Mecanismos inmunológicos en Cnidaria: un sistema inmune basal de gran complejidad e interés bioprospectivo / Immunological mechanisms in Cnidaria: A highly complex basal immune system with bioprospective interest

Introducción: La protección ante agentes biológicos propios y externos de los cnidarios dependen de la inmunidad innata, la cual consta de tres procesos inmunológicos principales: 1) reconocimiento inmunológico, 2) señalización intracelular, y 3) respuesta efectora. Objetivo: Revisar críticamente el conocimiento actual del repertorio molecular involucrado en la respuesta inmune en cnidarios, así como, su papel en el establecimiento de la simbiosis, y las posibles aplicaciones biotecnológicas de las moléculas involucradas en el proceso de inmunidad. Métodos: Se realizó una revisión de artículos científicos encontrados a través de las bases de datos del NCBI, Google Scholar y Scielo, con palabras claves como inmunidad y/o reconocimiento inmunológico en cnidarios, en una ventana de tiempo de la última década, sin descartar literatura clásica más antigua. Resultados: El reconocimiento inmunológico consiste en receptores inmunológicos que reconocen patrones moleculares e inducen respuestas efectoras como la movilización de moléculas al sitio de la infección, la ingestión microbiana y la formación de moléculas que activan cascadas de señalización. La fase de señalización involucra mediadores de la traducción de señales que activan genes de trascripción, y cascadas de señalización intracelular que inician respuestas de defensa adecuadas. Las respuestas efectoras incluyen la capa superficial del mucus, péptidos antimicrobianos, especies reactivas de oxígeno y la respuesta celular mediada por fagocitosis. Por último, se presenta un esquema y una tabla integral de las vías de respuesta inmune en los cnidario. Conclusiones: La inmunidad en Cnidaria está mediada por mecanismos de defensa complejos integrados por receptores de reconocimiento de patógenos, vías de señalización intracelular, células y moléculas efectoras encargadas de la eliminación del patógeno, y reconocimiento-aceptación de simbiontes. El estudio de compuestos activos del sistema inmune en Cnidaria ha sido poco explorado, sin embargo, el trabajo realizado con otros compuestos presentes en las toxinas de este filo, los sitúa como una fuente importante de moléculas antimicrobianas dignas de un análisis de bioprospección.

Introduction: Cnidarians depend on innate immunity for protection against both their own and external biological agents. It consists of three main immunological processes: 1) immune recognition, 2) intracellular signaling, and 3) effector response. Objective: To critically review current knowledge of the molecular repertoire involved in the immune response in cnidarians, its role in symbiosis, and possible biotechnological applications. Methods: We used keywords such as immunity, and immunological recognition in cnidarians, in the NCBI, Scielo and Google Scholar databases, for the last decade. Results: Cnidarian immune recognition consists of molecular pattern receptors and responses such as the mobilization of molecules to the site of infection, microbial ingestion, and the formation of molecules that activate signaling cascades. The signaling phase involves translation mediators that activate transcriptional genes and intracellular signaling cascades that initiate defenses. Effector responses include surface layer mucus, antimicrobial peptides, reactive oxygen species, and the cellular response mediated by phagocytosis. Conclusions: Immunity in Cnidaria is mediated by complex defense mechanisms composed of pathogen recognition receptors, intracellular signaling pathways, effector cells and molecules responsible for pathogen elimination, and recognition of symbionts. There is a potential for toxin compounds useful as antimicrobial molecules.

Trasplante pulmonar: una perspectiva desde la inmunología / Lung transplantation: a perspective from immunology

Resumen El trasplante pulmonar implica una serie de desafíos, que como lo ha demostrado la historia, no sólo depende de un adecuado desarrollo de técnicas quirúrgicas, sino también de la comprensión de una serie de complejas interacciones inmunológicas celulares y humorales que serán las responsables del tipo de respuesta (innata y/o adquirida) fisiológica y que pudiesen desencadenar las complicaciones asociadas al trasplante (rechazo hiperagudo, agudo o crónico). Cada una de las cuales tiene su potencial prevención y/o tratamiento. El poder conocer esta serie de respuestas, permite al clínico anticiparse a algunos de estos eventos y evitar de mejor forma el daño y las consecuencias que pueden producir en los casos de trasplante pulmonar.

Lung transplantation involves a series of challenges, which as history has shown, depends not only on an adequate development of surgical techniques, but also on the understanding of a series of complex cellular and humoral immunological interactions that will be responsible for the type of physiological response (innate - acquired) and that could trigger the complications associated with transplantation (hyperacute, acute or chronic rejection). Each of which has its potential prevention and treatment. Being able to know this series of responses, allows the clinician to anticipate some of these events and to avoid in a better way the damage and the consequences that can occur in cases of lung transplantation.

