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.

Haplotypes in CCR5-CCR2 , CCL3 and CCL5 are associated with natural resistance to HIV-1 infection in a Colombian cohort / Los haplotipos en CCR5-CCR2 , CCL3 y CCL5 se asocian con resistencia natural a la infección por el HIV-1 en una cohorte colombiana

RESUMEN Introduction: Variants in genes encoding for HIV-1 co-receptors and their natural ligands have been individually associated to natural resistance to HIV-1 infection. However, the simultaneous presence of these variants has been poorly studied. Objective: To evaluate the association of single and multilocus haplotypes in genes coding for the viral co-receptors CCR5 and CCR2, and their ligands CCL3 and CCL5, with resistance or susceptibility to HIV-1 infection. Materials and methods: Nine variants in CCR5-CCR2, two SNPs in CCL3 and two in CCL5 were genotyped by PCR-RFLP in 35 seropositive (cases) and 49 HIV-1-exposed seronegative Colombian individuals (controls). Haplotypes were inferred using the Arlequin software, and their frequency in individual or combined loci was compared between cases and controls by the chi-square test. A p' value <0.05 after Bonferroni correction was considered significant. Results: Homozygosis of the human haplogroup (HH) E was absent in controls and frequent in cases, showing a tendency to susceptibility. The haplotypes C-C and T-T in CCL3 were associated with susceptibility (p'=0.016) and resistance (p'<0.0001) to HIV-1 infection, respectively. Finally, in multilocus analysis, the haplotype combinations formed by HHC in CCR5-CCR2, T-T in CCL3 and G-C in CCL5 were associated with resistance (p'=0.006). Conclusion: Our results suggest that specific combinations of variants in genes from the same signaling pathway can define an HIV-1 resistant phenotype. Despite our small sample size, our statistically significant associations suggest strong effects; however, these results should be further validated in larger cohorts.

ABSTRACT Introducción. Algunas variantes en genes que codifican los correceptores del HIV-1 y sus ligandos se han asociado individualmente a la resistencia natural frente a dicha infección. Sin embargo, su presencia simultánea ha sido poco estudiada. Objetivo. Evaluar la asociación de haplotipos individuales y multilocus en genes que codifican los correceptores virales CCR5 y CCR2 y sus ligandos CCL3 y CCL5 con la resistencia o la propensión a la infección por el HIV-1. Materiales y métodos. Nueve variantes en CCR5-CCR2, dos en CCL3 y dos en CCL5 fueron genotipificadas mediante reacción en cadena de la polimerasa de polimorfismos de longitud de fragmentos de restricción (Restriction Fragment Length Polymorphism-PCR-RFLP) en 35 individuos seropositivos (casos) y 49 seronegativos expuestos (controles) de Colombia. Los haplotipos se infirieron utilizando el programa Arlequín, y su frecuencia individual o combinada se comparó en los casos y los controles mediante la prueba de ji al cuadrado. Se consideró significativo un valor de p'<0,05 después de la corrección de Bonferroni. Resultados. La homocigosis del haplogrupo humano (HH) E estaba ausente en los controles y era frecuente en los casos, es decir, con tendencia hacia la propensión. Los haplotipos C-C y T-T en CCL3 se asociaron con la propensión (p'=0,016) y la resistencia (p'<0,0001), respectivamente. Por último, en el análisis multilocus, el haplotipo combinado formado por HHC en CCR5-CCR2, T-T en CCL3 y G-C en CCL5 se asoció con la resistencia (p'=0,006). Conclusión. Los resultados de este estudio sugieren que ciertas combinaciones específicas de variantes en los genes de una misma vía de señalización pueden definir un fenotipo resistente al HIV-1. Aunque el tamaño de la muestra era pequeño, las asociaciones estadísticamente significativas sugieren un efecto considerable; sin embargo, estos resultados deben validarse en cohortes de mayor tamaño.

