps (NETs) formation represents a protective innate immune mechanism of the neutrophils. However, excessive release of NETs (NETosis) has been shown to exert a potent pro-inflammatory and pro-thrombotic effect. Even though NETosis is increasingly implicated in the thrombo-inflammatory environment of cardiovascular disease, experimental and clinical data regarding the association between NETs and EH are scarce. Design and method: We recruited newly diagnosed, untreated hypertensives (UHTs) without overt cardiovascular disease and healthy, normotensive individuals (NTs). Office BP was measured according to guidelines. Ambulatory and central BP parameters were measured with the Mobil-O-Graph device. Plasma levels of NETs including myeloperoxidase (MPO)-DNA were determined by ELISA. Results: A total of 139 individuals including 99 UHTs and 40 NTs were included in the study. Levels of MPO-DNA were increased in UHTs compared to NTs (p<0.001). In multivariate analysis after adjustment for confounding variables (body mass index, hemoglobin, uric acid, high sensitivity c-reactive protein), hypertension was the strongest independent predictor of incident NETosis (p<0.001). Among the ambulatory BP indices, peripheral nighttime systolic BP (F:5.937; p=0.016) and central nighttime diastolic BP (F:4.751; p=0.031) were the strongest prognosticators of hypertension related NETosis (Optimal Scaling ANOVA; p=0.028). Conclusions: In a cohort of newly diagnosed, treatment-naïve hypertensive patients, nighttime BP indices are the strongest factors that can predict, independently, an increased NETosis, adding to the superior significance of nocturnal BP in cardiovascular prognosis. Further research is needed to clarify the association of NETs with hypertension as well as hypertension-mediated target organ damage.

Proteome profile of Leishmania donovani Centrin1−/− parasite-infected human macrophage cell line and its implications in determining possible mechanisms of protective immunity

Our developed cell division-specific ‘centrin’ gene deleted Leishmania donovani (LdCen1−/−) the causative parasite of the fatal visceral-leishmaniasis (VL), exhibits a selective growth arrest at the intracellular stage and is anticipated as a live attenuated vaccine candidate against VL. LdCen1−/− immunization in animals has shown increased IFN-γ secreting CD4+ and CD8+ T cells along with protection conferred by a protective proinflammatory immune response. A label-free proteomics approach has been employed to understand the physiology of infection and predict disease interceptors during Leishmania-host interactions. Proteomic modulation after infection of human macrophage cell lines suggested elevated annexin A6, implying involvement in various biological processes such as membrane repair, transport, actin dynamics, cell proliferation, survival, differentiation, and inflammation, thereby potentiating its immunological protective capacity. Additionally, S100A8 and S100A9 proteins, known for maintaining homeostatic balance in regulating the inflammatory response, have been upregulated after infection. The inhibitory clade of serpins, known to inhibit cysteine proteases (CPs), was upregulated in host cells after 48 h of infection. This is reflected in the diminished expression of CPs in the parasites during infection. Such proteome analysis confirms LdCen1−/− efficacy as a vaccine candidate and predicts potential markers in future vaccine development strategies against infectious diseases.

A novel method to assess antibody-dependent cell-mediated cytotoxicity against influenza A virus M2 in immunized murine models

The matrix protein 2 (M2) is a preferred target for developing a universal vaccine against the influenza A virus (IAV). This study aimed to develop a method for assessing antibody-dependent cell-mediated cytotoxicity (ADCC) associated with M2-based immunization in mice. We first established a stable cell line derived from mouse lymphoma cells (YAC-1) expressing M2 of H3N2. This cell line, designated as YAC-1-M2, was generated using a second-generation lentiviral tricistronic plasmid system to transduce the M2 gene into YAC-1 cells. The ADCC effect induced by polyclonal antibodies targeting matrix protein 2 ectodomain (M2e) was demonstrated by YAC-1-M2 cell lysis by natural killer cells (NK) derived from mice, in the presence of anti-M2 antibodies obtained from mice immunized with an mRNA vaccine based on M2e. This ADCC effect was found to be stronger compared to the effect induced by monoclonal antibodies (14C2) against M2. Moreover, the ADCC effect was enhanced as the effector-to-target ratio of NK to YAC-1-M2 cells increased. In conclusion, we established a novel method to detect ADCC of M2 of IAV, which paves the way for the development of an M2-based universal vaccine against IAV and an in-depth analysis of its mechanism of broad-spectrum immune protection in mice.

