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Human Vaccines & Immunotherapeutics Dec 2024Mucosal immunity plays a crucial role in combating and controlling the spread of highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recombinant...
Mucosal immunity plays a crucial role in combating and controlling the spread of highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recombinant subunit vaccines have shown safety and efficacy in clinical trials, but further investigation is necessary to evaluate their feasibility as mucosal vaccines. This study developed a SARS-CoV-2 mucosal vaccine using spike (S) proteins from a prototype strain and the omicron variant, along with a cationic chitosan adjuvant, and systematically evaluated its immunogenicity after both primary and booster immunization in mice. Primary immunization through intraperitoneal and intranasal administration of the S protein elicited cross-reactive antibodies against prototype strains, as well as delta and omicron variants, with particularly strong effects observed after mucosal vaccination. In the context of booster immunization following primary immunization with inactivated vaccines, the omicron-based S protein mucosal vaccine resulted in a broader and more robust neutralizing antibody response in both serum and respiratory mucosa compared to the prototype vaccine, enhancing protection against different variants. These findings indicate that mucosal vaccination with the S protein has the potential to trigger a broader and stronger antibody response during primary and booster immunization, making it a promising strategy against respiratory pathogens.
Topics: Animals; Spike Glycoprotein, Coronavirus; Administration, Intranasal; Mice; Immunization, Secondary; COVID-19 Vaccines; Antibodies, Neutralizing; Antibodies, Viral; SARS-CoV-2; COVID-19; Mice, Inbred BALB C; Female; Immunity, Mucosal; Immunogenicity, Vaccine; Cross Reactions; Chitosan; Adjuvants, Vaccine; Vaccines, Inactivated
PubMed: 38880868
DOI: 10.1080/21645515.2024.2364519 -
Scientific Reports Jun 2024Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and...
Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses.
Topics: Influenza Vaccines; Animals; Mice; Hemagglutinin Glycoproteins, Influenza Virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Adjuvants, Immunologic; Antibodies, Viral; Orthomyxoviridae Infections; Administration, Intranasal; Female; Mice, Inbred BALB C; Intercellular Signaling Peptides and Proteins; Adjuvants, Vaccine
PubMed: 38877101
DOI: 10.1038/s41598-024-64351-7 -
Life Science Alliance Sep 2024Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to...
Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs), and the HIF-1α subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46 ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46 ILC1s but a concomitant rise in neutrophils and Ly6C macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.
Topics: Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Natural Cytotoxicity Triggering Receptor 1; Mice; Colitis; Fibrosis; Mice, Knockout; Lymphocytes; Intestinal Mucosa; Inflammation; Mice, Inbred C57BL; Chronic Disease; Immunity, Innate; Signal Transduction; Disease Models, Animal; Male; Intestines; Antigens, Ly
PubMed: 38876796
DOI: 10.26508/lsa.202402593 -
Journal of Virology Jun 2024The reoccurrence of successive waves of SARS-CoV-2 variants suggests the exploration of more vaccine alternatives is imperative. Modified vaccinia virus Ankara (MVA) is...
UNLABELLED
The reoccurrence of successive waves of SARS-CoV-2 variants suggests the exploration of more vaccine alternatives is imperative. Modified vaccinia virus Ankara (MVA) is a virus vector exhibiting excellent safety as well as efficacy for vaccine development. Here, a series of recombinant MVAs (rMVAs) expressing monomerized or trimerized S proteins from different SARS-CoV-2 variants are engineered. Trimerized S expressed from rMVAs is found predominantly as trimers on the surface of infected cells. Remarkably, immunization of mice with rMVAs demonstrates that S expressed in trimer elicits higher levels of binding IgG and IgA, as well as neutralizing antibodies for matched and mismatched S proteins than S in the monomer. In addition, trimerized S expressed by rMVA induces enhanced cytotoxic T-cell responses than S in the monomer. Importantly, the rMVA vaccines expressing trimerized S exhibit superior protection against a lethal SARS-CoV-2 challenge as the immunized animals all survive without displaying any pathological conditions. This study suggests that opting for trimerized S may represent a more effective approach and highlights that the MVA platform serves as an ideal foundation to continuously advance SARS-CoV-2 vaccine development.