Immunoregulation in human malaria: the challenge of understanding asymptomatic infection

Asymptomatic Plasmodium infection carriers represent a major threat to malaria control worldwide as they are silent natural reservoirs and do not seek medical care. There are no standard criteria for asymptomaticPlasmodium infection; therefore, its diagnosis relies on the presence of the parasite during a specific period of symptomless infection. The antiparasitic immune response can result in reducedPlasmodium sp. load with control of disease manifestations, which leads to asymptomatic infection. Both the innate and adaptive immune responses seem to play major roles in asymptomatic Plasmodiuminfection; T regulatory cell activity (through the production of interleukin-10 and transforming growth factor-β) and B-cells (with a broad antibody response) both play prominent roles. Furthermore, molecules involved in the haem detoxification pathway (such as haptoglobin and haeme oxygenase-1) and iron metabolism (ferritin and activated c-Jun N-terminal kinase) have emerged in recent years as potential biomarkers and thus are helping to unravel the immune response underlying asymptomatic Plasmodium infection. The acquisition of large data sets and the use of robust statistical tools, including network analysis, associated with well-designed malaria studies will likely help elucidate the immune mechanisms responsible for asymptomatic infection.

New insights on the development of fungal vaccines: from immunity to recent challenges

Fungal infections are emerging as a major problem in part due to high mortality associated with systemic infections, especially in the case of immunocompromised patients. With the development of new treatments for diseases such as cancer and the acquired immune deficiency syndrome pandemic, the number of immunosuppressed patients has increased and, as a consequence, also the number of invasive fungal infections has increased. Several studies have proposed new strategies for the development of effective fungal vaccines. In addition, better understanding of how the immune system works against fungal pathogens has improved the further development of these new vaccination strategies. As a result, some fungal vaccines have advanced through clinical trials. However, there are still many challenges that prevent the clinical development of fungal vaccines that can efficiently immunise subjects at risk of developing invasive fungal infections. In this review, we will discuss these new vaccination strategies and the challenges that they present. In the future with proper investments, fungal vaccines may soon become a reality.

Toll-like receptor 3 (TLR3) and the development of type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is a chronic, progressive autoimmune disease characterized by metabolic decompensation often leading to dehydration and ketoacidosis. Viral agents seem to play an important role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, the enterovirus family has been consistently associated with the onset of T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The Toll-like receptor 3 (TLR3) gene codes for an endoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, plays an important role in the innate immune response triggered by viral infection. Binding of dsRNA to the TLR3 triggers the release of proinflammatory cytokines, such as interferons, which exhibit potent antiviral action; thus, protecting uninfected cells and inducing apoptosis of infected ones. Therefore, the TLR3 gene is a good candidate for the development of T1DM. Within this context, the objective of the present review was to address the role of the TLR3 gene in the development of T1DM. Arch Endocrinol Metab. 2015;59(1):4-12.

Implicancia de la inmunidad innata del epitelio bronquiolar en la modulación y prevención del asma / Implication of innate immunity in modulating bronchial epithelium and prevention of asthma

El asma alérgica ha incrementado su prevalencia, constituyéndose como un problema mundial de salud. Factores ambientales derivados de la vida moderna han sido vinculados a este fenómeno a través de la hipótesis de la higiene; la cual postula que la vida urbana disminuye la potenciación de la inmunidad innata, lograda a través del reconocimiento de estímulos microbianos por los receptores Toll-like (TLRs), conduciendo a la mayor prevalencia de respuestas alérgicas. Las investigaciones en asma en el último siglo han tenido como objetivo la disminución de la respuesta inmune adaptativa Th2 asociada a las alergias; sin embargo han conseguido escasos avances terapéuticos. Actualmente, es creciente el número de evidencias que implican a los componentes estructurales de la vía aérea en el inicio y progresión del asma; no obstante su rol en la prevención de la inflamación alérgica no ha sido suficientemente evaluado. Por lo tanto, el presente trabajo de Tesis Doctoral tuvo como objetivo general el estudio de la interacción de la inmunidad innata del epitelio bronquiolar y la inflamación alérgica del asma.