Immunopathology in human pulmonary tuberculosis: Inflammatory changes in the plasma milieu and impaired host immune cell functions.

Host immune response is key for protection in tuberculosis, but the causative agent, Mycobacterium (M.) tuberculosis, manages to survive despite immune surveillance. Key mechanisms of immune protection have been identified, but the role of immunopathology in the peripheral blood of tuberculosis patients remains unclear. Tuberculosis immunopathology in the blood is characterised by patterns of immunosuppression and hyperinflammation. These seemingly contradictory findings and the pronounced heterogeneity made it difficult to interpret the results from previous studies and to derive implications of immunopathology. However, novel approaches based on comprehensive data analyses and revitalisation of an ancient plasma milieu in vitro assay connected inflammation with immunosuppressive factors in tuberculosis. Moreover, interrelations between the aberrant plasma milieu and immune cell pathology were observed. This review provides an overview of studies on changes in plasma milieu and discusses recent findings linking plasma factors to T-cell and monocyte/macrophage pathology in pulmonary tuberculosis patients.

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

Protective efficacy of short-term infection with Necator americanus hookworm larvae in healthy volunteers in the Netherlands: a single-centre, placebo-controlled, randomised, controlled, phase 1 trial

Vaccine development against hookworm is hampered by the absence of the development of protective immunity in populations repeatedly exposed to hookworm, limiting identification of mechanisms of protective immunity and new vaccine targets. Immunisation with attenuated larvae has proven effective in dogs and partial immunity has been achieved using an irradiated larvae model in healthy volunteers. We aimed to investigate the protective efficacy of immunisation with short-term larval infection against hookworm challenge. We did a single-centre, placebo-controlled, randomised, controlled, phase 1 trial at Leiden University Medical Center (Leiden, Netherlands). Healthy volunteers (aged 18-45 years) were recruited using advertisements on social media and in publicly accessible areas. Volunteers were randomly assigned (2:1) to receive three short-term infections with 50 infectious Necator americanus third-stage filariform larvae (50L3) or placebo. Infection was abrogated with a 3-day course of albendazole 400 mg, 2 weeks after each exposure. Subsequently all volunteers were challenged with two doses of 50L3 at a 2-week interval. The primary endpoint was egg load (geometric mean per g faeces) measured weekly between weeks 12 and 16 after first challenge, assessed in the per-protocol population, which included all randomly assigned volunteers with available data on egg counts at week 12-16 after challenge. This study is registered with ClinicalTrials.gov, NCT03702530. Between Nov 8 and Dec 14, 2018, 26 volunteers were screened, of whom 23 enrolled in the trial. The first immunisation was conducted on Dec 18, 2018. 23 volunteers were randomly assigned (15 to the intervention group and eight to the placebo group). Egg load after challenge was lower in the intervention group than the placebo group (geometric mean 571 eggs per g [range 372-992] vs 873 eggs per g [268-1484]); however, this difference was not statistically significant (p=0·10). Five volunteers in the intervention group developed a severe skin rash, which was associated with 40% reduction in egg counts after challenge (geometric mean 742 eggs per g [range 268-1484] vs 441 eggs per g [range 380-520] after challenge; p=0·0025) and associated with higher peak IgG1 titres. To our knowledge, this is the first study to describe a protective effect of short-term exposure to hookworm larvae and show an association with skin response, eosinophilic response, and IgG1. These findings could inform future hookworm vaccine development. Dioraphte Foundation.

