DSpace Angular :: Browsing by Author "Kalergis, Alexis M."

Browsing by Author "Kalergis, Alexis M."

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11 beta-hydroxysteroid dehydrogenase type-2 and type-1 (11 beta-HSD2 and 11 beta-HSD1) and 5 beta-reductase activities in the pathogenia of essential hypertension
(HUMANA PRESS INC, 2010) Campino, Carmen; Carvajal, Cristian A.; Cornejo, Javiera; San Martin, Betty; Olivieri, Oliviero; Guidi, Giancesare; Faccini, Giovanni; Pasini, Francesco; Sateler, Javiera; Baudrand, Rene; Mosso, Lorena; Owen, Gareth I.; Kalergis, Alexis M.; Padilla, Oslando; Fardella, Carlos E.
Cortisol availability is modulated by several enzymes: 11 beta-HSD2, which transforms cortisol (F) to cortisone (E) and 11 beta-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5 alpha- and 5 beta-reductase) inactivate cortisol (together with 3 alpha-HSD) to tetrahydrometabolites: 5 alpha THF, 5 beta THF, and THE. The aim was to assess 11 beta-HSD2, 11 beta-HSD1, and 5 beta-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11 beta-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11 beta-HSD1 in compare to 11 beta-HSD2 was inferred by the (5 alpha THF + 5 beta THF)/THE ratio and 5 beta-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11 beta-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5 alpha THF + 5 beta THF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11 beta-HSD2 and 5 beta-reductase decreased activity and imbalance of 11 beta-HSDs should be considered in the future management of hypertensive patients.
11β-hydroxysteroid dehydrogenase type 2 polymorphisms and activity in a Chilean essential hypertensive and normotensive cohort.
(2012) Campino, Carmen; Quinteros, Hector; Owen, Gareth I.; Carvajal, Cristian A.; Morales, Mauricio; Olivieri, Oliviero; Guidi, Giancesare; Faccini, Giovanni; Pasini, Francesco; Baudrand, Rene; Padilla, Oslando; Valdivia, Carolina; Thichauer, Juan; Lagos, Carlos F.; Kalergis, Alexis M.; Fardella, Carlos E.
BACKGROUND: 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) inactivates cortisol (F) to cortisone (E); its impairment is associated with hypertension. We reported that 15.7% of the Chilean essential hypertensives possessed a high F/E ratio suggesting a partial deficit in 11β-HSD2 activity. It has been reported that the G534A(Glu178/Glu) polymorphism in the HSD11B2 gene is associated with hypertension. Investigate the frequency of the G534A polymorphism and its correlation with the glucocorticoid profile in Chilean essential hypertensive and normotensive subjects. METHODS: Essential hypertensive outpatients (n = 232) and normotensive subjects (n = 74) were recruited. A change in the AluI restriction enzyme digest pattern, caused by the presence of the G534A polymorphism, was utilized to screen DNA isolated from leukocytes within the cohort before confirmation by sequencing. Plasma renin activity (PRA), serum aldosterone, F, and E were measured by radioimmunoassay. Urinary tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF), and tetrahydrocortisone (THE) were measured by gas chromatography-mass spectrometry. RESULTS: G534A polymorphism frequency was similar between hypertensive patients (19 of 232; 8.2%) and normotensive subjects (7 of 74; 9.5%). When categorized by presence or absence of the G534A polymorphism, no significant differences in the serum F/E ratio or other measured biochemical variables were detected. Despite a previous report that the G534A polymorphism is associated with a neighboring C468A (Thr156/Thr) polymorphism, analysis within our cohort showed that only one patient in each group presented with this double polymorphism. CONCLUSIONS: We report the frequency of the G534A polymorphism in the Spanish-Amerindian population. No correlation was detected between this polymorphism and the presence of hypertension and biochemical parameters in this Chilean cohort.
A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I
(2010) Carvajal, C. A.; Stehr, C. B.; González, P. A.; Riquelme, E. M.; Montero, T.; Santos, M. J.; Kalergis, Alexis M.; Fardella, C. E.