Nuocytes from mesenteric lymph node promote allergic responses in a mouse model / Nuócitos de linfonodo mesentérico promovem respostas alérgicas em um modelo de camundongo

Abstract Introduction: Nuocytes play an important role in Type 2 immunity. However, the contribution of ILC2s to allergic rhinitis remains to be clearly elucidated. Objective: To evaluate the role of nuocytes from mesenteric lymph node on allergic responses in mice. Methods: After intraperitoneal administration of interleukin IL-25 and IL-33 to wild-type and Il17br-/-Il1rl1-/- double-deficient mice, nuocytes were purified from the the nasal-associated lymphoid tissue and mesenteric lymph nodes. Then, we assessed productions of IL-5 and IL-13 in nuocytes' cultures. Finally, we adoptively transferred the mesenteric lymph node-derived nuocytes from wild-type and Il17br-/-Il1rl1-/- mice to the murine model of allergic rhinitis to evaluate their roles in nasal allergic responses. Results: We showed that nuocytes in the mesenteric lymph nodes of wild-type mice were upregulated after application of IL-25 and IL-33, and were induced to produce IL-5 and IL-13. Numbers of sneezing and nasal rubbing as well as eosinophils were all enhanced after the adoptive transfer of wild-type nuocytes. Concentrations of IL-5, IL-13, IL-25 and IL-33 in nasal lavage fluid of allergic mice were also increased. However, nuocytes fromIl17br-/-Il1rl1-/- mice did not increase sneezing and nasal rubbing and eosinophilia, and upregulate the above cytokines in the nasal lavage fluid. Conclusion: The findings demonstrate that nuocytes from the mesenteric lymph nodes of wildtype mice promote allergic responses in a mouse model.

Resumo Introdução: Os nuócitos desempenham um papel importante na imunidade do tipo 2. No entanto, a contribuição das interleucinas ILC2s na rinite alérgica ainda precisa ser elucidada. Objetivo: Avaliar o papel dos nuócitos de linfonodos mesentéricos nas respostas alérgicas em camundongos. Método: Após a administração intraperitoneal de interleucina (IL)-25 e IL-33 em camundongos do tipo selvagem e camundongos Il17br-/-Il1rl1-/- com deficiência dupla, os nuócitos foram purificados do tecido linfoide associado a mucosa nasal e linfonodos mesentéricos. Em seguida, avaliamos as produções de IL-5 e IL-13 em culturas de nuócitos. Finalmente, transferimos adotivamente os nuócitos derivados de linfonodos mesentéricos de camundongos do tipo selvagem e camundongos Il17br-/-Il1rl1-/- para o modelo murino de rinite alérgica para avaliar seu papel nas respostas alérgicas nasais. Resultados: Mostramos que os nuócitos nos linfonodos mesentéricos de camundongos do tipo selvagem estavam up-regulados após a aplicação de IL-25 e IL-33 e foram induzidos a produzir IL-5 e IL-13. Os espirros e friçcão nasal, bem como os eosinófilos, aumentaram após a transferência adotiva de nuócitos do tipo selvagem. As concentrações de IL-5, IL-13, IL-25 e IL-33 no líquido da lavagem nasal de camundongos alérgicos também estavam aumentadas. Entretanto, os nuócitos de camundongos Il17br-/-Il1rl1-/- não aumentaram os espirros e a friçcão nasal ou eosinofilia e up-regularam as citocinas acima no líquido de lavagem nasal. Conclusão: Os achados demonstram que os nuócitos dos linfonodos mesentéricos de camundongos selvagens promovem respostas alérgicas em um modelo de camundongo.

Reinfección, inmunidad y prevención de la transmisión en la COVID-19 / Reinfection, immunity and prevention of transmission of COVID-19

Introducción: La duración de la inmunidad natural generada por la COVID-19 está por definir, lo que determina la probable reinfección. Objetivo: Destacar la necesidad de mantener las medidas de prevención a propósito de un caso de reinfección en un trabajador sanitario. Presentación de caso: Paciente femenina de 48 años de edad con antecedentes de salud que, en junio, 2020 y marzo, 2021 se le diagnóstica la COVID-19, en ambos casos con el comportamiento de enfermedad sintomática leve. Después de 24 horas de comenzar con cefalea, mareos y tos seca se confirma el diagnóstico de infección por SARS CoV-2 con PCR positivo y umbral de ciclo (CT) en 24.84. Pasados 9 meses y 9 días de la infección original, y dos días posteriores a recibir la vacuna BNT162b2 (Pfizer-BioNTech), comienza con malestar general, tos seca, secreción nasal y dolor de garganta, con PCR positivo y CT de 17.61. Conclusiones: La posibilidad de la reinfección por la COVID-19 orienta la necesidad de fortalecer las acciones de prevención de la transmisión en instituciones de salud en tanto las evidencias científicas nos provean de recursos más eficaces para su control(AU)

Introduction: The duration of natural immunity generated by COVID-19 is yet to be defined, which determines the probable reinfection. Objective: To analyze issues related to natural infection and the need to maintain prevention practices regarding a case of reinfection in a health care worker. Case presentation: Forty-eight-year-old female patient without comorbidities who was diagnosed with COVID-19 in June 2020 and March 2021, in both cases as a mild symptomatic disease. Twenty-four hours after the onset with headache, dizziness, and dry cough, the diagnosis of SARS CoV-2 infection was confirmed by positive PCR and cycle threshold (CT) at 24.84. Nine months and nine days after original infection, and two days after receiving the BNT162b2 vaccine (Pfizer-BioNTech), the patient began with general malaise, dry cough, runny nose, and sore throat, with a positive PCR and CT of 17.61. Conclusions: The possibility of reinfection by COVID-19 points to the need to strengthen transmission prevention practices in healthcare facilities as long as scientific evidence provides us with more effective resources for its control(AU)

Relação entre resposta imune inata do receptor toll-like-4 (TLR-4) e o processo fisiopatológico da cardiomiopatia da obesidade / Relationship between innate immune response toll-like receptor 4 (TLR-4) and the pathophysiological process of obesity cardiomyopathy

