RESUMO
The conventional function described for platelets is maintaining vascular integrity. Nevertheless, increasing evidence reveals that platelets can additionally play a crucial role in responding against microorganisms. Activated platelets release molecules with antimicrobial activity. This ability was first demonstrated in rabbit serum after coagulation and later in rabbit platelets stimulated with thrombin. Currently, multiple discoveries have allowed the identification and characterization of PMPs (platelet microbicidal proteins) and opened the way to identify kinocidins and CHDPs (cationic host defense peptides) in human platelets. These molecules are endowed with microbicidal activity through different mechanisms that broaden the platelet participation in normal and pathologic conditions. Therefore, this review aims to integrate the currently described platelet molecules with antimicrobial properties by summarizing the pathways towards their identification, characterization, and functional evaluation that have promoted new avenues for studying platelets based on kinocidins and CHDPs secretion.
Assuntos
Anti-Infecciosos/sangue , Plaquetas/química , Plaquetas/microbiologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/classificação , Anti-Infecciosos/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Antiparasitários/imunologia , Antivirais/imunologia , Plaquetas/imunologia , Humanos , Ribonucleases/imunologiaRESUMO
The term host defense peptides arose at the beginning to refer to those peptides that are part of the host's immunity. Because of their broad antimicrobial capacity and immunomodulatory activity, nowadays, they emerge as a hope to combat resistant multi-drug microorganisms and emerging viruses, such as the case of coronaviruses. Since the beginning of this century, coronaviruses have been part of different outbreaks and a pandemic, and they will be surely part of the next pandemics, this review analyses whether these peptides and their derivatives are ready to be part of the treatment of the next coronavirus pandemic.
Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Pandemias , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/imunologia , Antivirais/síntese química , Antivirais/imunologia , Ensaios Clínicos como Assunto , Coronavirus/efeitos dos fármacos , Coronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunomodulação , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologiaRESUMO
INTRODUCTION: Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection. METHODS: We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment. RESULTS: Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1ß by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC. CONCLUSION: Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Calcitriol/administração & dosagem , Infecções por HIV/prevenção & controle , Ativação Linfocitária/efeitos dos fármacos , Vitaminas/administração & dosagem , Desaminase APOBEC-3G/imunologia , Desaminase APOBEC-3G/metabolismo , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Feminino , Infecções por HIV/sangue , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Masculino , Cultura Primária de Células , CatelicidinasRESUMO
Selective pressure imposed by millions of years of relentless biological attack has led to the development of an extraordinary array of defense strategies in plants. Among these, antimicrobial peptides (AMPs) stand out as one of the most prominent components of the plant immune system. These small and usually basic peptides are deployed as a generalist defense strategy that grants direct and durable resistance against biotic stress. Even though their name implies a function against microbes, the range of plant-associated organisms affected by these peptides is much broader. In this review, we highlight the advances in our understanding on the role of AMPs in plant immunity. We demonstrate that the capacity of plant AMPs to act against a large spectrum of enemies relies on their diverse mechanism of action and remarkable structural stability. The efficacy of AMPs as a defense strategy is evidenced by their widespread occurrence in the plant kingdom, an astonishing heterogeneity in host peptide composition, and the extent to which plant enemies have evolved effective counter-measures to evade AMP action. Plant AMPs are becoming an important topic of research due to their significance in allowing plants to thrive and for their enormous potential in agronomical and pharmaceutical fields.
Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Imunidade Vegetal/genética , Antibiose/imunologia , Peptídeos Catiônicos Antimicrobianos/genética , Interações Hospedeiro-Parasita/imunologia , Interações Hospedeiro-Patógeno/imunologiaRESUMO
Since the early 19th century, host-defense peptides (HDPs) have been known to play a crucial role in innate host defense. Subsequent work has demonstrated their role in adaptive immunity as well as their involvement in cancer and also a number of inflammatory and/or autoimmune diseases. In addition to these multiple functional activities, several studies have shown that HDP accumulation might be correlated with various human diseases and, therefore, could be used as a biomarkers for such. Thus, research has aimed to validate the clinical use of HDPs for diagnosis, prognosis, and further treatment. In this review, we outline the most recent findings related to the use of HDPs as biomarkers, their clinical and epidemiological value, and the techniques used to determine the levels of HDPs.
Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/metabolismo , Imunidade Adaptativa , Peptídeos Catiônicos Antimicrobianos/imunologia , Bactérias/imunologia , Bactérias/metabolismo , Biomarcadores/metabolismo , Diagnóstico Precoce , Interações Hospedeiro-Patógeno , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Imunidade Inata , Valor Preditivo dos Testes , PrognósticoRESUMO
Antimicrobial peptides (AMPs) are key elements of plant defense mechanisms, resembling conserved protection strategies also present in mammals. Among the AMPs, plant thionins are particularly interesting due that display antibacterial and antifungal activities. In Arabidopsis thaliana have been described four thionins: Thi2.1, Thi2.2, Thi2.3 and Thi2.4. Work from our group shows that Thi2.1 expressed by bovine endothelial cells has direct antibacterial activity against Staphylococcus aureus mastitis isolates, bacteria able to persist inside bovine mammary epithelial cells (bMECs). Thus, the objective of this work was to analyze the immunomodulatory effects of the AMP thionin Thi2.1 from A. thaliana on bMECs during S. aureus infection. According to the results, S. aureus internalization into bMECs was reduced in cells pre-treated with Thi2.1 at 5 and 10⯵g/mL during 24â¯h, effect related to the participation of TLR2. In addition, bMECs pre-treated with Thi2.1 (24â¯h) significantly increased TNF-α (~2-fold) and IL-6 (~7-fold), whereas decreased IL-10 gene expression (~0.5-fold). Interestingly, Thi2.1 inhibits the up-regulation induced by S. aureus of TNF-α and IL-10 gene expression, as well as NO production. In addition, Thi2.1 (10⯵g/mL) up-regulates the expression of the chemokine IL-8 (~3-fold) in infected bMECs. Some of these effects are related to TLR2 activation. In this sense, Thi2.1 also reduces S. aureus-induced TLR2 gene expression and membrane abundance. In conclusion, Thi2.1 from A. thaliana modulates bMEC innate immune response by inducing the production of pro- and anti-inflammatory molecules while inhibits S. aureus internalization. Some of these effects are mediated by TLR2.
Assuntos
Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/imunologia , Proteínas de Arabidopsis/imunologia , Células Epiteliais/fisiologia , Fatores Imunológicos/uso terapêutico , Infecções Estafilocócicas/terapia , Staphylococcus aureus/fisiologia , Animais , Arabidopsis/imunologia , Bovinos , Células Cultivadas , Células Epiteliais/microbiologia , Humanos , Interleucina-10/metabolismo , Interleucina-8/metabolismo , Glândulas Mamárias Humanas/citologia , Transdução de Sinais , Infecções Estafilocócicas/imunologia , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The amphibian skin plays an important role protecting the organism from external harmful factors such as microorganisms or UV radiation. Based on biorational strategies, many studies have investigated the cutaneous secretion of anurans as a source of bioactive molecules. By a peptidomic approach, a novel antioxidant peptide (AOP) with in vitro free radical scavenging ability was isolated from Physalaemus nattereri. The AOP, named antioxidin-I, has a molecular weight [M+H]+ = 1543.69Da and a TWYFITPYIPDK primary amino acid sequence. The gene encoding the antioxidin-I precursor was expressed in the skin tissue of three other Tropical frog species: Phyllomedusa tarsius, P. distincta and Pithecopus rohdei. cDNA sequencing revealed highly homologous regions (signal peptide and acidic region). Mature antioxidin-I has a novel primary sequence with low similarity compared with previously described amphibian's AOPs. Antioxidin-I adopts a random structure even at high concentrations of hydrophobic solvent, it has poor antimicrobial activity and poor performance in free radical scavenging assays in vitro, with the exception of the ORAC assay. However, antioxidin-I presented a low cytotoxicity and suppressed menadione-induced redox imbalance when tested with fibroblast in culture. In addition, it had the capacity to substantially attenuate the hypoxia-induced production of reactive oxygen species when tested in hypoxia exposed living microglial cells, suggesting a potential neuroprotective role for this peptide.