Familial hyperaldosteronism type I (FH-I) is an autosomal dominant disorder caused by an unequal cross-over of the gene encoding steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), giving rise to a chimeric CYP11B1/CYP11B2 gene that displays aldosterone synthase activity regulated by ACTH instead of angiotensin II.To report an unprecedented case of a de novo unequal crossover mutation between CYP11B1 and CYP11B2 genes causing FH-I.The index case is a 45-yr-old Chilean male diagnosed with primary aldosteronism (PA). All family members were also studied: his biological parents, 1 brother, 6 sisters, 2 daughters, and 1 son. Plasma renin activity, serum aldosterone, and its ratio were measured in all patients. Genetic analyses were performed using long-extension PCR (XL-PCR), DNA sequencing and Southern blot methods.PA was diagnosed for the index case, 1 of his daughters, his son but not for his parents or siblings. XLPCR and Southern blotting demonstrated the presence of the chimeric CYP11B1/CYP11B2 gene solely in PA-affected subjects, suggesting a case of a de novo mutation. Sequence analysis showed the unequal cross-over CYP11B1/CYP11B2 at intron 2 (c.2600-273 CYP11B2). We also identified a polymorphism at the same intron (c.2600-145C>A CYP11B2) in the genome of the index case's father.We describe an unprecedented case of unequal cross-over mutation for the chimeric CYP11B1/CYP11B2 gene causing FH-I, which may be linked to a polymorphism in the index case's father germ line.
A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency
(ENDOCRINE SOC, 2008) Artigas, Rocio A.; Gonzalez, Angel; Riquelme, Erick; Carvajal, Cristian A.; Cattani, Andreina; Martinez Aguayo, Alejandro; Kalergis, Alexis M.; Perez Acle, Tomas; Fardella, Carlos E.
Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by unresponsiveness to ACTH. In this study, two mutations of the ACTH receptor (MC2R) gene are reported in this FGD clinical case.
A polymorphic GT short tandem repeat affecting beta-ENaC mRHA expression is associated with low renin essential hypertension
(OXFORD UNIV PRESS, 2007) Gonzalez, Alexis A.; Carvajal, Cristian A.; Riquelme, Erick; Krall, Paola M.; Munoz, Carlos R.; Mosso, Lorena M.; Kalergis, Alexis M.; Fardella, Carlos E.
Background: The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat [STR]) was identified in intron 8 of beta-ENaC gene (SCNN I B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the beta-ENaC gene expression in vitro.
Aldosterone Promotes Autoimmune Damage by Enhancing Th17-Mediated Immunity
(AMER ASSOC IMMUNOLOGISTS, 2010) Herrada, Andres A.; Contreras, Francisco J.; Marini, Natacha P.; Amador, Cristian A.; Gonzalez, Pablo A.; Cortes, Claudia M.; Riedel, Claudia A.; Carvajal, Cristian A.; Figueroa, Fernando; Michea, Luis F.; Fardella, Carlos E.; Kalergis, Alexis M.
Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8(+) T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-beta in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4(+) T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8(+) T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease. The Journal of Immunology, 2010, 184: 191-202.
Altered Chemokine Receptor Expression in Papillary Thyroid Cancer
(MARY ANN LIEBERT, INC, 2009) Gonzalez, Hernan E.; Leiva, Andrea; Tobar, Hugo; Boehmwald, Karen; Tapia, Grace; Torres, Javiera; Mosso, Lorena M.; Bueno, Susan M.; Gonzalez, Pablo; Kalergis, Alexis M.; Riedel, Claudia A.
Background: Papillary thyroid cancer (PTC), the most prevalent type of differentiated thyroid carcinoma, displays a strikingly high frequency of lymph node metastasis (LNM). Recent data suggest that chemokines can play an important role in promoting tumor progression and metastatic migration of tumor cells. Here we have evaluated whether PTC tissues express a different pattern of chemokine receptors and if the expression of these receptors correlates with LNM.
