Browsing by Author "González Muñoz, Pablo Alberto"

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    Anti-herpetic Activity ofMacrocystis pyriferaandDurvillaea antarcticaAlgae Extracts Against HSV-1 and HSV-2
    (2020) Castillo, E.; Duarte Peñaloza, Luisa Fernanda; Corrales, N.; Álvarez Espejo, Diana Claudia Marcela; Farías León, Mónica Andrea; Henríquez, A.; Smith Ferrer, Patricio; Agurto Muñoz, C.; González Muñoz, Pablo Alberto
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    Asymptomatic Herpes Simplex Virus Type 1 Infection Causes an Earlier Onset and More Severe Experimental Autoimmune Encephalomyelitis
    (2021) Duarte Peñaloza, Luisa Fernanda; Altamirano Lagos, María J.; Tabares Guevara, Jorge H.; Opazo, María Cecilia; Díaz, Máximo; Navarrete, Romina; Muza, Catalina; Vallejos Galvez, Omar Patricio; Riedel Soria, Claudia; Bueno Ramírez, Susan; Kalergis Parra, Alexis Mikes; González Muñoz, Pablo Alberto
    Multiple sclerosis (MS) is an increasingly prevalent progressive autoimmune and debilitating chronic disease that involves the detrimental recognition of central nervous system (CNS) antigens by the immune system. Although significant progress has been made in the last decades on the biology of MS and the identification of novel therapies to treat its symptoms, the etiology of this disease remains unknown. However, recent studies have suggested that viral infections may contribute to disease onset. Interestingly, a potential association between herpes simplex virus type 1 (HSV-1) infection and MS has been reported, yet a direct relationship among both has not been conclusively demonstrated. Experimental autoimmune encephalomyelitis (EAE) recapitulates several aspects of MS in humans and is widely used to study this disease. Here, we evaluated the effect of asymptomatic brain infection by HSV-1 on the onset and severity of EAE in C57BL/6 mice. We also evaluated the effect of infection with an HSV-1-mutant that is attenuated in neurovirulence and does not cause encephalitis. Importantly, we observed more severe EAE in mice previously infected either, with the wild-type (WT) or the mutant HSV-1, as compared to uninfected control mice. Also, earlier EAE onset was seen after WT virus inoculation. These findings support the notion that a previous exposure to HSV-1 can accelerate and enhance EAE, which suggests a potential contribution of asymptomatic HSV-1 to the onset and severity of MS.
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    BCG-induced cross-protection and development of trained immunity: implication for vaccine design
    (2019) Covián, Camila; Fernández Fierro, Ayleen Lorena; Retamal Díaz, Angello Ricardo; Díaz Acevedo, Fabián Esteban; Vásquez Veloso, Abel; Lay Remolcoi, Margarita Kam-len; Riedel Soria, Claudia; González Muñoz, Pablo Alberto; Bueno Ramírez, Susan; Kalergis Parra, Alexis Mikes
    The Bacillus Calmette-Guerin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.
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    Central nervous system alterations caused by infection with the human respiratory syncytial virus
    (2014) Bohmwald Prieto, Karen; Espinoza Véliz, Janyra Alejandra; González Muñoz, Pablo Alberto; Bueno Ramírez, Susan; Riedel, C.; Kalergis Parra, Alexis Mikes
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    Characterization of the anti-inflammatory capacity of IL-10-Producing neutrophils in response to streptococcus pneumoniae infection
    (FRONTIERS MEDIA SA, 2021) González Carreño, Liliana Andrea; Melo González, Felipe Andrés; Sebastián Quijada, Valentina Pilar; Vallejos Galvez, Omar Patricio; Noguera Mijares, Loreani Paola; Suazo Galvez, Isidora del Carmen; Schultz Lombardic, Bárbara M.; Manosalva, Andres H.; Peñaloza, Hernán F.; Soto Ramírez, Jorge Andres; Parker, Dane; Riedel, Claudia A.; González Muñoz, Pablo Alberto; Kalergis Parra, Alexis Mikes; Bueno Ramírez, Susan
    Neutrophils are immune cells classically defined as pro-inflammatory effector cells. However, current accumulated evidence indicates that neutrophils have more versatile immune-modulating properties. During acute lung infection with Streptococcus pneumoniae in mice, interleukin-10 (IL-10) production is required to temper an excessive lung injury and to improve survival, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during S. pneumoniae infection remain unknown. Here we show that neutrophils are the main myeloid cells that produce IL-10 in the lungs during the first 48 h of infection. Importantly, in vitro assays with bone-marrow derived neutrophils confirmed that IL-10 can be induced by these cells by the direct recognition of pneumococcal antigens. In vivo, we identified the recruitment of two neutrophil subpopulations in the lungs following infection, which exhibited clear morphological differences and a distinctive profile of IL-10 production at 48 h post-infection. Furthermore, adoptive transfer of neutrophils from WT mice into IL-10 knockout mice (Il10(-/-) ) fully restored IL-10 production in the lungs and reduced lung histopathology. These results suggest that IL-10 production by neutrophils induced by S. pneumoniae limits lung injury and is important to mediate an effective immune response required for host survival.