Assuntos
Proteínas de Anfíbios/genética , Peptídeos Catiônicos Antimicrobianos/genética , Anuros/fisiologia , Infecções Bacterianas/imunologia , Fibroblastos/fisiologia , Microglia/metabolismo , Pele/metabolismo , Proteínas de Anfíbios/imunologia , Proteínas de Anfíbios/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Antioxidantes/metabolismo , Clonagem Molecular , Sequestradores de Radicais Livres/metabolismo , Camundongos , Estrutura Molecular , Células NIH 3T3 , Neuroproteção , Oxirredução , Conformação Proteica , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cathelicidin are innate antimicrobial peptides with broad immunomodulatory functions; however, their role in regulating intestinal defenses is not well characterized. This study aimed to investigate the role of cathelicidin modulating expression of Toll-like receptors (TLRs) 4 and 9 in colonic epithelium in response to bacterial patterns. We demonstrated herein that intestinal epithelial cells, when primed by bacterial lipopolysaccharide (LPS), responded to cathelicidin by increased transcription and protein synthesis of TLR4. This cathelicidin-induced response required the interaction of LPS-TLR4 and activation of MAPK signalling pathways. However, cathelicidin blocked TLR9 responses induced by TLR9 ligand CpG oligodeoxynucleotide (CpG ODN) in these colonic epithelial cells. Modulations of TLRs triggered by cathelicidin in intestinal epithelium occurred mainly in the apical compartment of intestinal cells. Activation of TLR4 by ligands in combination with cathelicidin promoted CXCL8 chemokine secretion and epithelial antimicrobial defenses against Escherichia coli. We concluded that cathelicidin selectively modulated synthesis of TLR4 and 9 in intestinal epithelium, but only when cells were exposed to virulence factors, mostly from apical surfaces. Enhanced TLR4 expression promoted by cathelicidin in intestinal epithelium may be crucial for controlling enteric infectious diseases.
Assuntos
Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Colo/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/imunologia , Receptor 4 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Linhagem Celular Tumoral , Colo/microbiologia , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-8/imunologia , Mucosa Intestinal/microbiologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Receptor 4 Toll-Like/agonistas , Receptor Toll-Like 9/agonistas , CatelicidinasRESUMO
En la actualidad existe consenso en que el daño de los tejidos de soporte dentario que se produce durante la periodontitis es un proceso complejo en el cual la presencia de los patógenos periodontales es necesaria, pero no suficiente, para explicar en su totalidad la extensión y severidad de dicho daño. Asimismo, la destrucción del tejido de soporte periodontal es en gran medida producida por el desbalance de la respuesta inmune generada por el paciente frente a antígenos y factores de virulencia derivados de los patógenos periodontales. Esta respuesta inmune, desencadenada por las bacterias periodontopatógenas, incluye tanto mecanismos asociados a inmunidad innata como adaptativa, siendo el rol de los péptidos antimicrobianos y mediadores lipídicos aspectos relacionados con ambas ramas de la inmunidad y que no han sido completamente dilucidados en relación con sus mecanismos de acción contra los patógenos periodontales. En esta revisión se describe el rol de los péptidos antimicrobianos y de los mediadores lipídicos en la enfermedad periodontal, enfocándonos en su contribución tanto a la protección como a la destrucción del tejido de soporte dentario durante la infección periodontal. Se destaca además la importancia de considerarlos dentro del complejo escenario de la respuesta inmune durante las enfermedades periodontales, ya que forman parte fundamental de la respuesta inmune del hospedero. Analizar la enfermedad periodontal ampliando la perspectiva de estudio a este tipo de moléculas que participan de la respuesta inmune permitiría en el futuro lograr un nuevo enfoque terapéutico de las enfermedades periodontales.
Currently, there is consensus that the damage of the tooth support tissues that occurs during periodontitis is a complex mechanism, in which the presence of specific periodontal pathogens is necessary, but not sufficient, to fully explain the extent and severity of the observed periodontal destruction. Moreover, the destruction of periodontal support tissue is largely the effect of the imbalance in the patient immune response, triggered by periodontal pathogen-derived antigens and virulence factors. The immune response elicited by periodontal pathogenic bacteria includes mechanisms associated with both innate and adaptive responses, where the role of antimicrobial peptides and lipid mediators are related to these two arms of immunity, and have not been fully elucidated in relation to their mechanisms of action against periodontal pathogens. In this review, a discussion is presented on the characteristics of these molecules and their role in periodontal disease in relation to both protection and destruction of tooth supporting tissue during periodontal infection. The relevance of considering these mediators within the complex scenario of the immune response during periodontal diseases is also highlighted, since they are a fundamental part of the host immune response. Periodontal diseases should be analysed in a broader perspective, where the study of these types of molecules involved in the immune response of periodontal tissues, may help to develop new therapeutic approaches to periodontal diseases in the future.
Assuntos
Humanos , Peptídeos Catiônicos Antimicrobianos/imunologia , Ácidos Docosa-Hexaenoicos/imunologia , Doenças Periodontais/imunologia , Defensinas/imunologiaRESUMO
Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.