Análisis de los fenotipos y genotipos de resistencia a eritromicina y clindamicina en cepas de Streptococcus pyogenes aisladas en Chile en un período de 10 años
(2011) Rodríguez, Carlos; Rojas, Pablo; Wozniak, Aniela; Kalergis, Alexis M.; Cerón, Inés; Riedel, Ingrid; Román, Juan C.; Villarroel, Luis A.; Berríos, Ximena; Bavestrello, Luis; García, Patricia
Background: Macrolide and lincosamide resistance in Streptococcus pyogenes is due to the acquisition of mef, ermB and ermA genes, which confer different resistance phenotypes, namely M, MLSBconstitutive and MLSBinducible respectively. The last report of resistance in Chile was done in the period 1990-1998, in which resistance to macrolides was 5.4%, with M phenotype as the predominant one. Aim: To characterize the evolution of erythromycin and clindamycin resistance and their associated genes in S. pyogenes strains isolated from patients with invasive and noninvasive infections in the period 1996 to 2005. Material and Methods: Resistance to erythromycin and clindamycin was determined in 1,282 clinical isolates using the disk diffusion test. Resistant isolates were analyzed by polymerase chain reaction (PCR) for the presence of the above mentioned resistance genes. Results: Global resistance to erythromycin and clindamycin was 3.5 and 0.7% respectively. Eighty percent of the resistant strains possessed the M. phenotype. Conclusions: Resistance levels of S. pyogenes have decreased in Chile in the last years. Most resistant strains have M phenotype in contrast to many countries in which the MLSB constitutive phenotype is the predominant one.
BCG-Based Vaccines Elicit Antigen-Specific Adaptive and Trained Immunity against SARS-CoV-2 and Andes orthohantavirus
(2022) Soto, Jorge A.; Díaz, Fabián E.; Retamal-Díaz, Angello; Gálvez, Nicolás M. S.; Melo-González, Felipe; Piña-Iturbe, Alejandro; Ramírez, Mario A.; Bohmwald, Karen; González, Pablo A.; Bueno Ramírez, Susan; Kalergis, Alexis M.
Bone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis
(PUBLIC LIBRARY SCIENCE, 2012) Macanas Pirard, Patricia; Leisewitz, Andrea; Broekhuizen, Richard; Cautivo, Kelly; Barriga, Francisco M.; Leisewitz, Francisco; Gidi, Victoria; Riquelme, Erick; Montecinos, Viviana P.; Swett, Pilar; Besa, Pelayo; Ramirez, Pablo; Ocqueteau, Mauricio; Kalergis, Alexis M.; Holt, Matthew; Rettig, Michael; DiPersio, John F.; Nervi, Bruno
Background: Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells.
Circulating Endothelial Cells From Septic Shock Patients Convert to Fibroblasts Are Associated With the Resuscitation Fluid Dose and Are Biomarkers for Survival Prediction.
(2019) Tapia, Pablo; Gatica, Sebastian; Cortés-Rivera, Cristian; Otero, Carolina; Becerra, Álvaro; Riedel, Claudia A.; Cabello-Verrugio, Claudio; Kalergis, Alexis M.; Simon, Felipe
OBJECTIVES:To determine whether circulating endothelial cells from septic shock patients and from nonseptic shock patients are transformed in activated fibroblast by changing the expression level of endothelial and fibrotic proteins, whether the level of the protein expression change is associated with the amount of administered resuscitation fluid, and whether this circulating endothelial cell protein expression change is a biomarker to predict sepsis survival. DESIGN:Prospective study. SETTING:Medical-surgical ICUs in a tertiary care hospital. PATIENTS:Forty-three patients admitted in ICU and 22 healthy volunteers. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Circulating mature endothelial cells and circulating endothelial progenitor cells from septic shock and nonseptic shock patients showed evidence of endothelial fibrosis by changing the endothelial protein expression pattern. The endothelial proteins were downregulated, whereas fibroblast-specific markers were increased. The magnitude of the expression change in endothelial and fibrotic proteins was higher in the septic shock nonsurvivors patients but not in nonseptic shock. Interestingly, the decrease in the endothelial protein expression was correlated with the administered resuscitation fluid better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in the septic shock nonsurvivors patients but not in nonseptic shock. Notably, the significant difference between endothelial and fibrotic protein expression indicated a nonsurvival outcome in septic shock but not in nonseptic shock patients. Remarkably, area under the receiver operating characteristic curve analysis showed that endothelial protein expression levels predicted the survival outcome better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in septic shock but not in nonseptic shock patients. CONCLUSIONS:Circulating endothelial cells from septic shock patients are acutely converted into fibroblasts. Endothelial and fibrotic protein expression level are associated with resuscitation fluid administration magnitude and can be used as biomarkers for an early survival diagnosis of sepsis.