Resumo Fundamento A obesidade é uma condição inflamatória crônica de baixo grau relacionada a distúrbios cardíacos. No entanto, o mecanismo responsável pela inflamação cardíaca relacionada à obesidade não é claro. O receptor do tipo toll 4 (TLR-4) pertence a um receptor da família das transmembranas, responsável pela resposta imune, cuja ativação estimula a produção de citocinas pró-inflamatórias. Objetivo Testar se a ativação do receptor TLR-4 participa do processo de cardiomiopatia da obesidade, devido à produção de citocinas por meio da ativação do NF-ĸB. Métodos Ratos Wistar machos foram randomizados em dois grupos: o grupo controle (C, n = 8 animais) que recebeu dieta padrão/água e o grupo obeso (OB, n = 8 animais) que foi alimentado com dieta rica em açúcar e gordura e água mais 25% de sacarose por 30 semanas. Análise nutricional: peso corporal, índice de adiposidade, alimentos, água e ingestão calórica. Análise de distúrbios relacionados à obesidade: glicose plasmática, ácido úrico e triglicerídeos, HOMA-IR, pressão arterial sistólica, TNF-α no tecido adiposo. A análise cardíaca incluiu: expressão das proteínas TLR-4 e NF-ĸB, níveis de TNF-α e IL-6. Comparação pelo teste t de Student não pareado ou teste de Mann-Whitney com um valor de p <0,05 como estatisticamente significativo. Resultados O grupo OB apresentou obesidade, glicose elevada, triglicerídeos, ácido úrico, HOMA, pressão arterial sistólica e TNF-α no tecido adiposo. O grupo OB apresentou remodelação cardíaca e disfunção diastólica. A expressão de TLR-4 e NF-ĸB e os níveis de citocinas foram maiores em OB. Conclusão Nossos achados concluem que, em uma condição obesogênica, a inflamação derivada da ativação do TLR-4 cardíaco pode ser um mecanismo capaz de levar à remodelação e disfunção cardíaca.

Abstract Background Obesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines. Objective To test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation. Methods Male Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student's t-test or Mann- Whitney test with a p-value < 0.05 as statistically significant. Results The OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB. Conclusion Our findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction.

Atualizando e expandindo o universo de: "Uma nova classe de doenças ­ doenças autoinflamatórias" / Updating and expanding the universe of: "A new class of diseases ­ autoinflammatory disorders"

As síndromes autoinflamatórias são doenças raras, genéticas de envolvimento prioritário da imunidade inata. Avanços nas técnicas de sequenciamento genético permitiram dissecar os genes envolvidos nestas doenças, continuamente organizando o quebra-cabeça genético e fisiopatológico de tais desordens. Este artigo revisa os últimos achados genéticos com seus respectivos fenótipos, código OMIM e ORPHA. Além disso, sugere cautela na triagem clínica e na indicação de métodos restritivos de sequenciamentos genéticos.

Autoinflammatory diseases comprise a group of rare, genetic disorders with priority involvement of innate immunity. Advances in genetic sequencing techniques allowed genetic dissection of genes involved in these diseases, with continuous organization of the genetic and pathophysiologic puzzle of these disorders. This article reviews the most recent genetic findings linked to respective phenotypes and OMIM and ORPHA codes. Moreover, it suggests caution in clinical screening and genetic sequencing indication with restrictive genetic panels.

Plasmacytoid dendritic cells in dermatology

Abstract Plasmacytoid dendritic cells are part of the dendritic cells family and are a relevant link between innate and adaptive immunity. They are the most potent producers of type 1 interferon, generating antiviral response, stimulating macrophages and dendritic cells and inducing activation and migration of natural killer cells. Plasmacytoid dendritic cells also exert a role as antigen-presenting cells, promote T-lymphocyte responses, immunoregulation, plasma cells differentiation and antibody secretion. Even though plasmacytoid dendritic cells are not usually present in normal skin, their presence is detected in healing processes, viral infections, and inflammatory, autoimmune, and neoplastic diseases. In recent years, the presence of plasmacytoid dendritic cells in several dermatological diseases has been described, enhancing their potential role in the pathogenesis of such conditions. Future studies on the role of plasmacytoid dendritic cells in dermatology may lead to new therapeutic targets.

Innate and Th1/Th17 adaptive immunity in acute and convalescent Brazilian borreliosis disease

ABSTRACT Introduction: Brazilian borreliosis (BB) disease is an infectious disease transmitted by ticks that mimics Lyme disease (LD) from the Northern Hemisphere. The BB clinical picture is characterized by a pathognomonic skin lesion (migratory erythema) and joint, neurological, cardiac and psychiatric symptoms. Innate and Th1/Th17 adaptive immunity seem to play an important role in the pathogenesis of Lyme disease. Objective: The aim of this study was to characterize the role of innate and Th1/Th17 adaptive immunity in BB patients with acute (<3 months) and convalescent (>3 months) disease. Methods: Fifty BB patients (28 with acute and 22 with convalescent disease) without treatment and 30 healthy subjects were evaluated. Levels of 20 cytokines or chemokines associated with innate and Th1/Th17 adaptive immunity were analyzed using Luminex (Millipore Corp., Billerica, MA). Results: Overall, BB patients had increased levels of IL-8 (6.29 vs 2.12 p = 0.002) and MIP-1α/CCL3 (5.20 vs 2.06, p = 0.030), associated with innate immunity, and MIP3B/CCL19 (Th1; 297.86 vs 212.41, p = 0.031) and IL-17A (Th17; 3.11 vs 2.20, p = 0.037), associated with adaptive immunity, compared with the levels of healthy controls. When comparing acute BB vs. convalescent BB subjects vs. healthy controls, IL-1β, IL-8 and MIP-1α/CCL3 (innate mediators) levels were highest in patients in the acute phase of disease (p < 0.05). TNF-α was associated with disseminated symptoms and with humoral reactivity against Borrelia burgdorferi. IL-10 was significantly correlated with IL-6 (r = 0.59, p = 0.003), IL-8 (r = 0.51, p < 0.001), MIP-1α/CCL3 (r = 0.42, p < 0.001) and MIP-3β/CCL19 (r = 0.40, p = 0.002) in all BB patients. Conclusions: This is the first study describing that innate and Th1/Th17 adaptive immunity play a crucial role in BB disease. Furthermore, innate mediators are particularly important in acute BB disease, and TNF-α is associated with evolution of BB symptoms.

