RESUMO
Several studies have investigated the antibody response to SARS-CoV-2, focusing particularly on the systemic humoral immune response and the production of immunoglobulin G (IgG) antibodies. IgA antibodies play a crucial role in protecting against respiratory viral infections but have also been associated with the pathophysiology of COVID-19. We performed a prospective study of 169 COVID-19 patients - 50 with critical/severe (ICU), 47 with moderate (Non-ICU), and 72 with asymptomatic COVID-19 - to explore the humoral immune response to SARS-CoV-2 infection. We found that the early systemic IgA response strongly induced in patients with severe disease did not block IgG neutralization functions and activated FcRs more effectively than IgG. However, even if SIgA levels were high, mucosal IgA antibodies could not control the infection effectively in patients with severe disease. Our findings highlight the complexity of the immune response to SARS-CoV-2 exhibiting high systemic levels of IgA with strong neutralizing capacity in severe cases, together with higher levels of IgA-FcR activation than in asymptomatic patients. They also suggest the need for further research to fully understand the role of IgA and its structural alterations in mucosal tissues in cases of severe disease and the impact of these antibodies on disease progression.
Assuntos
Anticorpos Antivirais , COVID-19 , Imunidade nas Mucosas , Imunoglobulina A , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Imunoglobulina A/imunologia , Estudos Prospectivos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Idoso , Adulto , Anticorpos Neutralizantes/imunologia , Índice de Gravidade de Doença , Imunidade HumoralRESUMO
Seminal plasma (SP) is the main vector of C. trachomatis (CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimental in vitro model to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.
Assuntos
Infecções por Chlamydia , Chlamydia trachomatis , Citocinas , Imunidade nas Mucosas , Neutrófilos , Sêmen , Chlamydia trachomatis/imunologia , Chlamydia trachomatis/fisiologia , Humanos , Feminino , Sêmen/imunologia , Sêmen/microbiologia , Sêmen/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Citocinas/metabolismo , Masculino , Células Epiteliais/microbiologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Fagocitose , Colo do Útero/microbiologia , Colo do Útero/imunologiaRESUMO
BACKGROUNDThe level of nasal spike-specific secretory IgA (sIgA) is inversely correlated with the risk of SARS-CoV-2 Omicron infection. This study aimed to evaluate the safety and immunogenicity of intranasal vaccination using Ad5-S-Omicron (NB2155), a replication-incompetent human type 5 adenovirus carrying Omicron BA.1 spike.METHODSAn open-label, single-center, investigator-initiated trial was carried out on 128 health care workers who had never been infected with SARS-CoV-2 and had previously received 2 or 3 injections of inactivated whole-virus vaccines, with the last dose given 3-19 months previously (median 387 days, IQR 333-404 days). Participants received 2 intranasal sprays of NB2155 at 28-day intervals between November 30 and December 30, 2022. Safety was evaluated by solicited adverse events and laboratory tests. The elevation of nasal mucosal spike-specific sIgA and serum neutralizing activities were assessed. All participants were monitored for infection by antigen tests, disease symptoms, and the elevation of nucleocapsid-specific sIgA in the nasal passage.RESULTSThe vaccine-related solicited adverse events were mild. Nasal spike-specific sIgA against 10 strains had a mean geometric mean fold increase of 4.5 after the first dose, but it increased much higher to 51.5 after the second dose. Serum neutralizing titers also increased modestly to 128.1 (95% CI 74.4-220.4) against authentic BA.1 and 76.9 (95% CI 45.4-130.2) against BA.5 at 14 days after the second dose. Due to the lifting of the zero-COVID policy in China on December 7, 2022, 57.3% of participants were infected with BA.5 between days 15 and 28 after the first dose, whereas no participants reported having any symptomatic infections between day 3 and day 90 after the second dose. The elevation of nasal nucleocapsid-specific sIgA on days 0, 14, 42, and 118 after the first dose was assessed to verify that these 2-dose participants had no asymptomatic infections.CONCLUSIONA 2-dose intranasal vaccination regimen using NB2155 was safe, was well tolerated, and could dramatically induce broad-spectrum spike-specific sIgA in the nasal passage. Preliminary data suggested that the intranasal vaccination may establish an effective mucosal immune barrier against infection and warranted further clinical studies.TRIAL REGISTRATIONChinese Clinical Trial Registry (ChiCTR2300070346).FUNDINGNatural Science Foundation of China, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunidade nas Mucosas , Imunoglobulina A Secretora , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenoviridae , Administração Intranasal , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vetores Genéticos/administração & dosagem , Imunoglobulina A Secretora/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodosRESUMO
SIV and HIV-based envelope V1-deleted (ΔV1) vaccines, delivered systemically by the DNA/ALVAC/gp120 platform, decrease the risk of mucosal SIV or SHIV acquisition more effectively than V1-replete vaccines. Here we investigated the induction of mucosal and systemic memory-like NK cells as well as antigen-reactive ILC response by DNA/ALVAC/gp120-based vaccination and their role against SIV/SHIV infection. ΔV1 HIV vaccination elicited a higher level of mucosal TNF-α+ and CD107+ memory-like NK cells than V1-replete vaccination, suggesting immunogen dependence. Mucosal memory-like NK cells, systemic granzyme B+ memory NK cells, and vaccine-induced mucosal envelope antigen-reactive IL-17+ NKp44+ ILCs, IL-17+ ILC3s, and IL-13+ ILC2 subsets were linked to a lower risk of virus acquisition. Additionally, mucosal memory-like NK cells and mucosal env-reactive IFN-γ+ ILC1s and env- reactive IL-13+ ILC2 subsets correlated with viral load control. We further observed a positive correlation between post-vaccination systemic and mucosal memory-like NK cells, suggesting vaccination enhances the presence of these cells in both compartments. Mucosal and systemic memory-like NK cells positively correlated with V2-specific ADCC responses, a reproducible correlate of reduced risk of SIV/HIV infection. In contrast, an increased risk was associated with the level of mucosal PMA/Ionomycin-induced IFN-γ+ and CD107+ NKG2A-NKp44- ILCs. Plasma proteomic analyses demonstrated that suppression of mucosal memory-like NK cells was linked to the level of CCL-19, LT-α, TNFSF-12, and IL-15, suppression of systemic env-reactive granzyme B+ memory-like NK cells was associated with the level of OLR1, CCL-3, and OSM, and suppression of IL-17+ ILCs immunity was correlated with the level of IL-6 and CXCL-9. In contrast, FLT3 ligand was associated with promotion of protective mucosal env-reactive IL-17+ responses. These findings emphasize the importance of mucosal memory-like NK cell and envelope- reactive ILC responses for protection against mucosal SIV/SHIV acquisition.
Assuntos
Memória Imunológica , Células Matadoras Naturais , Vacinas contra a SAIDS , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Células Matadoras Naturais/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vacinas contra a SAIDS/imunologia , Vacinas contra a SAIDS/administração & dosagem , Imunidade nas Mucosas , Macaca mulatta , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinação , Humanos , Mucosa/imunologiaRESUMO
BACKGROUND: Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome. METHODS: We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently. RESULTS: We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts. CONCLUSION: S. haematobium induces distinct alterations in the host's immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.
Assuntos
Imunidade nas Mucosas , Microbiota , Schistosoma haematobium , Esquistossomose Urinária , Esquistossomose Urinária/imunologia , Esquistossomose Urinária/tratamento farmacológico , Humanos , Animais , Schistosoma haematobium/genética , Schistosoma haematobium/imunologia , Anti-Helmínticos/uso terapêutico , Expressão Gênica , FenótipoRESUMO
A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunização Secundária , Imunoglobulina A , SARS-CoV-2 , Animais , Imunoglobulina A/imunologia , SARS-CoV-2/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Macaca mulatta , Adenoviridae/imunologia , Adenoviridae/genética , Imunidade nas Mucosas , Vacinas contra Adenovirus/imunologia , Vacinas contra Adenovirus/administração & dosagem , Feminino , Pulmão/virologia , Pulmão/imunologia , Linfócitos B/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Administração Intranasal , Vacinação/métodos , HumanosRESUMO
The mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-ß), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections.
Assuntos
Microbioma Gastrointestinal , Imunidade nas Mucosas , Imunoglobulina A , Humanos , Animais , Imunoglobulina A/imunologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos B/imunologia , Anticorpos Antibacterianos/imunologia , Linfócitos T/imunologia , Imunidade InataRESUMO
The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota and feeding schedule. Disruption of epithelial HDAC3 decreases tuft cell numbers, impairing antihelminth immunity and norovirus infection. Mechanistically, HDAC3 functions noncanonically to activate transforming growth factor-ß (TGF-ß) signaling, which promotes rhythmic expression of Pou2f3, a lineage-defining transcription factor of tuft cells. Our findings reveal an environmental-epigenetic link that controls the diurnal differentiation of tuft cells and promotes rhythmic mucosal surveillance and immune responses in anticipation of exogenous challenges.