Protective effects of dietary Astragalus polysaccharides on large yellow croaker (Larimichthys crocea) against Vibrio alginolyticus infection

As one of the effective immunopotentiators, Astragalus polysaccharides (APS) are being used widely in prevention and control of fish bacteriosis. However, the understanding of the related immune protection mechanisms is still limited. In this study, the protective effects of dietary APS on large yellow croaker (Larimichthys crocea) following Vibrio alginolyticus infection were investigated. After continuous feeding for 42 d, fish in APS group exhibited higher survival rates against V. alginolyticus infection compared to the control group, and 500 mg/kg APS produced the highest relative percent survival (RPS) of 53.33%, therefore, 500 mg/kg (0.05%) supplementation was recommended in large yellow croaker farming from a standpoint of antibacterial infection. APS could enhance antioxidant level of fish by increasing serum T-AOC capacity and SOD activity and reducing MDA content, and improve innate immune response by increasing serum AKP and ACP activities. Head kidney differential transcriptome analysis between control group and 500 mg/kg APS group before and after V. alginolyticus infection corroborated the effects of APS on activation of antioxidant capacity and innate immunity by up-regulating the antioxidant-related genes and activating CTLR pathway, respectively. Additionally, APS could also activate fish adaptive immunity by reversing V. alginolyticus-induced inhibition on T and B cell receptor signaling pathways. All these findings suggested that APS may exert the protective effects against V. alginolyticus infection by improving antioxidant ability, innate and adaptive immune responses of large yellow croaker, thus providing insights into the protection mechanisms of APS in fish and highlighting their potential application in fish aquaculture.

Evaluating vaccine-elicited antibody activities against Neisseria gonorrhoeae: cross-protective responses elicited by the 4CMenB meningococcal vaccine.

The bacterial pathogen Neisseria gonorrhoeae is an urgent global health problem due to increasing numbers of infections, coupled with rampant antibiotic resistance. Vaccines against gonorrhea are being prioritized to combat drug-resistant N. gonorrhoeae. Meningococcal serogroup B vaccines such as four-component meningococcal B vaccine (4CMenB) are predicted by epidemiology studies to cross-protect individuals from natural infection with N. gonorrhoeae and elicit antibodies that cross-react with N. gonorrhoeae. Evaluation of vaccine candidates for gonorrhea requires a suite of assays for predicting efficacy in vitro and in animal models of infection, including the role of antibodies elicited by immunization. Here, we present the development and optimization of assays to evaluate antibody functionality after immunization of mice: antibody binding to intact N. gonorrhoeae, serum bactericidal activity, and opsonophagocytic killing activity using primary human neutrophils [polymorphonuclear leukocytes (PMNs)]. These assays were developed with purified antibodies against N. gonorrhoeae and used to evaluate serum from mice that were vaccinated with 4CMenB or given alum as a negative control. Results from these assays will help prioritize gonorrhea vaccine candidates for advanced preclinical to early clinical studies and will contribute to identifying correlates and mechanisms of immune protection against N. gonorrhoeae.

Impact of COVID-19 vaccination on saliva immune barriers: IgA, lysozyme, and lactoferrin.

Understanding the role of salivary constituents, such as lactoferrin, lysozyme, and secretory immunoglobulin A (sIgA), in immune protection and defense mechanisms against microbial invasion and colonization of the airways is important in light of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The salivary immune barrier in individuals affected by COVID-19 may contribute to disease prognosis. Thus, the aim of the present review is to evaluate the effect of COVID-19 vaccines on the immunological composition of saliva. IgA antibodies generated by vaccination can neutralize the virus at mucosal surfaces, whereas antimicrobial peptides, such as lysozyme and lactoferrin, have broad-spectrum antimicrobial activity. Collectively, these components contribute to the protective immune response of the oral cavity and may help minimize viral transmission as well as the severity of COVID-19. Measuring the levels of these components in the saliva of COVID-19-vaccinated individuals can help in evaluating the vaccine's ability to induce mucosal immunity, and it might also provide insights into whether saliva can be used in diagnostics or surveillance for monitoring immune responses following vaccination. This also has implications for viral transmission.

Advancing Vaccine Strategies against Candida Infections: Exploring New Frontiers.