NK cells at the crossroads in COVID-19: a question of timing / Células NK en la encrucijada en COVID-19: una cuestión de tiempo

The outbreak of the novel coronavirus SARS-CoV-2 and the attendant physiological symptoms associated with the COVID-19 disease have led to an explosion of interest studying different aspects of the immune response. As of yet, the particular roles of natural killer cells are not well understood in this disease. NK cells are critical first-response cytotoxic cells of the innate immune system. NK cells are traditionally considered important for their roles in innate immunity against tumors and viral infected cells, as well as their ability to produce cytokines, particularly interferon-γ, and participate in antibody dependent cell cytotoxicity (ADCC). Here, we describe the role of NK cells in peripheral blood and in the lungs with respect to the pathology caused by SARS-CoV-2 and discuss the implications of proposed different types of therapies on NK cells. Evidence is accumulating that NK cells play an important role in initial surveillance as part of innate immunity. With the progression of the disease and rising inflammation, these cells, when in circulation, appear to become exhausted and ineffective. In the COVID lung, however, a complex interplay between inflammatory cells, chemokines, cytokines and aberrantly activated migratory NK cells occurs, potentiating local inflammation and the critical situation in the lungs.

El brote del nuevo coronavirus SARS-CoV-2 y los síntomas fisiológicos concomitantes asociados con la enfermedad COVID-19 han provocado una explosión de interés en la investigación de diferentes aspectos de la respuesta inmune. Hasta el momento, no se comprenden bien las funciones particulares de las células asesinas naturales (NK, por sus siglas en inglés: natural killer) en esta enfermedad. Las células NK son importantes células citotóxicas de primera línea que forman parte del sistema inmune innato. Las células NK se consideran tradicionalmente importantes por su papel en la inmunidad innata contra tumores y contra células infectadas por virus, así como por su capacidad para producir citoquinas y participar en la citotoxicidad celular dependiente de anticuerpos (ADCC, por sus siglas en inglés: antibody-dependent cell-mediated cytotoxicity). Aquí, se describe el papel de las células NK en sangre periférica y en pulmones con respecto a la nueva patología causada por SARS-CoV-2 y discute las implicaciones de los diferentes tipos de terapias propuestos con respecto a células NK. Al momento, diversos tipos de evidencia comienzan a revelar que las células NK podrían desempeñar un papel crucial en la vigilancia inicial contra el SARS-CoV-2. Con la progresión de la enfermedad y el aumento de la inflamación, estas células cuando están en circulación, parecen agotarse ("exhausted") y volverse ineficaces. En los pulmones de pacientes con COVID-19, sin embargo, se produce una interacción compleja entre células inflamatorias, quimioquinas, citoquinas y células NK migratorias activadas de manera aberrante, lo que potencia la inflamación local, contribuyendo a una situación más crítica a la función pulmonar.

Apoptosis de neutrófilos en la infección asintomática por Virus de la Inmunodeficiencia Humana / Neutrophil apoptosis in asymptomatic Human Immunodeficiency Virus infection

En los últimos años se ha determinado que los neutrófilos son células altamente versátiles y sofisticadas, cuyas funciones van mucho más allá de la eliminación de los microorganismos. En la infección con el Virus de Inmunodeficiencia Humana (HIV), si bien el papel de los neutrófilos no está totalmente caracterizado, actualmente está claro que la relación entre los neutrófilos y el virus es mucho más compleja de lo que se pensaba. Los objetivos de este trabajo fueron evaluar en pacientes con infección asintomática, y sin tratamiento antirretroviral, el efecto de la infección por el HIV sobre la muerte celular de los neutrófilos y la expresión de receptores de superficie. En pacientes seropositivos sin tratamiento hubo un aumento de la apoptosis temprana de los neutrófilos en relación a los grupos controles. Esta apoptosis aumentada no depende de la activación de la vía extrínseca o intrínseca. En estos pacientes hubo un aumento de la expresión de TLR2 que, unido al aumento de la apoptosis temprana, podría ser indicativo de un fenotipo activado de los neutrófilos. En conclusión, este trabajo aporta información sobre aspectos relacionados con la apoptosis de los neutrófilos en estadios tempranos de la infección por HIV, contribuyendo así a una mayor comprensión acerca del efecto de este virus sobre componentes de la respuesta inmune innata.