ABSTRACT: Recently, asthma rates have increased becoming a global health problem. The role of environmental factors in this increase, due to modern lifestyles, has been suggested by the hygiene hypothesis, which postulated that the urban hygienic conditions skip the early exposure to microbes hence that are clue to promote innate immune activation by signalling through the Toll-like receptors (TLRs) and thus preventing the allergic responses. Even though many investigations on asthma have been focused on the reduction of the allergic Th2-nflammatory response in the last century, the therapeutic advances have been scarce. Nowadays, there is increasing evidence of the involvement of the airway epithelial cells on the origin and progression of asthma. However, the role of these cells in preventing the triggering of allergic inflammation has not been evaluated. Therefore, the main objective of this thesis was to study the interaction of innate immunity of bronchiolar epithelium and allergic inflammation in asthma.

Inmunosenescencia: efectos de la edad sobre el sistema inmune / Immunosenescence: effects of aging process on immune system

El proceso de envejecimiento provoca cambios en el sistema inmune que afectan su funcionamiento y desarrollo. Estos cambios pueden manifestarse desde la linfopoyesis hasta la respuesta que orquesta el sistema inmune frente a determinada enfermedad o agente infeccioso. Ambas ramas de la inmunidad, innata y adaptativa, se afectan en este proceso, lo que genera un impacto negativo en la respuesta inmune de los ancianos y los predispone a padecer enfermedades infecciosas, cáncer, autoinmunidad y a desarrollar respuestas pobres tras la administración de vacunas...

The aging process produces functional and developmental changes in the immune system. Those changes may appear from lymphopoiesis up to the final response of the immune system facing a certain disease. Both branches of immunity, innate and adaptive, are affected by the aging process; hence these changes can have a negative impact on the immune response of elderly patients and increase their susceptibility to infectious diseases, cancer and decreased vaccine efficacy...

The Role of High Mobility Group Box 1 in Innate Immunity

With growing accounts of inflammatory diseases such as sepsis, greater understanding the immune system and the mechanisms of cellular immunity have become primary objectives in immunology studies. High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is implicated in various aspects of the innate immune system as a damage-associated molecular pattern molecule and a late mediator of inflammation, as well as in principal cellular processes, such as autophagy and apoptosis. HMGB1 functions in the nucleus as a DNA chaperone; however, it exhibits cytokine-like activity when secreted by injurious or infectious stimuli. Extracellular HMGB1 acts through specific receptors to promote activation of the NF-kappaB signaling pathway, leading to production of cytokines and chemokines. These findings further implicate HMGB1 in lethal inflammatory diseases as a crucial regulator of inflammatory, injurious, and infectious responses. In this paper, we summarize the role of HMGB1 in inflammatory and non-inflammatory states and assess potential therapeutic approaches targeting HMGB1 in inflammatory diseases.

New insights in the pathogenesis of type 1 and type 2 lepra reaction.

In the current scenario of leprosy elimination, lepra reactions (LRs) remain a major persistent problem. Type 1 LR (T1LR) and type 2 LR (T2LR) are the major causes of nerve damage and permanent disabilities. The immunopathogenesis of LR have recently become an important fi eld of research, since it may provide the relevant targets for the early detection and control of these episodes. Presently, there are no uniformly acceptable laboratory markers for LR. Genetic and serum markers in human host may predict susceptibility to reactions as well as progression of nerve damage in leprosy. Therefore, a deeper understanding of the molecular mechanisms involved in LR may provide a rational strategy for early diagnosis and prevention of the catastrophic consequences of LR.

Leukocytes respiratory burst activity as indicator of innate immunity of pacu Piaractus mesopotamicus / Atividade respiratória de leucócitos como indicador de imunidade inata de pacu (Piaractus mesopotamicus)

The present study evaluated the assay to quantify the respiratory burst activity of blood leukocytes of pacu as an indicator of the innate immune system, using the reduction of nitroblue tetrazolium (NBT) to formazan as a measure of the production of reactive oxygen species (ROS). In order to assess the accuracy of the assay, fish were challenged by Aeromonas hydrophila and sampled one week after challenge. The A. hydrophila infection increased the leukocyte respiratory burst activity. The protocol showed a reliable and easy assay, appropriate to determine the respiratory burst activity of blood leukocytes of pacu, a neotropical fish, in the present experimental conditions.