Candida albicans, along with several non-albicans Candida species, comprise a prominent fungal pathogen in humans, leading to candidiasis in various organs. The global impact of candidiasis in terms of disease burden, suffering, and fatalities is alarmingly high, making it a pressing global healthcare concern. Current treatment options rely on antifungal drugs such as azoles, polyenes, and echinocandins but are delimited due to the emergence of drug-resistant strains and associated adverse effects. The current review highlights the striking absence of a licensed antifungal vaccine for human use and the urgent need to shift our focus toward developing an anti-Candida vaccine. A number of factors affect the development of vaccines against fungal infections, including the host, intraspecies and interspecies antigenic variations, and hence, a lack of commercial interest. In addition, individuals with a high risk of fungal infection tend to be immunocompromised, so they are less likely to respond to inactivated or subunit whole organisms. Therefore, it is pertinent to discover newer and novel alternative strategies to develop safe and effective vaccines against fungal infections. This review article provides an overview of current vaccination strategies (live attenuated, whole-cell killed, subunit, conjugate, and oral vaccine), including their preclinical and clinical data on efficacy and safety. We also discuss the mechanisms of immune protection against candidiasis, including the role of innate and adaptive immunity and potential biomarkers of protection. Challenges, solutions, and future directions in vaccine development, namely, exploring novel adjuvants, harnessing the trained immunity, and utilizing immunoinformatics approaches for vaccine design and development, are also discussed. This review concludes with a summary of key findings, their implications for clinical practice and public health, and a call to action for continued investment in candidiasis vaccine research.

The Role of Inflammatory Biomarkers of Crevicular Fluid Involved in Modulating of Immune Protection Mechanisms in Chronic Periodontitis

INTRODUCTION: Chronic periodontal inflammation is provoked by persistence of subgingival bacterial flora and is mediated through the production of proinflammatory cytokines that induce the innate immune reactions.
 АIM: To establish the interrelation of secretion of interleukin 1 and immune component of soluble CD14 co-receptor with the main periodontopathogenic microorganisms in patients with chronic generalized periodontitis.
 MATERIALS AND METHODS: A clinical and laboratory examination of patients with chronic generalized periodontitis (n = 100) and individuals with the intact parodontium (n = 63) was conducted. Molecular genetic studies (isolation of periodontal pathogens by polymerase chain reaction in real time), immune enzyme assay (isolation of interleukin 1 and soluble CD14 co-receptor) and statistical analysis of the data obtained were performed.
 RESULTS: The frequency of isolation of periodontopathogenic bacteria in patients with the diagnosis of chronic periodontitis was 96.4% (T. forsythia 81%, р 0.001; P. gingivalis 69%, р 0.001; Tr. denticola 63%, р = 0.054). In 25% of cases, C. Albicans (р 0.001), in 37% Pr. intermedia (р 0.001) and in 30% A. actinomycetemcomitans (р 0.001) were isolated. The average concentrations of soluble CD14 co-receptor were 2.13 [1.89; 2.76] pg/ml in the control group and 20.3 [17.3; 22.5] ng/ml in the group of patients with chronic periodontitis (р 0.001). Concentrations of interleukin 1 were 3.187 [2.356; 4.633] pg/ml in the control group and 33.68 [17.255; 56.915] pg/ml in the group of patients with chronic periodontitis (р 0.001).
 CONCLUSION: Inflammation of periodontal tissues is supported by the factors of aggression and toxins not only of known periodontal pathogens, but also by their associations, which leads to enhancement of virulence factors and increase in secretion of interleukin 1 and soluble CD14 co-receptor, which, in turn, causes destruction of alveolar bone.

Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80-90%) against lethal murine salmonellosis, in comparison with a moderately protective (40-50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity.

Pre-vaccination monocyte-to-lymphocyte ratio as a biomarker for the efficacy of malaria candidate vaccines: A subgroup analysis of pooled clinical trial data.