In recent years it has been determined that neutrophils are highly versatile and sophisticated cells whose functions go far beyond the elimination of microorganisms. In Human Immunodeficiency Virus (HIV) infection, the role of neutrophils is not fully characterized but it is now clear that the relationship between neutrophils and HIV is much more complex than previously thought. The aims of this study were to evaluate the effect of HIV infection on neutrophil cell death and the expression of surface molecules on neutrophils in patients with asymptomatic infection and without antiretroviral treatment (ART). In HIV seropositive patients without antiretroviral therapy there was an increase in the early apoptosis of neutrophils in relation to the control groups. This increased apoptosis does not depend on the activation of the extrinsic or intrinsic pathway. In these patients there was an increase in the expression of TLR2 which, together with the increase of early apoptosis, could be indicative of an activated phenotype of neutrophils. In conclusion, this study provides information on aspects related to the apoptosis of neutrophils in early stages of HIV infection and therefore contributes to a better understanding of the effect of this virus on components of the innate immune response.

Nos últimos anos, determinou-se que os neutrófilos são células altamente versáteis e sofisticadas, cujas funções vão muito além da eliminação dos microrganismos. Na infecção pelo HIV, embora o papel dos neutrófilos não esteja totalmente caracterizado, atualmente fica bem claro que a relação entre os neutrófilos e o vírus é muito mais complexa do que se pensava anteriormente. Os objetivos deste trabalho foram avaliar em pacientes com infecção assintomática, e sem tratamento antirretroviral, o efeito da infecção pelo HIV na morte celular dos neutrófilos e a expressão de receptores de superfície. Nos pacientes soropositivos sem tratamento, houve um aumento da apoptose precoce dos neutrófilos em relação aos grupos controle.Esta apoptose aumentada não depende da ativação da via extrínseca ou intrínseca. Nestes pacientes, houve um aumento da expressão de TLR2 que, juntamente com o aumento da apoptose precoce, poderia ser indicativo de um fenótipo ativado dos neutrófilos. Em conclusão, este trabalho fornece informações sobre aspectos relacionados com a apoptose dos neutrófilos em estágios precoces da infecção pelo HIV, contribuindo desse modo para uma maior compreensão sobre o efeito deste vírus nos componentes da resposta imune inata.

Otro desafío de la naturaleza: el nuevo coronavirus virología y fisiopatología del SARS-COV-2 / Another challenge of nature: the new coronavirus virology and physiopathology of SARS-CoV-2

The recent outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been brought to global attention in the search of knowledge about the virus and its pathogenesis. The immune response is essential to control and eliminate the infection, however, maladjusted immune responses may result in severe disease fisiopathology. Gaining a deeper understanding of the interaction between SARS-CoV-2 and the immune systems of the hosts may help us anticipate the development of persistent pulmonary inflammation and, why not, be the first step to therapeutic success and trying to save more lives. In this review, we provide an update on CoV virology and our vision of pathogenesis understanding it from the stages of infection, without forgetting the cytokine storm resulting from the interaction of the virus with ACE2 receptors widely distributed in the body.

La reciente emergencia de síndrome de distrés respiratorio agudo producido por coronavirus 2 (SARS-CoV-2), enfermedad denominada COVID-19 ha traído la atención mundial a la búsqueda de conocimiento sobre este virus y su patogenia. La respuesta inmune es esencial para controlar y erradicar la infección, sin embargo, las respuestas inmunes descontroladas pueden resultar en la fisiopatología de la enfermedad grave. Lograr una comprensión más profunda de la interacción entre SARS-COV-2 y el sistema inmune de los huéspedes podría ayudar a anticiparnos al desarrollo de una inflamación pulmonar persistente causada por el SARS-CoV-2, y por qué no, ser la puerta de entrada al éxito terapéutico e intentar salvar mayor número de vidas. En esta revisión, proporcionamos una actualización sobre la virología y nuestra visión de la patogenia, entendiéndola desde las fases o etapas de la infección, sin olvidar el estallido de citoquinas resultantes de la interacción del virus con los receptores ACE2 ampliamente distribuidos en el organismo.

17ß-Estradiol, a potential ally to alleviate SARS-CoV-2 infection

Considering that female sexual hormones may modulate the inflammatory response and also exhibit direct effects on the cells of the immune system, herein, we intend to discuss the sex differences and the role of estradiol in modulating the lung and systemic inflammatory response, focusing on its possible application as a treatment modality for SARS-CoV-2 patients. COVID-19 patients develop severe hypoxemia early in the course of the disease, which is silent most of the time. Small fibrinous thrombi in pulmonary arterioles and a tumefaction of endothelial were observed in the autopsies of fatal COVID-19 cases. Studies showed that the viral infection induces a vascular process in the lung, which included vasodilation and endothelial dysfunction. Further, the proportions of CD4+ T and CD8+ T lymphocytes were strongly reduced in patients with severe SARS-CoV-2 infection. Estradiol is connected with CD4+ T cell numbers and increases T-reg cell populations, affecting immune responses to infection. It is known that estradiol exerts a protective effect on endothelial function, activating the generation of nitric oxide (NO) via endothelial nitric oxide synthase. Estrogen attenuates the vasoconstrictor response to various stimuli and induces vasodilation in the pulmonary vasculature during stress situations like hypoxia. It exerts a variety of rapid actions, which are initiated after its coupling with membrane receptors, which in turn, may positively modulate vascular responses in pulmonary disease and help to maintain microvascular flow. Direct and indirect mechanisms underlying the effects of estradiol were investigated, and the results point to a possible protective effect of estradiol against COVID-19, indicating that it may be considered as an adjuvant therapeutic element for the treatment of patients affected by the novel coronavirus.

