RESUMO
Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.
Assuntos
Armadilhas Extracelulares/fisiologia , Mucosa/imunologia , Dermatopatias/imunologia , Células Epiteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/fisiologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Dermatopatias/patologiaRESUMO
Lactic acid bacteria comprise a large group of Gram-positive organisms capable of converting sugar into lactic acid. They have been studied due to their therapeutic potential on the mucosal surface. Among the species, Lactococcus lactis is considered the model bacterium and it has been explored as an important vehicle for providing therapeutic molecules and antigens in the mucosa. They can be genetically engineered to produce a variety of molecules as well as deliver heterologous DNA and protein. DNA vaccines consist of the administration of a bacterial plasmid under the control of a eukaryotic promoter encoding the antigen of interest. The resulting proteins are capable of stimulating the immune system, becoming a promising technique for immunization against a variety of tumors and infection diseases and having several advantages compared to conventional nucleic acid delivery methods (such as bioballistic delivery, electroporation, and intramuscular administration).
Assuntos
Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Lactobacillales , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Administração Intranasal , Administração Sublingual , Animais , Camundongos , Mucosa/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologiaRESUMO
While most HPV infections are asymptomatic and clear spontaneously, persistent infection with high-risk HPVs is associated with cervical cancer and with increased risk of HIV acquisition. Although several hypotheses have been proposed to explain this phenomenon, none has been confirmed. Our aim was to investigate the expression of host factors involved in the susceptibility to HIV infection among HPV-infected women. Cervical samples were collected to characterize the expression levels of HIV susceptibility markers in the mucosa of HPV-infected compared with HPV-uninfected women. No differences in the frequency of CCR5+, integrin α4ß7+, activated and memory CD4+ T-cell were detected between the groups. We additionally evaluated the expression levels of genes involved in innate immune responses and in cell adhesion. HPV infected patients expressed higher levels of TLR9 and lower levels of pattern recognition receptors that recognize RNA (TLR3, TLR7, and MDA5/IFIH1). We also detected an impaired IFN pathway, with an increased Type I IFN and a decreased IFNα2 receptor expression. HPV+ samples displayed reduced expression of genes for adherens and tight junctions. Taken together, these results suggest that although HPV infection does not result in the recruitment/activation of susceptible CD4+ T-cell in the female genital tract, it leads to changes in the innate antiviral immune responses and in cell adhesion that are likely to favor HIV infection.
Assuntos
Moléculas de Adesão Celular/genética , Colo do Útero/patologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Mucosa/imunologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/imunologia , Adulto , Biomarcadores/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade Inata , Pessoa de Meia-Idade , Risco , Transcriptoma , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
BACKGROUND: Host-microbiota interactions shape T-cell differentiation and promote tumour immunity. Although IL-9-producing T cells have been described as potent antitumour effectors, their role in microbiota-mediated tumour control remains unclear. METHODS: We analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice. RESULTS: We show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Long-term antibiotic treatment promotes host dysbiosis, diminishes intestinal IL-4 and TGF-ß gene expression, decreases the frequency of colonic lamina propria IL-9-producing T cells, increases the susceptibility to tumour development and reduces the frequency of IL-9-producing T cells in the tumour microenvironment. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Finally, recombinant IL-9 injection enhances tumour control in dysbiotic mice. CONCLUSIONS: Host-microbiota interactions are required for adequate differentiation and antitumour function of IL-9-producing T cells.
Assuntos
Antibacterianos/efeitos adversos , Disbiose/imunologia , Vida Livre de Germes , Interleucina-9/metabolismo , Melanoma/microbiologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Disbiose/induzido quimicamente , Disbiose/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Interleucina-4/metabolismo , Masculino , Melanoma/imunologia , Camundongos , Mucosa/efeitos dos fármacos , Mucosa/imunologia , Transplante de Neoplasias , Linfócitos T/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Microambiente TumoralRESUMO
KEY MESSAGE: A plant-based multiepitopic protein (LTBentero) containing epitopes from ETEC, S. typhimurium, and V. parahaemolyticus was produced in plants cells and triggered systemic and intestinal humoral responses in immunized mice. Around 200 million people suffer gastroenteritis daily and more than 2 million people die annually in developing countries due to such pathologies. Vaccination is an alternative to control this global health issue, however new low-cost vaccines are needed to ensure proper vaccine coverage. In this context, plants are attractive hosts for the synthesis and delivery of subunit vaccines. Therefore, in this study a plant-made multiepitopic protein named LTBentero containing epitopes from antigens of enterotoxigenic E. coli, S. typhimurium, and V. parahaemolyticus was produced and found immunogenic in mice. The LTBentero protein was expressed in tobacco plants at up to 5.29 µg g-1 fresh leaf tissue and was deemed immunogenic when administered to BALB/c mice either orally or subcutaneously. The plant-made LTBentero antigen induced specific IgG (systemic) and IgA (mucosal) responses against LTB, ST, and LptD epitopes. In conclusion, multiepitopic LTBentero was functionally produced in plant cells, being capable to trigger systemic and intestinal humoral responses and thus it constitutes a promising oral immunogen candidate in the fight against enteric diseases.