Assuntos
Ritmo Circadiano , Histona Desacetilases , Mucosa Intestinal , Fator de Crescimento Transformador beta , Animais , Histona Desacetilases/metabolismo , Histona Desacetilases/imunologia , Ritmo Circadiano/imunologia , Camundongos , Mucosa Intestinal/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/imunologia , Camundongos Endogâmicos C57BL , Vigilância Imunológica , Microbioma Gastrointestinal/imunologia , Masculino , Camundongos Knockout , Feminino , Imunidade nas Mucosas , Células em TufoRESUMO
The importance of the complex interplay between the microbiome and mucosal immunity, particularly within the respiratory tract, has gained significant attention due to its potential implications for the severity and progression of lung diseases. Therefore, this review summarizes the specific interactions through which the respiratory tract-specific microbiome influences mucosal immunity and ultimately impacts respiratory health. Furthermore, we discuss how the microbiome affects mucosal immunity, considering tissue-specific variations, and its capacity in respiratory diseases containing asthma, chronic obstructive pulmonary disease, and lung cancer. Additionally, we investigate the external factors which affect the relationship between respiratory microbiome and mucosal immune responses. By exploring these intricate interactions, this review provides valuable insights into the potential for microbiome-based interventions to modulate mucosal immunity and alleviate the severity of respiratory diseases.
Assuntos
Progressão da Doença , Imunidade nas Mucosas , Microbiota , Humanos , Microbiota/imunologia , Asma/imunologia , Asma/microbiologia , Sistema Respiratório/microbiologia , Sistema Respiratório/imunologia , Animais , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doenças Respiratórias/imunologia , Doenças Respiratórias/microbiologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/microbiologiaRESUMO
Anticoccidial vaccines comprising living oocysts of Eimeria tenella, Eimeria necatrix, Eimeria maxima, and Eimeria acervulina are used to control coccidiosis. This study explored the potential of IL-1ß to act as a molecular adjuvant for enhancing the immunogenicity of Eimeria necatrix and mucosal immunity. We engineered E. necatrix to express a functional chIL-1ß (EnIL-1ß) and immunized chickens with oocysts of the wild type (EnWT) and tranegenic (EnIL-1ß) strains, respectively. The chickens were then challenged with EnWT oocysts to examine the immunogenicity-enhancing potential of chIL-1ß. As expected, the oocyst output of EnIL-1ß-immunized chickens was significantly reduced compared to those immunized using EnWT. No difference in body weight gain and lesion scores of EnIL-1ß and EnWT groups was observed. The parasite load in the small intestine and caeca showed that the invasion and replication of EnIL-1ß was not affected. However, the markers of immunogenicity and mucosal barrier, Claudin-1 and avian ß-defensin-1, were elevated in EnIL-1ß-infected chickens. Ectopic expression of chIL-1ß in E. necatrix thus appears to improve its immunogenicity and mucosal immunity, without increasing pathogenicity. Our findings support chIL-1ß as a candidate for development of effective live-oocyst-based anticoccidial vaccines.
Assuntos
Galinhas , Coccidiose , Eimeria , Imunidade nas Mucosas , Interleucina-1beta , Doenças das Aves Domésticas , Vacinas Protozoárias , Animais , Coccidiose/imunologia , Coccidiose/veterinária , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Galinhas/imunologia , Eimeria/imunologia , Vacinas Protozoárias/imunologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/parasitologia , Doenças das Aves Domésticas/prevenção & controle , Imunização , Oocistos/imunologia , Microrganismos Geneticamente ModificadosRESUMO
IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.