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    Clinical applications of antigen-specific detection of T lymphocytes
    (2004) Kalergis Parra, Alexis Mikes; González Muñoz, Pablo Alberto; Tobar Rubio, Jaime Andrés
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    Contribution of Fc gamma receptors to human respiratory syncytial virus pathogenesis and the impairment of T-cell activation by dendritic cells
    (2016) Gómez Johnson, Roberto Sebastian; Ramírez Cornejo, Bruno Alexis; Céspedes Donoso, Pablo Francisco; Cautivo Reyes, Kelly Margarita; Riquelme Colet, Sebastián Alejandro; Prado Terrazas, Carolina Elizabeth; González Muñoz, Pablo Alberto; Kalergis Parra, Alexis Mikes
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    Contribution of hypoxia inducible factor-1 during viral infections
    (2020) Reyes Muñoz, Antonia Paz; Corrales Bonilla, Nicolás; Gálvez Arriagada, Nicolás Marcelo Salvador; Bueno Ramírez, Susan; Kalergis Parra, Alexis Mikes; González Muñoz, Pablo Alberto
    Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays critical roles during the cellular response to hypoxia. Under normoxic conditions, its function is tightly regulated by the degradation of its alpha subunit (HIF-1α), which impairs the formation of an active heterodimer in the nucleus that otherwise regulates the expression of numerous genes. Importantly, HIF-1 participates in both cancer and infectious diseases unveiling new therapeutic targets for those ailments. Here, we discuss aspects related to the activation of HIF-1, the effects of this transcription factor over immune system components, as well as the involvement of HIF-1 activity in response to viral infections in humans. Although HIF-1 is currently being assessed in numerous clinical settings as a potential therapy for different diseases, up to date, there are no clinical studies evaluating the pharmacological modulation of this transcription factor as a possible new antiviral treatment. However, based on the available evidence, clinical trials targeting this molecule are likely to occur soon. In this review we discuss the role of HIF-1 in viral immunity, the modulation of HIF-1 by different types of viruses, as well as the effects of HIF-1 over their life cycle and the potential use of HIF-1 as a new target for the treatment of viral infections.
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    Different Safety Pattern of an Inactivated SARS-CoV-2 Vaccine (CoronaVac®) According to Age Group in a Pediatric Population from 3 to 17 Years Old, in an Open-Label Study in Chile
    (2023) Le Corre, Nicole; Abarca Villaseca, Katia; Astudillo, Patricio André; Potin Santander, Marcela Patricia; López, Sofía; Goldsack, Macarena; Valenzuela Guerrero, Vania; Schilling Redlich, Andrea; Gaete, Victoria; Rubio, Lilian; Calvo, Mario; Twele, Loreto; González, Marcela; Fuentes, Daniela; Gutiérrez Muñoz, Valentina José; Reyes Zaldivar, Felipe Tomás; Tapia, Lorena I.; Villena, Rodolfo; Retamal Díaz, Angello; Cárdenas, Antonio; Alarcón Bustamante, Eduardo; Xin, Qianqian; González Aramundiz, José Vicente; Álvarez Figueroa, María Javiera; González Muñoz, Pablo Alberto; Bueno Ramírez, Susan; Soto Ramírez, Jorge Andrés; Perret Pérez, Cecilia; Meng, Xing; Kalergis Parra, Alexis Mikes
    During the COVID-19 pandemic, the importance of vaccinating children against SARS-CoV-2 was rapidly established. This study describes the safety of CoronaVac® in children and adolescents between 3- and 17-years-old in a multicenter study in Chile with two vaccine doses in a 4-week interval. For all participants, immediate adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were registered throughout the study. In the safety subgroup, AEs were recorded 28 days after each dose. COVID-19 surveillance was performed throughout the study. A total of 1139 individuals received the first and 1102 the second dose of CoronaVac®; 835 were in the safety subgroup. The first dose showed the highest number of AEs: up to 22.2% of participants reported any local and 17.1% systemic AE. AEs were more frequent in adolescents after the first dose, were transient, and mainly mild. Pain at the inoculation site was the most frequent AE for all ages. Fever was the most frequent systemic AE for 3–5 years old and headache in 6–17 years old. No SAEs or AESIs related to vaccination occurred. Most of the COVID-19 cases were mild and managed as outpatients. CoronaVac® was safe and well tolerated in children and adolescents, with different safety patterns according to age.