Pre-vaccination monocyte-to-lymphocyte ratio was previously suggested as a marker for malaria vaccine effectiveness. We investigated the potential of this cell ratio as a marker for malaria vaccine efficacy and effectiveness. Effectiveness was investigated by using clinical malaria endpoint, and efficacy was investigated by using surrogate endpoints of Plasmodium falciparum prepatent period, parasite density, and multiplication rates in a controlled human malaria infection trial (CHMI). We evaluated the correlation between monocyte-to-lymphocyte ratio and RTS,S vaccine effectiveness using Cox regression modeling with clinical malaria as the primary endpoint. Of the 1704 participants in the RTS,S field trial, data on monocyte-to-lymphocyte ratio was available for 842 participants, of whom our analyses were restricted. We further used Spearman Correlations and Cox regression modeling to evaluate the correlation between monocyte-to-lymphocyte ratio and Whole Sporozoite malaria vaccine efficacy using the surrogate endpoints. Of the 97 participants in the controlled human malaria infection vaccine trials, hematology and parasitology information were available for 82 participants, of whom our analyses were restricted. The unadjusted efficacy of RTS,S malaria vaccine was 54% (95% CI: 37%-66%, p <0.001). No correlation was observed between monocyte-to-lymphocyte ratio and RTS,S vaccine efficacy (Hazard Rate (HR):0.90, 95%CI:0.45-1.80; p = 0.77). The unadjusted efficacy of Whole Sporozoite malaria vaccine in the appended dataset was 17.6% (95%CI:10%-28.5%, p<0.001). No association between monocyte-to-lymphocyte ratio and the Whole Sporozoite malaria vaccine was found against either the prepatent period (HR = 1.16; 95%CI:0.51-2.62, p = 0.72), parasite density (rho = 0.004, p = 0.97) or multiplication rates (rho = 0.031, p = 0.80). Monocyte-to-lymphocyte ratio alone may not be an adequate marker for malaria vaccine efficacy. Further investigations on immune correlates and underlying mechanisms of immune protection against malaria could provide a clearer explanation of the differences between those protected in comparison with those not protected against malaria by vaccination.

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen-/- and compared those with virulent L.major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen-/- parasites, in contrast to virulent L.major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling.

Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes

Leishmaniasis is a tropical disease prevalent in 90 countries. Presently, there is no approved vaccine for human use. We developed a live attenuated L.mexicana Cen-/-(LmexCen-/-) strain as a vaccine candidate that showed excellent efficacy, characterized by reduced Th2 and enhanced Th1 responses in C57BL/6 and BALB/c mice, respectively, compared to wild-type L.mexicana (LmexWT) infection. Toward understanding the immune mechanisms of protection, we applied untargeted mass spectrometric analysis to LmexCen-/- and LmexWT infections. Data showed enrichment of the pentose phosphate pathway (PPP) in ears immunized with LmexCen-/-versus naive and LmexWT infection. PPP promotes M1 polarization in macrophages, suggesting a switch to a pro-inflammatory phenotype following LmexCen-/- inoculation. Accordingly, PPP inhibition in macrophages infected with LmexCen-/- reduced the production of nitric oxide and interleukin (IL)-1β, hallmarks of classical activation. Overall, our study revealed the immune regulatory mechanisms that may be critical for the induction of protective immunity.

Механизмы экологичного восстановления иммунной защиты Oreochromis niloticus прополисом с сенсибилизаторами на фоне развития кандидамикозов

In the last decade, with aquarium maintenance, pathogenic Candida albicans species are isolated from fish, causing up to 95-100% mortality. This paper describes the mechanisms of natural immune protection of Oreochromis niloticus, against the background of the development of candidiasis of the digestive tube under the influence of an environmentally friendly biologically active beekeeping product (BAPP) – propolis in combination with sensitizers. It was found that the use of propolis (group 3), propolis in combination with methylene blue (group 4), proflavin acetate (group 5), zinc phthalocyanine (group 6) contributed to an increase in lysozyme activity of blood serum, compared with the data of fish of group 2 (patients, untreated) by a maximum of 14.3; 19.13; 5.69 and 5.43 times, the bactericidal activity of blood serum – 4.1; 4.78; 2.27 and 2.25 times. This indicates the high efficiency, environmental friendliness of the use of propolis in combination with methylene blue for the prevention and therapy of developed candidiasis. Keywords: CANDIDAMYCOSIS, DIGESTIVE TRACT, CANDIDA ALBICANS, OREOCHROMIS NILOTICUS, PROPOLIS, LYSOZYME AND BACTERICIDAL ACTIVITY OF BLOOD SERUM