Assuntos
Imunidade nas Mucosas , Imunoglobulina A , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Receptores do Leucotrieno B4 , Transdução de Sinais , Animais , Metabolismo dos Lipídeos/imunologia , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Transdução de Sinais/imunologia , Camundongos , Receptores do Leucotrieno B4/metabolismo , Receptores do Leucotrieno B4/imunologia , Ácido Araquidônico/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Feminino , Microbioma Gastrointestinal/imunologia , Camundongos KnockoutRESUMO
The outbreak of coronavirus disease 19 (COVID-19) has highlighted the demand for vaccines that are safe and effective in inducing systemic and airway mucosal immunity against the aerosol transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we developed a novel helper-dependent adenoviral vector-based COVID-19 mucosal vaccine encoding a full-length SARS-CoV-2 spike protein (HD-Ad-FS). Through intranasal immunization (single-dose and prime-boost regimens), we demonstrated that the HD-Ad-FS was immunogenic and elicited potent systemic and airway mucosal protection in BALB/c mice, transgenic ACE2 (hACE2) mice, and hamsters. We detected high titers of neutralizing antibodies (NAbs) in sera and bronchoalveolar lavages (BALs) in the vaccinated animals. High levels of spike-specific secretory IgA (sIgA) and IgG were induced in the airway of the vaccinated animals. The single-dose HD-Ad-FS elicited a strong immune response and protected animals from SARS-CoV-2 infection. In addition, the prime-boost vaccination induced cross-reactive serum NAbs against variants of concern (VOCs; Beta, Delta, and Omicron). After challenge, VOC infectious viral particles were at undetectable or minimal levels in the lower airway. Our findings highlight the potential of airway delivery of HD-Ad-FS as a safe and effective vaccine platform for generating mucosal protection against SARS-CoV-2 and its VOCs.
Assuntos
Administração Intranasal , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunidade nas Mucosas , Camundongos Endogâmicos BALB C , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , COVID-19/prevenção & controle , COVID-19/imunologia , Camundongos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Cricetinae , Feminino , Humanos , Camundongos Transgênicos , Adenoviridae/genética , Adenoviridae/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , MesocricetusRESUMO
Introduction: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged as a deadly pathogen with a mortality rate of up to 36.2%. MERS-CoV can cause severe respiratory tract disease and multiorgan failure. Therefore, therapeutic vaccines are urgently needed. This intensive review explores the human immune responses and their immunological mechanisms during MERS-CoV infection in the mucosa of the upper and lower respiratory tracts (URT and LRT, respectively). Objective: The aim of this study is to provide a valuable, informative, and critical summary of the protective immune mechanisms against MERS-CoV infection in the URT/LRT for the purpose of preventing and controlling MERS-CoV disease and designing effective therapeutic vaccines. Methods: In this review, we focus on the immune potential of the respiratory tract following MERS-CoV infection. We searched PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar using the following terms: "MERS-CoV", "B cells", "T cells", "cytokines", "chemokines", "cytotoxic", and "upper and lower respiratory tracts". Results: We found and included 152 studies in this review. We report that the cellular innate immune response, including macrophages, dendritic cells, and natural killer cells, produces antiviral substances such as interferons and interleukins to prevent the virus from spreading. In the adaptive and humoral immune responses, CD4+ helper T cells, CD8+ cytotoxic T cells, B cells, and plasma cells protect against MERS-CoV infection in URT and LRT. Conclusion: The human nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) could successfully limit the spread of several respiratory pathogens. However, in the case of MERS-CoV infection, limited research has been conducted in humans with regard to immunopathogenesis and mucosal immune responses due to the lack of relevant tissues. A better understanding of the immune mechanisms of the URT and LRT is vital for the design and development of effective MERS-CoV vaccines.
Assuntos
Infecções por Coronavirus , Imunidade nas Mucosas , Coronavírus da Síndrome Respiratória do Oriente Médio , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Infecções por Coronavirus/prevenção & controle , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , Citocinas/imunologia , Imunidade Inata , Animais , Sistema Respiratório/imunologia , Sistema Respiratório/virologiaRESUMO
Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.
Assuntos
Imunidade nas Mucosas , Imunomodulação , Humanos , Animais , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Tecido Linfoide/imunologia , Vacinas/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Administração IntranasalRESUMO
Short-chain fatty acids (SCFAs), a subset of organic fatty acids with carbon chains ranging from one to six atoms in length, encompass acetate, propionate, and butyrate. These compounds are the endproducts of dietary fiber fermentation, primarily catalyzed by the glycolysis and pentose phosphate pathways within the gut microbiota. SCFAs act as pivotal energy substrates and signaling molecules in the realm of animal nutrition, exerting a profound influence on the intestinal, immune system, and intestinal barrier functions. Specifically, they contibute to 60-70% of the total energy requirements in ruminants and 10-25% in monogastric animals. SCFAs have demonstrated the capability to effectively modulate intestinal pH, optimize the absorption of mineral elements, and impede pathogen invasion. Moreover, they enhance the expression of proteins associated with intestinal tight junctions and stimulate mucus production, thereby refining intestinal tissue morphology and preserving the integrity of the intestinal structure. Notably, SCFAs also exert anti-inflammatory properties, mitigating inflammation within the intestinal epithelium and strengthening the intestinal barrier's defensive capabilities. The present review endeavors to synthesize recent findings regarding the role of SCFAs as crucial signaling intermediaries between the metabolic activities of gut microbiota and the status of porcine cells. It also provides a comprehensive overview of the current literature on SCFAs' impact on immune responses within the porcine intestinal mucosa.