O presente estudo avaliou o ensaio para quantificar a atividade respiratória dos leucócitos do sangue de pacu como um indicador do sistema imune inato, usando a redução do nitroazul tetrazólio (NBT) a formazan como medida da produção de espécies reativas de oxigênio (EROs). Para avaliar a precisão do ensaio, peixes foram desafiados por Aeromonas hydrophila e amostrados uma semana após o desafio. A infecção com A. hydrophila aumentou a atividade respiratória dos leucócitos. O protocolo se mostrou confiável e de fácil aplicação, apropriado para determinar a atividade respiratória de leucócitos do sangue do pacu, peixe neotropical, nas condições experimentais apresentadas.

Autophagy and bacterial infectious diseases

Autophagy is a housekeeping process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic constituents. Over the past several years, accumulating evidence has suggested that autophagy can function as an intracellular innate defense pathway in response to infection with a variety of bacteria and viruses. Autophagy plays a role as a specialized immunologic effector and regulates innate immunity to exert antimicrobial defense mechanisms. Numerous bacterial pathogens have developed the ability to invade host cells or to subvert host autophagy to establish a persistent infection. In this review, we have summarized the recent advances in our understanding of the interaction between antibacterial autophagy (xenophagy) and different bacterial pathogens.

La vitamina D, el sistema inmune y las enfermedades de la piel / Vitamin D, immune system and skin diseases

El sistema endocrino de la vitamina D tiene un rol esencial en la regulación del metabolismo óseo y la homeostasis del calcio. Sin embargo, los hallazgos de las últimas décadas han revelado un amplio rango de acciones que incluyen la regulación de la diferenciación y proliferación celular y la modulación del sistema inmune y otros sistemas endocrinos. A través de la regulación de la inmunidad innata y adquirida participa en la regulación de la respuesta a diversos antígenos. Estas nuevas acciones sugieren que la vitamina D es un factor ambiental con un rol importante en el desarrollo de enfermedades autoinmunes. El nuevo rol modulador de la vitamina D en el sistema inmune ha dado explicación a muchos fenómenos antes desconocidos y ha abierto nuevas oportunidades en el tratamiento de las enfermedades inflamatorias.

The vitamin D endocrine system plays an essential role in calcium ho-meostasis and bone metabolism. Nevertheless, research during the pastdecades has revealed a diverse range of biological actions that includeinduction of cell diff erentiation, inhibition of cell growth,immunomodulation, and control of other hormonal systems.Through the innate and adaptative immune systems modulation, vitamin D regulates the response to many antigens. These new actions suggest an importantrole for vitamin D as a modifi able environmental factor in autoimmune disease.The new fi ndings on vitamin D actions on immunity have explained its role in the pathogenesis of skin autoimmune diseases, and have offered new possibilities for their treatment.

Defense mechanisms of Solanum tuberosum L. in response to attack by plant-pathogenic bacteria