Caracterização fenotípica e funcional de células do sistema imune inato na malária cerebral experimental / Phenotypic and functional characterization of innate immune cells in experimental cerebral malaria

A malária cerebral (MC) é responsável por muitas mortes ocasionadas pela infecção por Plasmodium falciparum. Devido à dificuldade em estudar os mecanismos imunes envolvidos no desenvolvimento de MC em humanos, o uso de modelos murinos de malária cerebral experimental (MCE) tem sido amplamente empregado. Este estudo tem como objetivo investigar o papel das células imunes inatas no desenvolvimento ou não de MCE utilizando os modelos experimentais de camundongos C57BL/6 e BALB/c infectados com Plasmodium berghei ANKA. A sobrevida, parasitemia, peso, temperatura corporal e a quebra da barreira hematoencefálica confirmaram a resistência e suscetibilidade dos camundongos BALB/c e C57BL/6 parasitados ao desenvolvimento de MCE, respectivamente. Embora os camundongos BALB/c e C57BL/6 infectados tenham apresentado diferentes cursos clínicos da doença, eles exibiram a mesma parasitemia. A esplenomegalia foi observada em ambas as linhagens de camundongos durante a infecção. Entre as subpopulações mieloides investigadas, encontramos o influxo de neutrófilos e monócitos inflamatórios em cinética e proporções diferentes entre as linhagens. Já os macrófagos da polpa vermelha (MPV) dos camundongos BALB/c mantiveram seus valores constante ao longo da infecção, entretanto, responderam ao processo infeccioso ampliando a expressão do receptor de manose CD206. Interessantemente, os animais C57BL/6 apresentaram redução no número total dos MPV e MPV CD206+ após a infecção.

A redução nos valores de MPV CD206+ foi acompanhada pelo aumento no número e percentual de MPV iNOS+. Curiosamente, o número total de macrófagos da polpa branca (MPB) e MPB iNOS+ aumentou nos animais BALB/c e se manteve constante nos animais C57BL/6 infectados. Ao avaliarmos a expressão de CD206 nos MPB, observamos diminuição no percentual e número total dessas células em ambos os animais após infecção. Também realizamos a análise da expressão de CD206 e iNOS em microglias, macrófagos residentes do sistema nervoso central. Estas células, em ambas as linhagens, apresentaram a mesma cinética de aumento na expressão do receptor de manose CD206, e redução diferenciada na expressão de iNOS ao longo da infecção. Toda essa regulação dos marcadores fenotípicos nos macrófagos esplênicos de camundongos BALB/c ocorreu na presença de níveis séricos elevados de INF-γ e da citocina regulatória IL-10, no 4º dia após infecção, quando comparados aos camundongos C57BL/6. Nossos dados sugerem que, apesar de camundongos resistentes à MCE desenvolverem uma forte resposta imune ao parasito, o animal é favorecido pelo desencadeamento de um perfil antiinflamatório de resposta, como a ativação de macrófagos do tipo M2 e produção de citocinas regulatórias. Enquanto que os animais suscetíveis ao desenvolvimento de MCE respondem a infecção montando uma resposta com perfil pró-inflamatório nos momentos inicias da resposta imune, através do aumento no número de macrófagos com perfil M1 e pela produção de TNF e IL-6. (AU)

Caracterização fenotípica e genotípica de cepas de Salmonella spp. e subtipagem molecular de plasmídeos carreando genes de beta-lactamases de espectro estendido e AmpC / Phenotypic and genotypic characterization of strains of Salmonella spp. and molecular subtyping of plasmids carrying extended-spectrum beta-lactamase and AmpC genes

Salmonella spp. são reconhecidas como um dos mais importantes patógenos que ocasionam doença entérica, sendo a terceira causa de morte entre as doenças transmitidas por alimentos (DTAs). A maior preocupação atual deve-se ao aumento da resistência aos beta-lactâmicos, e a produção de beta-lactamases mediadas por plasmídeos dentro do gênero. O objetivo deste trabalho foi caracterizar fenotipicamente e genotipicamente 44 isolados de Salmonella spp. produtores de beta lactamases além de, realizar a subtipagem dos plasmídeos de resistência aos beta lactâmicos de cepas de origem humana e não humana. Foi realizado o teste de sensibilidade aos antimicrobianos e a determinação da Concentração Inibitória Mínima (CIM). A PCR foi utilizada para a identificação dos genes blaESBL e blaAmpC, em seguida, confirmados por sequenciamento de Sanger. Para a subtipagem plasmídial dos isolados foram utilizadas as técnicas de PBRT e pMLST. Os resultados do teste de sensibilidade aos antimicrobianos mostrou que 97,7% dos isolados foram resistentes à cefotaxima, 86,3% resistentes à sulfonamida e tetraciclina, 81,9% resistentes ao ácido nalidíxico, 68,1% resistentes a ceftriaxona e 56,8% a estreptomicina. De acordo com a PCR, 24 isolados (54,5%) foram positivos para ESBLs (CTX-M), e 20 isolados (45,5%) positivos para beta-lactamase do tipo AmpC, CMY-2. A variante CTX-M-2 foi encontrada em 27,2% dos isolados, seguido da variante CTX-M-8 (22,7%). As variantes CTX-M-15 e CTX-M-65 foram detectadas em um isolado respectivamente. De acordo com a tipagem plasmidial foram encontrados os grupos de incompatibilidade IncI1/ST12 e IncA/C/ST2 em cepas positivas para blaCMY-2. Para as variantes de CTX-M foram detectados os grupos de incompatibilidade IncHI2 em cepas produtoras de CTX-M-2, IncI1, IncF e IncL/M identificados em cepas CTX-M-8, e dois isolados não tipáveis nas variantes CTX-M-15 e CTX-M-65. A análise do perfil genético dos isolados por PFGE sugerem a circulação de cepas geneticamente relacionadas entre fontes humanas e não humanas no sorotipo Muenchenn, e um perfil de similaridade de 82,3% no sorotipo Heidelberg, em cepas provenientes de fontes de origem e anos de isolamento diferentes. Os resultados encontrados neste estudo revelam o cenário atual da resistência aos beta-lactâmicos e reforçam a necessidade de intensificar o monitoramento de isolados portadores de plasmídeos epidêmicos carreadores de beta-lactamases (ESBL e AmpC) na clínica, ambiente e na cadeia produtiva. (AU)