Citosine-Adenine-Repeat Microsatellite of 11 beta-hydroxysteroid dehydrogenase 2 Gene in Hypertensive Children
(OXFORD UNIV PRESS, 2016) Valdivia, Carolina; Carvajal, Cristian A.; Campino, Carmen; Allende, Fidel; Martinez Aguayo, Alejandro; Baudrand, Rene; Vecchiola, Andrea; Lagos, Carlos F.; Tapia Castillo, Alejandra; Fuentes, Cristobal A.; Aglony, Marlene; Solari, Sandra; Kalergis, Alexis M.; Garcia, Hernan; Owen, Gareth I.; Fardella, Carlos E.
BACKGROUND
Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation.
(2019) Arce, Maximiliano; Pinto, Mauricio P.; Galleguillos, Macarena; Muñoz, Catalina; Lange, Soledad; Ramirez, Carolina; Erices, Rafaela; Gonzalez, Pamela; Velasquez, Ethel; Tempio, Fabián; Lopez, Mercedes N.; Salazar-Onfray, Flavio; Cautivo, Kelly; Kalergis, Alexis M.; Cruz, Sebastián; Lladser, Álvaro; Lobos-González, Lorena; Valenzuela, Guillermo; Olivares, Nixa; Sáez, Claudia; Koning, Tania; Sánchez, Fabiola A.; Fuenzalida, Patricia; Godoy, Alejandro; Contreras Orellana, Pamela; Leyton, Lisette; Lugano, Roberta; Dimberg, Anna; Quest, Andrew F.G.; Owen, Gareth I.
Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.
Contribution of Cytokines to Tissue Damage During Human Respiratory Syncytial Virus Infection.
(2019) Bohmwald, Karen; Gálvez, Nicolás M. S.; Canedo-Marroquín, Gisela; Pizarro-Ortega, Magdalena S.; Andrade-Parra, Catalina; Gómez-Santander, Felipe; Kalergis, Alexis M.
The human respiratory syncytial virus (hRSV) remains one of the leading pathogens causing acute respiratory tract infections (ARTIs) in children younger than 2 years old, worldwide. Hospitalizations during the winter season due to hRSV-induced bronchiolitis and pneumonia increase every year. Despite this, there are no available vaccines to mitigate the health and economic burden caused by hRSV infection. The pathology caused by hRSV induces significant damage to the pulmonary epithelium, due to an excessive inflammatory response at the airways. Cytokines are considered essential players for the establishment and modulation of the immune and inflammatory responses, which can either be beneficial or harmful for the host. The deleterious effect observed upon hRSV infection is mainly due to tissue damage caused by immune cells recruited to the site of infection. This cellular recruitment takes place due to an altered profile of cytokines secreted by epithelial cells. As a result of inflammatory cell recruitment, the amounts of cytokines, such as IL-1, IL-6, IL-10, and CCL5 are further increased, while IL-10 and IFN-γ are decreased. However, additional studies are required to elicit the mediators directly associated with hRSV damage entirely. In addition to the detrimental induction of inflammatory mediators in the respiratory tract caused by hRSV, reports indicating alterations in the central nervous system (CNS) have been published. Indeed, elevated levels of IL-6, IL-8 (CXCL8), CCL2, and CCL4 have been reported in cerebrospinal fluid from patients with severe bronchiolitis and hRSV-associated encephalopathy. In this review article, we provide an in-depth analysis of the role of cytokines secreted upon hRSV infection and their potentially harmful contribution to tissue damage of the respiratory tract and the CNS.
Contribution of Dysregulated DNA Methylation to Autoimmunity
(2021) Funes, Samanta C.; Fernández Fierro, Ayleen; Rebolledo Zelada, Diego; Mackern Oberti, Juan P.; Kalergis, Alexis M.
Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs are known regulators of gene expression and genomic stability in cell growth, development, and differentiation. Because epigenetic mechanisms can regulate several immune system elements, epigenetic alterations have been found in several autoimmune diseases. The purpose of this review is to discuss the epigenetic modifications, mainly DNA methylation, involved in autoimmune diseases in which T cells play a significant role. For example, Rheumatoid Arthritis and Systemic Lupus Erythematosus display differential gene methylation, mostly hypomethylated 5′-C-phosphate-G-3′ (CpG) sites that may associate with disease activity. However, a clear association between DNA methylation, gene expression, and disease pathogenesis must be demonstrated. A better understanding of the impact of epigenetic modifications on the onset of autoimmunity will contribute to the design of novel therapeutic approaches for these diseases.
Contribution of Fcγ Receptor-Mediated Immunity to the Pathogenesis Caused by the Human Respiratory Syncytial Virus.
(2019) Acevedo, Orlando A.; Díaz, Fabián E.; Beals, Tomas E.; Benavente, Felipe M.; Soto, Jorge A.; Escobar-Vera, Jorge; González, Pablo A.; Kalergis, Alexis M.
The human Respiratory Syncytial Virus (hRSV) is the leading cause of severe acute lower respiratory tract infections (ALRTIs) in humans at all ages and is the main cause of hospitalization due to pneumonia, asthma, and bronchiolitis in infants. hRSV symptoms mainly develop due to an excessive host immune and inflammatory response in the respiratory tissue. hRSV infection during life is frequent and likely because of non-optimal immunological memory is developed against this virus. Vaccine development against this pathogen has been delayed after the detrimental effects produced in children by vaccination with a formalin-inactivated hRSV preparation (FI-hRSV), which caused enhanced disease upon natural viral infection. Since then, several studies have focused on understanding the mechanisms underlying such disease exacerbation. Along these lines, several studies have suggested that antibodies elicited by immunization with FI-hRSV show low neutralizing capacity and promote the formation of immune complexes containing hRSV (hRSV-ICs), which contribute to hRSV pathogenesis through the engagement of Fc gamma receptors (FcγRs) expressed on the surface of immune cells. Furthermore, a role for FcγRs is supported by studies evaluating the contribution of these molecules to hRSV-induced disease. These studies have shown that FcγRs can modulate viral clearance by the host and the inflammatory response triggered by hRSV infection. In addition, ICs can facilitate viral entry into host cells expressing FcγRs, thus extending hRSV infectivity. In this article, we discuss current knowledge relative to the contribution of hRSV-ICs and FcγRs to the pathogenesis caused by hRSV and their putative role in the exacerbation of the disease caused by this virus after FI-hRSV vaccination. A better understanding FcγRs involvement in the immune response against hRSV will contribute to the development of new prophylactic or therapeutic tools to promote virus clearance with limited inflammatory damage to the airways.
Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus.
(2019) Altamirano-Lagos, María José; Díaz, Fabián E.; Mansilla, Miguel Andrés; Rivera-Pérez, Daniela; Soto, Daniel; McGill, Jodi L.; Vasquez, Abel E.; Kalergis, Alexis M.
The human respiratory syncytial virus (hRSV) is the main etiologic agent of severe lower respiratory tract infections that affect young children throughout the world, associated with significant morbidity and mortality, becoming a serious public health problem globally. Up to date, no licensed vaccines are available to prevent severe hRSV-induced disease, and the generation of safe-effective vaccines has been a challenging task, requiring constant biomedical research aimed to overcome this ailment. Among the difficulties presented by the study of this pathogen, it arises the fact that there is no single animal model that resembles all aspects of the human pathology, which is due to the specificity that this pathogen has for the human host. Thus, for the study of hRSV, different animal models might be employed, depending on the goal of the study. Of all the existing models, the murine model has been the most frequent model of choice for biomedical studies worldwide and has been of great importance at contributing to the development and understanding of vaccines and therapies against hRSV. The most notable use of the murine model is that it is very useful as a first approach in the development of vaccines or therapies such as monoclonal antibodies, suggesting in this way the direction that research could have in other preclinical models that have higher maintenance costs and more complex requirements in its management. However, several additional different models for studying hRSV, such as other rodents, mustelids, ruminants, and non-human primates, have been explored, offering advantages over the murine model. In this review, we discuss the various applications of animal models to the study of hRSV-induced disease and the advantages and disadvantages of each model, highlighting the potential of each model to elucidate different features of the pathology caused by the hRSV infection.