The natural resistance of plants to disease is based not only on preformed mechanisms, but also on induced mechanisms. The defense mechanisms present in resistant plants may also be found in susceptible ones. This study attempted to analyze the metabolic alterations in plants of the potato Solanum tuberosum L. cv. Agata that were inoculated with the incompatible plant-pathogenic bacteria X. axonopodis and R. solanacearum, and the compatible bacterium E. carotovora. Levels of total phenolic compounds, including the flavonoid group, and the activities of polyphenol oxidase (PPO) and peroxidase (POX) were evaluated. Bacteria compatibility was evaluated by means of infiltration of tubers. The defense response was evaluated in the leaves of the potato plants. Leaves were inoculated depending on their number and location on the stem. Multiple-leaf inoculation was carried out on basal, intermediate, and apical leaves, and single inoculations on intermediate leaves. Leaves inoculated with X. axonopodis and with R. solanacearum showed hypersensitive responses within 24 hours post-inoculation, whereas leaves inoculated with E. carotovora showed disease symptoms. Therefore, the R. solanacearum isolate used in the experiments did not exhibit virulence to this potato cultivar. Regardless of the bacterial treatments, the basal leaves showed higher PPO and POX activities and lower levels of total phenolic compounds and flavonoids, compared to the apical leaves. However, basal and intermediate leaves inoculated with R. solanacearum and X. axonopodis showed increases in total phenolic compounds and flavonoid levels. In general, multiple-leaf inoculation showed the highest levels of total phenolics and flavonoids, whereas the single inoculations resulted in the highest increase in PPO activity. The POX activity showed no significant difference between single- and multiple-leaf inoculations. Plants inoculated with E. carotovora showed no significant increase ...

Sistema imunológico: atualidades e perspectivas para a prática clínica / Immune system: present time and perspectives for clinical practice

O sistema imunológico (SI), à semelhança do sistema nervoso, tem uma participação central na biologia do Homo sapiens sapiens (sic), tendo na comunicação um dos esteios para sua organização e funcionamento. Além de ser capaz de distinguir o que é próprio (self) do que é não-próprio (non-self), o SI estrutura-se em rede, processando informações de modo a permitir o aprendizado e o desenvolvimento da memória, aspectos fundamentais para a relação do organismo com o meio ambiente, com importantes implicações no adoecimento humano. Com base nestas considerações, objetiva-se, no presente manuscrito, apresentar, de modo sintético, os principais aspectos do sistema imunológico.

The immune system (IS), like the nervous system, plays a central role in the biology of Homo sapiens sapiens (sic), eith communication as a base for its organization and operation. In addition to an ability to distinguish self from non-self, the IS structures itself in a network, processing information in a way to allow learning and the development of memory, fundamental aspects in the organim's relation with the environment, with important implications in human illnesses. Based on these considerations, this review aims to present, in a synthetic manner, the principal aspects of the immune system.

Disease associations of mannose-binding lectin & potential of replacement therapy.

Mannose-binding lectin (MBL) is an important component of the immune defence able to bind to repeating mannose based structural patterns typical of microbial surface (bacteria, viruses, fungi, parasites) leading to opsonization and phagocytosis, and activation of the complement pathway resulting in lysis of the pathogen. MBL thus plays a very important role in the first line of host immune response. MBL deficiency has been implicated in susceptibility and modulating the severity in viral, bacterial, fungal, and protozoan infections. High MBL levels, on the contrary might be helpful to intracellular organisms, which take the advantage of C3 opsonization and C3 receptor on monocytes/macrophages to enter their host. MBL replacement therapy to help patients with MBL deficiency has undergone phase I clinical trials. Phase II and III trials and production of recombinant MBL for replacement therapy are currently underway.

Dysfunction of innate immunity and associated pathology in neonates.

The neutrophils and complement system are the critical elements of innate immunity mainly due to participation in the first line of defense against microorganisms by means of phagocytosis, lysis of bacteria and activation of naive B-lymphocytes. In this report we provide an overview of the up to date information regarding the neutrophil and complement system's functional ability in newborn infants in association with the maternal conditions that exist during the intrauterine stage, gestational age and post-neonatal pathology. The neonates' capacity to control the neutrophil and complement protein activation process has also been discussed because of the evidence that uncontrolled activation of these immune elements provides a significant contribution to the tissue damage and subsequent pathology. The authors are confident that despite the many unanswered questions this review updates their knowledge and points the need for further research to clarify the role of the age-associated dysfunction of neutrophils and complement system in the infection and inflammation related pathology of newborn infants.

Toll-like Receptors are Key Participants in Innate Immune Responses

During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR- mediated signaling pathways. TLR-mediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.