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    Differential Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Response in Inactivated Virus-Vaccinated, Convalescent, and Breakthrough-Infected Subjects
    (OXFORD UNIV PRESS INC, 2023) Duarte Peñaloza, Luisa Fernanda; Vazquez Hernandez Yaneisi; Diethelm Varela, Benjamin Manuel; Pavez, Valentina; Berrios-Rojas, Roslye; Riedel, Claudia A.; Mendez, Constanza; White, Jessica A.; Kalergis Parra, Alexis Mikes; Bueno Ramírez, Susan Marcela; González Muñoz, Pablo Alberto
    Background. We sought to identify potential antigens for discerning between humoral responses elicited after vaccination with CoronaVac (a severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] inactivated vaccine), natural infection, or breakthrough infection., Methods. Serum samples obtained from volunteers immunized with CoronaVac (2 and 3 doses), breakthrough case patients, and from convalescent individuals were analyzed to determine the immunoglobulin (Ig) G responses against 3 structural and 8 nonstructural SARS-CoV-2 antigens., Results. Immunization with CoronaVac induced higher levels of antibodies against the viral membrane (M) protein compared with convalescent subjects both after primary vaccination and after a booster dose. Individuals receiving a booster dose displayed equivalent levels of IgG antibodies against the nucleocapsid (N) protein, similar to convalescent subjects. Breakthrough case patients produced the highest antibody levels against the N and M proteins. Antibodies against nonstructural viral proteins were present in >50% of the convalescent subjects., Conclusions. Vaccinated individuals elicited a different humoral response compared to convalescent subjects. The analysis of particular SARS-CoV-2 antigens could be used as biomarkers for determining infection in subjects previously vaccinated with CoronaVac.
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    Enhanced specialized transduction using recombineering in mycobacterium tuberculosis
    (2014) Tufariello, J. M.; González Muñoz, Pablo Alberto
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    Evaluating the impact of asymptomatic herpes simplex virus type 1 infection on multiple sclerosis disease in a mouse model
    (2020) Duarte Peñaloza, Luisa Fernanda; González Muñoz, Pablo Alberto; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La esclerosis múltiple es una enfermedad autoinmune desmielinizante del sistema nervioso central (SNC) que perjudica severamente las funciones sensoriales y motoras del individuo. Hoy en día, la causa o causas de esta enfermedad son desconocidas y el tratamiento disponible solo disminuye la frecuencia de las recaídas inflamatorias, pero no previene del daño crónico y el declive neurológico. Existe evidencia que sugiere que los virus pueden tener un papel importante en el inicio y la patogénesis de la esclerosis múltiple por actuar como gatillantes ambientales. Notablemente, virus que pertenecen a la familia Herpesviridae, los cuales son adquiridos en etapas tempranas de la vida y causan infecciones latentes de por vida, han sido definidos como principales candidatos para iniciar o exacerbar esta enfermedad. Actualmente, pocos estudios han evaluado el potencial papel de los virus del herpes simple en esclerosis múltiple. Cabe resaltar, que el virus del herpes simple tipo 1 (VHS-1) se ha detectado en líquido cefalorraquídeo y en sangre periférica de pacientes con esclerosis múltiple durante recaídas inflamatorias, así como también en mayor frecuencia en muestras de cerebro post muerte de individuos con esclerosis múltiple que en individuos sanos. Además, las infecciones producidas por VHS-1 son principalmente asintomáticas y este virus podría alcanzar el cerebro a lo largo de la vida sin síntomas clínicos evidentes. Además, datos acumulados sugieren que la infección persistente con VHS-1 en el cerebro produce prolongada neuroinflamación debido a continuas reactivaciones subclínicas que conduce a desordenes neurodegenerativos en personas susceptibles. El objetivo de esta tesis fue determinar si la infección asintomática con VHS-1 favorece el inicio de la esclerosis múltiple y su severidad. Nosotros abordamos esta pregunta usando animales que recapitulan varios aspectos relacionados con la enfermedad de la esclerosis múltiple y la infección con VHS-1 en humanos. Primero, infectamos ratones con una dosis no letal de VHS-1, esperamos a la recuperación de la infección aguda, al menos 30 días, y luego inducimos la enfermedad de encefalomielitis autoinmune experimental (EAE), la cual es el principal modelo animal usado para estudiar la enfermedad de esclerosis múltiple. El inicio y severidad de síntomas de esclerosis múltiple en el modelo murino de EAE fue comparado con animales no infectados. Determinamos las poblaciones de células inmunes infiltrando SNC de ratones después de la infección con VHS-1 e inducción de EAE, así como también las citoquinas producidas en este tejido luego del inicio de la autoinmunidad. También evaluamos la permeabilidad de la barrera hemato-encefálica 30 días post infección con VHS-1. Nuestros resultados muestran que una infección previa con VHS-1 acelera el inicio de EAE y aumenta la severidad de la enfermedad en el modelo murino. Además, animales previamente infectados con VHS-1 e inducidos a desarrollar EAE padecen una mayor inflamación de SNC que los animales no infectados, lo cual se caracterizó por prolongada activación de microglía, una elevada infiltración de células T CD4+ en el cerebro y neutrófilos en la médula espinal, y niveles de expresión significativos de mRNA de las citoquinas IL-6 e IL-1β en estos tejidos. Notablemente, también encontramos que después de la infección asintomática con VHS-1, la barrera hematoencefálica permanece alterada hasta por 30 días cuando no son detectados viriones. Esperamos que este estudio ayude a definir mejor la posible contribución de la infección por VHS-1 en la enfermedad de la esclerosis múltiple y a garantizar futuros estudios y ensayos con intervenciones antivirales como un potencial tratamiento de esta enfermedad para retardar su progresión.