Efficient Lung Recruitment of Respiratory Syncytial Virus-Specific Th1 Cells Induced by Recombinant Bacillus Calmette-Guerin Promotes Virus Clearance and Protects from Infection
(AMER ASSOC IMMUNOLOGISTS, 2010) Cautivo, Kelly M.; Bueno, Susan M.; Cortes, Claudia M.; Wozniak, Aniela; Riedel, Claudia A.; Kalergis, Alexis M.
Infection by the respiratory syncytial virus (RSV) can cause extensive inflammation and lung damage in susceptible hosts due to a Th2-biased immune response. Such a deleterious inflammatory response can be enhanced by immunization with formalin- or UV-inactivated RSV, as well as with vaccinia virus expressing the RSV-G protein. Recently, we have shown that vaccination with rBCG-expressing RSV Ags can prevent the disease in the mouse. To further understand the immunological mechanisms responsible for protection against RSV, we have characterized the T cell populations contributing to virus clearance in mice immunized with this BCG-based vaccine. We found that both CD4(+) and CD8(+) T cells were recruited significantly earlier to the lungs of infected mice that were previously vaccinated. Furthermore, we observed that simultaneous adoptive transfer of CD8(+) and CD4(+) RSV-specific T cells from vaccinated mice was required to confer protection against virus infection in naive recipients. In addition, CD4(+) T cells induced by vaccination released IFN-gamma after RSV challenge, indicating that protection is mediated by a Th1 immune response. These data suggest that vaccination with rBCG-expressing RSV Ags can induce a specific effector/memory Th1 immune response consisting on CD4(+) and CD8(+) T cells, both necessary for a fully protective response against RSV. These results support the notion that an effective induction of Th1 T cell immunity against RSV during childhood could counteract the unbalanced Th2-like immune response triggered by the natural RSV infection. The Journal of Immunology, 2010, 185: 7633-7645.
Excision of an Unstable Pathogenicity Island in Salmonella enterica Serovar Enteritidis Is Induced during Infection of Phagocytic Cells
(PUBLIC LIBRARY SCIENCE, 2011) Quiroz, Tania S.; Nieto, Pamela A.; Tobar, Hugo E.; Salazar Echegarai, Francisco J.; Lizana, Rodrigo J.; Quezada, Carolina P.; Santiviago, Carlos A.; Araya, Daniela V.; Riedel, Claudia A.; Kalergis, Alexis M.; Bueno, Susan M.
The availability of the complete genome sequence of several Salmonella enterica serovars has revealed the presence of unstable genetic elements in these bacteria, such as pathogenicity islands and prophages. This is the case of Salmonella enterica serovar Enteritidis (S. Enteritidis), a bacterium that causes gastroenteritis in humans and systemic infection in mice. The whole genome sequence analysis for S. Enteritidis unveiled the presence of several genetic regions that are absent in other Salmonella serovars. These regions have been denominated "regions of difference'' (ROD). In this study we show that ROD21, one of such regions, behaves as an unstable pathogenicity island. We observed that ROD21 undergoes spontaneous excision by two independent recombination events, either under laboratory growth conditions or during infection of murine cells. Importantly, we also found that one type of excision occurred at higher rates when S. Enteritidis was residing inside murine phagocytic cells. These data suggest that ROD21 is an unstable pathogenicity island, whose frequency of excision depends on the environmental conditions found inside phagocytic cells.
From animal studies into clinical trials: the relevance of animal models to develop vaccines and therapies to reduce disease severity and prevent hRSV infection
(2022) Soto, J. A.; Gálvez, N. M. S; Rivera, D. B; Díaz, F. E.; Riedel, C. A.; Bueno Ramirez, Susan Marcela; Kalergis, Alexis M.

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