Salmonella spp. are recognized as one of the most important pathogens that cause enteric disease, being the third leading cause of death among foodborne diseases. The greatest current concern should be the increase in resistance to beta-lactams and the production of plasmidmediated beta-lactamases within the genus. The objective of this work was to characterize phenotypically and genotypically 44 isolates of Salmonella spp. beta-lactamase producers, in addition to subtyping plasmids resistant to beta-lactams from human and non-human strains. The antimicrobial sensitivity test was performed and the Minimum Inhibitory Concentration (MIC) was determined. A PCR was used to identify the blaESBL and blaAmpC genes, followed by Sanger sequencing. For plasmid subtyping were used PBRT and pMLST techniques. The results of the antimicrobial sensitivity test showed that 97.7% of the strains were resistant to cefotaxime, 86.3% resistant to sulfonamide and tetracycline, 81.9% resistant to nalidic acid, 68.1% resistant to ceftriaxone and 56.8% streptomycin. According to the PCR, 24 (54.5%) were positive for ESBLs (CTX-M) and 20 (45.5%) positive for AmpC-type beta-lactamase, CMY-2. A CTX-M-2 variant was found in 27.2% of isolates followed by the CTX-M-8 variant (22.7%). The variants, CTX-M-15 and CTX-M-65 were detected in one isolate, respectively. According to plasmid typing, the incompatibility groups IncI1/ST12 and IncA/C/ST2 were found in positive strains for blaCMY-2. For the CTX-M variants, the IncHI2 incompatibility groups were detected in the CTX-M-2, IncI1, IncF and IncL/M were found in the CTX-M-8 strains, and CTX-M-15 and CTX-M-65 variants were not typeable. The analysis of the genetic profile by PFGE suggests the circulation of strains related between human and non-human sources in the Muenchen serotype, and a similarity index of 82.3% in the Heidelberg serotype, in strains from different sources and years. The results found in this study reveal the current scenario of resistance to betalactams and reinforce the need to intensify the monitoring of epidemic plasmids carrying beta-lactamases (ESBL and AmpC) in the clinic, environment and productive chain. (AU)

Bases genéticas y moleculares del COVID-19 (SARS-CoV-2): mecanismos de patogénesis y de respuesta inmune / Genetic and molecular basis of COVID-19 (SARS-CoV-2) mechanisms of pathogenesis and imnune

A fines de diciembre de 2019, un nuevo coronavirus (SARS-CoV-2) fue identificado como el agente causal de una nueva enfermedad respiratoria llamada COVID-19 por la OMS. Sus síntomas incluyen fiebre, tos seca y dificultad respiratoria. Estos síntomas en general son leves, aunque, pueden ser fatales en adultos mayores y pacientes con comorbilidades. Se realizó búsqueda bibliográfica en Pubmed y Clinical Key donde se seleccionaron 22 artículos de acuerdo con los criterios de inclusión. SARS-CoV-2 pertenece al género de los Betacoronavirus y tiene similitudes genómicas con SARS-CoV y MERS-CoV. El virión de SARS-CoV-2 consta de una nucleocápside y de una envoltura externa compuesta por proteínas estructurales principales y accesorias. Su material genético consiste en una cadena de RNA monocatenario de polaridad positiva, en el que, se codifican proteínas importantes para su transcripción y replicación. El mecanismo de infección de SARS-CoV-2 comienza con la unión del virión a un receptor (ACE2) de la célula huésped y su posterior entrada por endocitosis. El genoma RNA viral se libera al citoplasma donde se transcriben y se traducen las proteínas necesarias para la producción de las proteínas estructurales y para la replicación de su material genético. Posteriormente, el RNA replicado se asocia con la nucleocápside y se ensambla junto con las proteínas estructurales para conformar las partículas víricas que serán liberadas de la célula infectada. El sistema inmune hace frente a la infección viral mediante el reconocimiento de patrones moleculares asociados a patógenos (PAMPs) por parte de la inmunidad innata y por la acción de los linfocitos T y B por parte de la inmunidad humoral. El conocimiento de las bases genéticas y moleculares de SARS-CoV-2 permite visualizar la posibilidad de establecer tratamientos farmacológicos o desarrollo de vacunas para controlar y disminuir los efectos patogénicos de la enfermedad.