Assuntos
Toxinas Bacterianas/imunologia , Epitopos/imunologia , Imunização , Proteínas de Plantas/imunologia , Proteínas Recombinantes/imunologia , Vacinas de Plantas Comestíveis/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Toxinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Escherichia coli Enterotoxigênica/genética , Escherichia coli Enterotoxigênica/imunologia , Epitopos/genética , Feminino , Regulação da Expressão Gênica de Plantas , Imunoglobulina A , Imunoglobulina G , Camundongos , Camundongos Endogâmicos BALB C , Mucosa/imunologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/imunologia , Plantas Geneticamente Modificadas/metabolismo , Proteínas Recombinantes/metabolismo , Nicotiana/genética , Vacinação , Vacinas de Plantas Comestíveis/genéticaRESUMO
In the context of HIV sexual transmission at the genital mucosa, initial interactions between the virus and the mucosal immunity determine the outcome of the exposure. Hence, these interactions have been deeply explored in attempts to undercover potential targets for developing preventative strategies. The knowledge gained has led to propose a hypothetical model for mucosal HIV transmission. Subsequent research studies on this topic further revealed new mechanisms and identified new host-HIV interactions. This review aims at integrating these findings to inform better and update the current model of HIV transmission. At the earliest stage of virus exposure, the epithelial integrity and the presence of antiviral factors are critical in preventing viral entry to the submucosa. However, the virus has been shown to enter to the submucosa in the presence of physical abrasion or via epithelial transmigration using paracellular passage or transcytosis mechanisms. The efficiency of these processes is greater with cell-associated viral inoculums and can be influenced by the presence of viral and immune factors, and by the structure of the exposed epithelium. Once the virus reaches the submucosa, dendritic cells and fibroblasts, as recently described, have been shown in vitro of being capable of facilitating the transfer of viral particles to susceptible cells, leading to viral dissemination, most likely in a trans-infection manner. The presence of activated CD4+ T cells in submucosa increases the probability of infection, where the predominant microbiota could be implicated through the modulation of an inflammatory microenvironment. Other factors such as genital fluids and hormones could also play an essential role in HIV transmission. Here, we review the most recent evidence described for mucosal HIV-transmission contributing with the understanding of this phenomenon.
Assuntos
Infecções por HIV/transmissão , Mucosa/virologia , Animais , Genitália/imunologia , Infecções por HIV/imunologia , Humanos , Imunidade nas Mucosas , Mucosa/imunologiaRESUMO
The aim of this study was to evaluate the effectiveness of antiretroviral treatment (ART) on the proportion and functions of Th17 and Treg cells in peripheral blood and female genital tract (FGT) respectively. To this aim, samples from 41 HIV-neg, 33 HIV+ ART-naïve and 32 HIV+ ART+ subjects were obtained. In peripheral blood, altered Th17 and Th17/Treg proportions were normalized in HIV+ ART+, but certain abnormal Treg and activated T-cell proportions were still observed. In FGT, abnormal patterns of secretion for Th17-related cytokines were observed in cervical mononuclear cells (CMCs) from HIV+ women, even in those from HIV+ ART+, compared to the HIV-neg group. Moreover, these altered patterns of secretion were associated with diminished levels of CXCL5 and CXCL1 chemokines and with an immunoregulatory skew in the CCL17/CCL20 ratio in ectocervix samples of these women. Finally, ART did not restore proportions of Th17-precursor cells with gut-homing potential in PBMCs, and positive correlations between these cells and the levels of IL-17F and IL-21 production by CMCs may suggest that a better homing of these cells to the intestine could also imply a better restoration of these cells in the female genital tract. These results indicate that antiretroviral treatment did not restore Th17-related immune functions completely at the female mucosal level.