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    Evasion of Early Antiviral Responses by Herpes Simplex Viruses
    (2015) Suazo, Paula A.; Ibáñez, Francisco J.; Retamal Díaz, Angello Ricardo; Paz-Fiblas, Marysol V.; Bueno Ramírez, Susan; Kalergis Parra, Alexis Mikes; González Muñoz, Pablo Alberto
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    Experimental Dissection of the Lytic Replication Cycles of Herpes Simplex Viruses in vitro
    (2018) Ibáñez Irribarra, Francisco Javier; Farías León, Mónica Andrea; González Troncoso Mp; Corrales N.; Duarte Peñaloza, Luisa Fernanda; Retamal Díaz, Angello Ricardo; González Muñoz, Pablo Alberto
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    Expression of heme oxygenase-1 in dendritic cells elicits T cell activation and confers protective immunity against HSV in an in vivo skin infection model
    (2023) Tognarelli Torres, Eduardo Ignacio; González Muñoz, Pablo Alberto; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    Los virus herpes simple tipo 1 (HSV-1) y tipo 2 (HSV-2) son altamente prevalentes en la población, en parte debido a su frecuente diseminación, aún desde individuos asintomáticos. La infección por HSV puede producir diversas manifestaciones clínicas incluyendo lesiones en piel, ceguera, o incluso encefalitis severa. Un aspecto importante de HSV es su capacidad para interferir con la viabilidad y función de células dendríticas (DC), células presentadoras de antígeno que inician y modulan la respuesta inmune en la interfase entre inmunidad innata y adaptativa. Una enzima del hospedero que participa en respuesta inducida frente a estrés es hemo oxigenasa-1 (HO-1), que se ha visto posee actividad antiviral contra HSV en células epiteliales y neuronales. En este estudio, buscamos evaluar si HO-1 puede modular positivamente la viabilidad de DCs y su función frente a la infección por HSV, lo cual podría ser clave para establecer inmunidad protectora contra estos virus. Nuestros hallazgos indican que HO-1 reduce la infección en DC por HSV-1 y HSV-2, y provee protección contra la muerte celular que inducen estos virus en estas células. La sobreexpresión de HO-1 en DCs no promueve un incremento de los marcadores de maduración y activación, por el contrario, aumentan la presencia de marcadores inhibitorios. Las DCs que expresan HO-1 y están infectadas con HSV, en ensayos de co-cultivo activaron células T CD4 vírgenes hacia fenotipos T regulador (Treg), determinado por la expresión de FoxP3 y OX40, y T helper (Th17) por la secreción de IL-17. La mejora de la función de DCs producto de la expresión de HO-1 se debería a un defecto en el ciclo de replicación de HSV por una disminución en la liberación de partículas infecciosas desde DCs, sin causar un efecto sobre la replicación del genoma y síntesis proteica viral. En un modelo de encefalitis, la transferencia de DCs que expresan HO-1 e infectadas con HSV causó que los animales susceptibles sufrieran un adelanto y aumento de la severidad de la patología. Mientras que, en un modelo de infección en piel, la transferencia de estas DCs demoró el inicio de la enfermedad y redujo el puntaje clínico de la infección por HSV. Adicionalmente, la inducción por HO-1 promueve la migración de DCs a linfonodos popliteos (pLNs) y estimuló células T CD4 Th17 y Tregs. Finalmente, se encontraron en lesiones de piel células Th17, mientras que hubo presencia de T CD8 y Treg a tiempos tempranos y tardíos, respectivamente. Estos resultados sugieren que la expresión de HO-1 en DCs promueve control viral, junto con una respuesta antinflamatoria contra HSV que puede proveer protección en un modelo animal de infección.
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    FOCIS goes south: advances in translational and clinical immunology
    (2017) Kalergis Parra, Alexis Mikes; Anegon, I.; González Muñoz, Pablo Alberto
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