IMPORTANCE
MVA is a promising vaccine vector and has been approved as a vaccine for smallpox and mpox. Our analyses suggested that recombinant MVA expressing S in trimer (rMVA-ST) elicited robust cellular and humoral immunity and was more effective than MVA-S-monomer. Importantly, the rMVA-ST vaccine was able to stimulate decent cross-reactive neutralization against pseudoviruses packaged using S from different sublineages, including Wuhan, Delta, and Omicron. Remarkably, mice immunized with rMVA-ST were completely protected from a lethal challenge of SARS-CoV-2 without displaying any pathological conditions. Our results demonstrated that an MVA vectored vaccine expressing trimerized S is a promising vaccine candidate for SARS-CoV-2 and the strategy might be adapted for future vaccine development for coronaviruses.
PubMed: 38874361
DOI: 10.1128/jvi.00521-24 -
International Journal of Reproductive... Mar 2023Endometriosis is a chronic estrogen-related inflammatory disorder that is known by proliferating endometrial cells in a place outside the uterus. The high presence of...
Human V 7.2-J 33 mucosal-associated invariant T cells in endometrial ectopic tissues tend to produce interferon-gamma: A new player in endometriosis etiology: A case-control study.
BACKGROUND
Endometriosis is a chronic estrogen-related inflammatory disorder that is known by proliferating endometrial cells in a place outside the uterus. The high presence of immune cells in the peritoneal fluid of women with endometriosis confirms the involvement of the immune system in the pathogenesis of the disease. Mucosal-associated invariant T (MAIT) cells play an undeniable impact on mucosal immunity by the production of interleukin-17, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha. The function of the cells in the pathogenesis of endometriosis is less investigated.
OBJECTIVE
This study aims to investigate the infiltration of MAIT cells by using the determination levels of gene expression in eutopic and ectopic tissue of endometriosis lesions.
MATERIALS AND METHODS
In this case-control study, the tested samples include 20 eutopic and 20 ectopic tissues of women with endometriosis and 20 uterine endometrial tissues of women in the control group. Expressions of the tumor necrosis factor-alpha, interleukin-17A, and -γ genes were analyzed by quantitative reverse transcriptase-polymerase chain reaction.
RESULTS
According to the results, gene expression did not show substantial elevation in the uterine and eutopic endometrial tissues compared to internal gene control as well as in ectopic tissues. Correlation analysis approved a positive relationship between expression genes and -γ levels in ectopic tissues.
CONCLUSION
Considering the low-expression specific gene of MAIT cells in ectopic tissue, it can be concluded that these cells are present in the endometriotic environment to a certain extent, and there is a possibility of their role in the progression of endometriosis by secreting IFN- .
PubMed: 38868448
DOI: 10.18502/ijrm.v22i3.16168 -
Microbial Cell Factories Jun 2024There is increasing evidence that probiotic and commensal bacteria play a role in substrate metabolism, energy harvesting and intestinal homeostasis, and may exert... (Review)
Review
There is increasing evidence that probiotic and commensal bacteria play a role in substrate metabolism, energy harvesting and intestinal homeostasis, and may exert immunomodulatory activities on human health. In addition, recent research suggests that these microorganisms interact with vitamins and minerals, promoting intestinal and metabolic well-being while producing vital microbial metabolites such as short-chain fatty acids (SCFAs). In this regard, there is a flourishing field exploring the intricate dynamics between vitamins, minerals, SCFAs, and commensal/probiotic interactions. In this review, we summarize some of the major hypotheses beyond the mechanisms by which commensals/probiotics impact gut health and their additional effects on the absorption and metabolism of vitamins, minerals, and SCFAs. Our analysis includes comprehensive review of existing evidence from preclinical and clinical studies, with particular focus on the potential interaction between commensals/probiotics and micronutrients. Finally, we highlight knowledge gaps and outline directions for future research in this evolving field.
Topics: Probiotics; Humans; Vitamins; Minerals; Gastrointestinal Microbiome; Fatty Acids, Volatile; Bacteria; Symbiosis; Animals
PubMed: 38867272
DOI: 10.1186/s12934-024-02449-3 -
Respiratory Research Jun 2024Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their...
BACKGROUND
Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein.