Assuntos
Antirretrovirais/farmacologia , Citocinas/análise , Genitália Feminina/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Quimiocina CCL17/análise , Quimiocina CCL20/análise , Quimiocina CXCL1/análise , Quimiocina CXCL5/análise , Feminino , Genitália Feminina/citologia , Genitália Feminina/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Interleucina-17/análise , Masculino , Pessoa de Meia-Idade , Mucosa/citologia , Mucosa/imunologia , Mucosa/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacosRESUMO
Zika virus (ZIKV) infection has extended rapidly all over the world in the last decades affecting humans of all ages, inducing severe illness such as the autoimmune Guillain-Barré syndrome as well as fetal neurodevelopmental defects. Despite the epidemiological importance of ZIKV, today there are no commercially available drugs or vaccines to combat or prevent this infection. Microalgae are attractive hosts to produce and deliver vaccines, with some candidates under preclinical evaluation. Herein, algae-based expression was assessed for the production of a new vaccine candidate against ZIKV called ZK. The Algevir technology was applied to express an antigenic protein called ZK comprising the B subunit of the heat labile Escherichia coli enterotoxin along with 3 epitopes from the ZIKV envelope glycoprotein. Efficient expression of the ZK antigen was achieved in Schizochytrium sp. with yields of up to 365⯵g g-1 microalgae fresh weight. Upon oral administration in mice, the microalgae-made ZK protein elicited significant humoral responses at a higher magnitude to those induced upon subcutaneous immunization. The algae-made ZK vaccine represents a promising candidate to formulate attractive vaccines against ZIKV.
Assuntos
Antígenos Virais/genética , Epitopos/genética , Microalgas/genética , Estramenópilas/genética , Proteínas do Envelope Viral/genética , Vacinas Virais , Zika virus/genética , Administração Oral , Animais , Antígenos Virais/imunologia , Epitopos/imunologia , Feminino , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Mucosa/imunologia , Proteínas do Envelope Viral/imunologia , Zika virus/imunologia , Infecção por Zika virus/prevenção & controleRESUMO
Immunological interdependence between the two eyes has been reported for the cornea and the retina but not for the ocular mucosal surface. Intriguingly, patients frequently report ocular surface-related symptoms in the other eye after unilateral ocular surgery. Here we show how unilateral eye injuries in mice affect the mucosal immune response of the opposite ocular surface. We report that, despite the lack of lymphatic cross-drainage, a neurogenic inflammatory reflex in the contralateral conjunctiva is sufficient to increase, first, epithelial nuclear factor kappa B signaling, then, dendritic cell maturation, and finally, expansion of effector, instead of regulatory, T cells in the draining lymph node, leading to disrupted ocular mucosal tolerance. We also show that damage to ocular surface nerves is required. Using pharmacological inhibitors and agonists, we identified transient receptor potential vanilloid 1 (TRPV1) channel as the receptor sensing tissue damage in the injured eye and substance P released in the opposite ocular surface as the effector of the sympathetic response. Finally, blocking either step prevented subsequent ocular allergic reactions in the opposite eye in a unilateral corneal alkali burn model. This study demonstrates that both ocular surfaces are immunologically linked and suggests potential therapeutic targets for intervention.
Assuntos
Olho/imunologia , Inflamação/imunologia , Mucosa/imunologia , Substância P/imunologia , Canais de Cátion TRPV/imunologia , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Linfonodos/imunologia , Melanoma , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Leishmania (Viannia) guyanensis is a causal agent of American tegumentary leishmaniasis (ATL). This protozoan has been poorly investigated; however, it can cause different clinical forms of ATL, ranging from a single cutaneous lesion to severe lesions that can lead to destruction of the nasopharyngeal mucosa. L. (V.) guyanensis and the disease caused by this species can present unique aspects revealing the need to better characterize this parasite species to improve our knowledge of the immunopathological mechanisms and treatment options for ATL. The mechanisms by which some patients develop a more severe form of ATL remain unclear. It is known that the host immune profile and parasite factors may influence the clinical manifestations of the disease. Besides intrinsic parasite factors, Leishmaniavirus RNA 1 (LRV1) infecting L. guyanensis can contribute to ATL immunopathogenesis. In this review, general aspects of L. guyanensis infection in humans and mouse models are presented.