Assuntos
Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Imunidade nas Mucosas , Mucosa Intestinal , Animais , Ácidos Graxos Voláteis/metabolismo , Suínos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Fenômenos Fisiológicos da Nutrição AnimalRESUMO
SARS-CoV-2 is a virus which infects the respiratory tract and may cause severe, occasionally life-threatening disease COVID-19. In more than 5% of symptomatic patients the infection is associated with post-acute symptoms. The initial contact of the virus with the immune system of the nasopharynx and oropharynx induces a mucosal immune response manifested by the production of secretory IgA (sIgA) antibodies which may contribute to the restriction of the infection to the upper respiratory tract and an asymptomatic or clinically mild disease. The current systemically administered vaccines protected against the severe COVID-19 infection and its post-acute sequelae. However, they do not induce antibodies in mucosal secretions in SARS-CoV-2-naive individuals. In contrast, in those who previously experienced mucosal infection, systemically administered vaccines may stimulate sIgA production. The clinical benefit of systemic vaccination convincingly documented in tens of millions of individuals overshadows the rare, sometimes controversial reports of complications encountered after vaccination. The inability of current SARS-CoV-2 vaccines to induce mucosal immune responses and to prevent the spreading of the virus by external secretions demonstrates the mutual independence of mucosal and systemic compartments of the immune system, and thus emphasizes need for the development of vaccines inducing protective immune responses in both compartments.
Assuntos
Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinação , Imunidade nas MucosasRESUMO
mRNA-based COVID-19 vaccines have played a critical role in reducing severe outcomes of COVID-19. Humoral immune responses against SARS-CoV-2 after vaccination have been extensively studied in blood; however, limited information is available on the presence and duration of SARS-CoV-2 specific antibodies in saliva and other mucosal fluids. Saliva offers a non-invasive sampling method that may also provide a better understanding of mucosal immunity at sites where the virus enters the body. Our objective was to evaluate the salivary immune response after vaccination with the COVID-19 Moderna mRNA-1273 vaccine. Two hundred three staff members of the U.S. Centers for Disease Control and Prevention were enrolled prior to receiving their first dose of the mRNA-1273 vaccine. Participants were asked to self-collect 6 saliva specimens at days 0 (prior to first dose), 14, 28 (prior to second dose), 42, and 56 using a SalivaBio saliva collection device. Saliva specimens were tested for anti-spike protein SARS-CoV-2 specific IgA and IgG enzyme immunoassays. Overall, SARS-CoV-2-specific salivary IgA titers peaked 2 weeks after each vaccine dose, followed by a sharp decrease during the following weeks. In contrast to IgA titers, IgG antibody titers increased substantially 2 weeks after the first vaccine dose, peaked 2 weeks after the second dose and persisted at an elevated level until at least 8 weeks after the first vaccine dose. Additionally, no significant differences in IgA/IgG titers were observed based on age, sex, or race/ethnicity. All participants mounted salivary IgA and IgG immune responses against SARS-CoV-2 after receiving the mRNA-1273 COVID-19 vaccine. Because of the limited follow-up time for this study, more data are needed to assess the antibody levels beyond 2 months after the first dose. Our results confirm the potential utility of saliva in assessing immune responses elicited by immunization and possibly by infection.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunoglobulina A , Imunoglobulina G , SARS-CoV-2 , Saliva , Vacinação , Humanos , Saliva/imunologia , Feminino , Masculino , Adulto , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Pessoa de Meia-Idade , Imunoglobulina A/imunologia , Imunoglobulina A/análise , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Vacina de mRNA-1273 contra 2019-nCoV , Adulto Jovem , Imunidade nas Mucosas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
IgA nephropathy is a mucosally driven disease and new therapeutic approaches are specifically targeting the mucosal production of IgA in the hope that this will lead to a reduction in circulating IgA immune complexes and mesangial IgA deposition. In this lecture, I discuss the rationale for targeting the mucosal immune system of the gut and the existing data from clinical trials supporting such an approach as a disease modifying treatment for IgA nephropathy.