METHODS
Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry.
RESULTS
Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls.
CONCLUSION
Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.
Topics: Humans; Male; HIV Infections; Female; Middle Aged; Adult; Respiratory Mucosa; CD8-Positive T-Lymphocytes; T-Lymphocytes, Cytotoxic; Smoking; Bronchoalveolar Lavage Fluid; Anti-Retroviral Agents; Anti-HIV Agents; Lung
PubMed: 38867225
DOI: 10.1186/s12931-024-02859-2 -
COVID-19 influenced gut dysbiosis, post-acute sequelae, immune regulation, and therapeutic regimens.Frontiers in Cellular and Infection... 2024The novel coronavirus disease 2019 (COVID-19) pandemic outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has garnered unprecedented global... (Review)
Review
The novel coronavirus disease 2019 (COVID-19) pandemic outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has garnered unprecedented global attention. It caused over 2.47 million deaths through various syndromes such as acute respiratory distress, hypercoagulability, and multiple organ failure. The viral invasion proceeds through the ACE2 receptor, expressed in multiple cell types, and in some patients caused serious damage to tissues, organs, immune cells, and the microbes that colonize the gastrointestinal tract (GIT). Some patients who survived the SARS-CoV-2 infection have developed months of persistent long-COVID-19 symptoms or post-acute sequelae of COVID-19 (PASC). Diagnosis of these patients has revealed multiple biological effects, none of which are mutually exclusive. However, the severity of COVID-19 also depends on numerous comorbidities such as obesity, age, diabetes, and hypertension and care must be taken with respect to other multiple morbidities, such as host immunity. Gut microbiota in relation to SARS-CoV-2 immunopathology is considered to evolve COVID-19 progression via mechanisms of biochemical metabolism, exacerbation of inflammation, intestinal mucosal secretion, cytokine storm, and immunity regulation. Therefore, modulation of gut microbiome equilibrium through food supplements and probiotics remains a hot topic of current research and debate. In this review, we discuss the biological complications of the physio-pathological effects of COVID-19 infection, GIT immune response, and therapeutic pharmacological strategies. We also summarize the therapeutic targets of probiotics, their limitations, and the efficacy of preclinical and clinical drugs to effectively inhibit the spread of SARS-CoV-2.
Topics: COVID-19; Humans; Dysbiosis; Gastrointestinal Microbiome; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Probiotics; Gastrointestinal Tract; COVID-19 Drug Treatment
PubMed: 38863829
DOI: 10.3389/fcimb.2024.1384939 -
Frontiers in Immunology 2024Known for their distinct antigen-sampling abilities, microfold cells, or M cells, have been well characterized in the gut and other mucosa including the lungs and... (Review)
Review
Known for their distinct antigen-sampling abilities, microfold cells, or M cells, have been well characterized in the gut and other mucosa including the lungs and nasal-associated lymphoid tissue (NALT). More recently, however, they have been identified in tissues where they were not initially suspected to reside, which raises the following question: what external and internal factors dictate differentiation toward this specific role? In this discussion, we will focus on murine studies to determine how these cells are identified (e.g., markers and function) and ask the broader question of factors triggering M-cell localization and patterning. Then, through the consideration of unconventional M cells, which include villous M cells, Type II taste cells, and medullary thymic epithelial M cells (microfold mTECs), we will establish the M cell as not just a player in mucosal immunity but as a versatile niche cell that adapts to its home tissue. To this end, we will consider the lymphoid structure relationship and apical stimuli to better discuss how the differing cellular programming and the physical environment within each tissue yield these cells and their unique organization. Thus, by exploring this constellation of M cells, we hope to better understand the multifaceted nature of this cell in its different anatomical locales.
Topics: Animals; Mice; Immunity, Mucosal; Lymphoid Tissue; Humans; Epithelial Cells; Cell Differentiation; Intestinal Mucosa; Stem Cell Niche; M Cells
PubMed: 38863701
DOI: 10.3389/fimmu.2024.1400739 -
Gut Jun 2024Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and...
OBJECTIVE
Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis.
DESIGN
We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model.
RESULTS
We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature.
CONCLUSIONS
Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.
PubMed: 38857990
DOI: 10.1136/gutjnl-2024-332043