In late December 2019, a new coronavirus (SARS-CoV-2) was identified as a causative agent of a new respiratory disease called COVID-19 by WHO. Its symptoms include fever, dry cough, and shortness of breath. Generally, these symptoms are mild, although, can be fatal in older adults and patients with comorbidities. A bibliographic search was carried out in Pubmed and Clinical Key. 22 articles were selected according to inclusion criteria. SARS-CoV-2 belongs to the genus of Betacoronaviruses and has genomic similarities to SARS-CoV and MERS-CoV. SARS-CoV-2 virion is made up of a nucleocapsid and external envelope composed of main structural and accesory proteins. Its genetic is a positive sense single stranded RNA in which important proteins are encoded for their transcription and replication. The mechanism of SARS-CoV-2 infection begins with the binding of the virion to (ACE2) receptor of the host cell and subsequent entry by endocytosis. This RNA genome is released into cytoplasm and the necessary proteins for the production of structural proteins and the replication of genetic material are transcribed and translated. Then, the replicated RNA associates with the nucleocapsid and assembles together with the structural proteins to form the viral particles that will be released from the infected cell. The immune system faces viral infection through the recognition of molecular patterns associated with pathogens (PAMPs) by innate immunity and the action of T cells and B cells by humoral immunity. Knowledge of the genetic and molecular basis of SARS-CoV-2 allows us to visualize the possibility of establishing pharmacological or vaccine treatments to control and reduce the pathogenic effects of the disease.

Leishmania infantum induces high phagocytic capacity and intracellular nitric oxide production by human proinflammatory monocyte

BACKGROUND The mechanism of resistance to SbIII in Leishmania is complex, multifactorial and involves not only biochemical mechanisms, but also other elements, such as the immune system of the host. OBJECTIVES In this study, putative changes in the immunological profile of human monocytes infected with wild-type (WT) and antimony (SbIII)-resistant Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum lines were evaluated. METHODS Susceptibility assays WT and SbIII-resistant L. braziliensis and L. infantum were performed using lines THP-1 human monocytic lineage. Phagocytic capacity, cytokine profile, intracellular nitric oxide (NO) production and surface carbohydrate residues profile were performed in peripheral blood monocytes by flow cytometry. FINDINGS The phagocytic capacity and intracellular NO production by classical (CD14++CD16-) and proinflammatory (CD14++CD16+) monocytes were higher in the presence of L. infantum lines compared to L. braziliensis lines. The results also highlight proinflammatory monocytes as the cellular subpopulation of major relevance in a phagocytosis event and NO expression. It is important to note that L. infantum induced a proinflammatory cytokine profile characterised by higher levels of TNF-α in culture supernatant than L. braziliensis. Conversely, both Leishmania lines induce high levels of IL-6 in culture supernatant. Analysis of the expression profile of surface carbohydrates showed that L. braziliensis presents 4.3-fold higher expression of galactose(β1,4)N-acetylglucosamine than L. infantum line. Interestingly, the expression level of α-N-acetylgalactosamine residues was 2-fold lower in the SbIII-resistant L. braziliensis line than its counterpart WT line, indicating differences in surface glycoconjugates between these lines. MAIN CONCLUSIONS Our results showed that L. braziliensis and L. infantum induce different innate immune responses and a highly inflammatory profile, which is characteristic of infection by L. infantum, the species associated with visceral disease.

La contaminación del aire atmosférico en la respuesta inmune innata antimicobacteriana / Atmospheric air pollution and innate antimycobacterial immunity

Indoor and outdoor air pollution has been considered a serious public health problem worldwide, and is associated annually with around 7 million deaths (4.8 million associated with outdoor air and 2.2 million indoor air). The main reasons for these deaths include: chronic obstructive pulmonary diseases, pneumonia, ischemic cardiopathy and lung cancer. In addition, epidemiological studies have associated exposure to this type of pollutants with a greater susceptibility to the development of infectious and non-infectious diseases. One of the most important infectious diseases is tuberculosis, which over the years has worsened with the emergence of resistant multi-drug strains, as well as with association with other diseases such as diabetes mellitus type 2 and the acquired immune deficiency syndrome (AIDS). In fact, despite efforts made by the World Health Organization to stop the epidemic, a large number of deaths (about 1.7 million worldwide) are still caused by this disease. In this review, a brief summary will be made of the effects of exposure to indoor and outdoor air pollution on the innate immune response against tuberculosis, and how these alterations could be linked to the development of pulmonary tuberculosis.

La contaminación del aire de interiores y de exteriores ha sido considerada un serio problema de salud pública a nivel mundial, el cual se asocia anualmente con alrededor de 7 millones de muertes (4.8 millones asociadas con el aire de exteriores y 2.2 millones con el aire de interiores). Entre las principales razones ligadas a estas muertes se encuentran: enfermedad pulmonar obstructiva crónica, neumonía, cardiopatía isquémica y cáncer de pulmón. Además, estudios epidemiológicos han asociado la exposición a este tipo de contaminantes con mayor susceptibilidad para la aparición de enfermedades infecciosas y no infecciosas. Entre las enfermedades infecciosas, una de las más importantes es la tuberculosis, la cual, durante el transcurso de los años, ha empeorado con el surgimiento de cepas resistentes a múltiples fármacos, así como por la asociación con otras afecciones como la diabetes mellitus tipo 2 y el síndrome de inmunodeficiencia adquirida (sida). A pesar del esfuerzo realizado por la Organización Mundial de la Salud (OMS) por detener esta epidemia, aún existen anualmente un gran número de muertes causadas por esta enfermedad: alrededor de 1.7 millones a nivel mundial. En esta revisión se hará un breve resumen de los efectos que tiene la exposición a la contaminación del aire de interiores y de exteriores en la respuesta inmune innata en contra de la tuberculosis, y cómo estas alteraciones pueden estar ligadas a la aparición de tuberculosis pulmonar.