Role of the complement system in antibody-dependent enhancement of flavivirus infections

Flavivirus infections have increased dramatically in the last decades in tropical and subtropical regions of the world. Antibody-dependent enhancement of dengue virus infections has been one of the main hypotheses to explain severity of disease and one of the major challenges to safe and effective vaccine development. In the presence of cross-reactive sub-neutralizing concentrations of anti-dengue antibodies, immune complexes can amplify viral infection in mononuclear phagocytic cells, triggering a cytokine cascade and activating the complement system that leads to severe disease. The complement system comprises a family of plasma and cellular surface proteins that recognize pathogen associated molecular patterns, modified ligands and immune complexes, interacting in a regulated manner and forming an enzymatic cascade. Pathogenic as well as protective effects of complement have been reported in flavivirus infections. This review provides updated knowledge on complement activation during flavivirus infection, including antiviral effects of complement and its regulation, as well as mechanisms of complement evasion and dysregulation of complement activity during viral infection leading to pathogenesis. Particularly, insights into classical pathway activation and its protective role on antibody-dependent enhancement of flavivirus infections are highlighted.Fil: Byrne, Alana Brooke. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Talarico, Laura Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Age-associated differences in clinical manifestations and laboratory parameters during a dengue virus type 4 outbreak in Argentina

Infection by any of the four dengue virus (DENV) serotypes produces a wide spectrum of clinical illness in humans. Differences in clinical manifestation and severity have been associated with secondary heterologous infection, patient age, and virus serotype. In this context, this retrospective study sought to analyze the presentation of dengue in patients during the 2014 DENV-4 outbreak affecting the City of Orán, Salta Province, Argentina. Demographic data, clinical manifestations, and laboratory abnormalities of laboratory-confirmed dengue patients were compared between age groups and between patients with and without warning signs. Of 301 patients with laboratory-confirmed dengue, 37.9% presented dengue with warning signs. Although nearly half of all patients had secondary DENV infections, no severe dengue cases, or deaths were reported. Furthermore, no association was found between incidence of warning signs and pre-existing immunity to DENV. Pediatric patients were least likely to present warning signs and showed significantly decreased risk of fever, retro-orbital pain, arthalgia, diarrhea and thrombocytopenia, and higher risk of rash compared to older patients. Female patients of all ages were also at higher risk of developing several symptoms. The characterization of DENV-4 infection in humans, a DENV serotype recently reported in Argentina, revealed differences in clinical manifestations, laboratory parameters and the presence/absence of warning signs based on age group. Further investigation of these age-related differences should contribute to better assessment of dengue disease in at risk populations.Fil: Byrne, Alana Brooke. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gutierrez, Francisco Guillermo. Hospital San Vicente de Paul; Argentina. Universidad Nacional de Tucumán. Facultad de Medicina; ArgentinaFil: Bruno, Agostina Alejandra. Hospital San Vicente de Paul; ArgentinaFil: Cordoba, María Teresa. Hospital San Vicente de Paul; ArgentinaFil: Bono, María M.. Hospital San Vicente de Paul; ArgentinaFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Talarico, Laura Beatriz. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Quipildor, Marcelo Omar. Hospital San Vicente de Paul; Argentin

A murine model of dengue virus infection in suckling C57BL/6 and BALB/c mice

Dengue is a significant public health concern across tropical and subtropical regions worldwide, principally causing disease in children. Very young children are at increased risk of severe manifestations of dengue infection. The mechanism of dengue disease in this population is not fully understood. In this study, we present a murine model of dengue virus primary infection in suckling C57BL/6 and BALB/c mice in order to investigate disease pathogenesis. Three‐day‐old C57BL/6 mice intraperitoneally infected with DENV‐2 NGC were more susceptible to infection than BALB/c mice, showing increased liver enzymes, extended viremia, dissemination to organs and histological alterations in liver and small intestine. Furthermore, the immune response in DENV‐infected C57BL/6 mice exhibited a marked Th1 bias compared to BALB/c mice. These findings highlight the possibility of establishing an immunocompetent mouse model of DENV‐2 infection in suckling mice that reproduces certain signs of disease observed in humans and that could be used to further study age‐related mechanisms of dengue pathogenesis.Fil: Byrne, Alana Brooke. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García, Ayelén G.. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Brahamian, Jorge Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Mauri, Aldana. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Ferretti, Adrián. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Talarico, Laura Beatriz. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Murine models of dengue virus infection for novel drug discovery

Introduction: Dengue virus (DENV) is the causative agent of the most prevalent human disease transmitted by mosquitoes in tropical and subtropical regions worldwide. At present, no antiviral drug is available and the difficulties to develop highly protective vaccines against the four DENV serotypes maintain the requirement of effective options for dengue chemotherapy. Areas covered: The availability of animal models that reproduce human disease is a very valuable tool for the preclinical evaluation of potential antivirals. Here, the main murine models of dengue infection are described, including immunocompetent wild-type mice, immunocompromised mice deficient in diverse components of the interferon (IFN) pathway and humanized mice. The main findings in antiviral testing of DENV inhibitory compounds in murine models are also presented. Expert opinion: At present, there is no murine model that fully recapitulates human disease. However, immunocompromised mice deficient in IFN-α/β and -γ receptors, with their limitations, have shown to be the most suitable system for antiviral preclinical testing. In fact, the AG129 mouse model allowed the identification of celgosivir, an inhibitor of cellular glucosidases, as a promising option for DENV therapy. However, clinical trials still were not successful, emphasizing the difficulties in the transition from preclinical testing to human treatment.Fil: Byrne, Alana Brooke. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Departamento de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Cybele. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Damonte, Elsa Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Talarico, Laura Beatriz. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Departamento de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Characterization of Type I Interferon Responses in Dengue and Severe Dengue in Children in Paraguay

Background: Infection with dengue virus (DENV) produces a wide spectrum of clinical illness ranging from asymptomatic infection to mild febrile illness, and to severe forms of the disease. Type I interferons (IFNs) represent an initial and essential host defense response against viruses. DENV has been reported to trigger a robust type I IFN response; however, IFN-α/β profile in the progression of disease is not well characterized.Objectives and study design: In this context, we conducted a retrospective study assessing the circulating serum levels of type I IFNs and related cytokines at different phases of illness in children during the 2011 outbreak of DENV in Paraguay. Demographic, clinical, laboratory and virological data were analyzed.Results: During defervescence, significantly higher levels of IFN-β, IL-6 and MIP-1β, were detected in severe vs. non-severe dengue patients. Additionally, a significant positive correlation between INF-α and viremia was detected in children with severe dengue. Significant positive correlations were also observed between IFN-β serum levels and hematocrit/hemoglobin during the febrile phase, whereas IFN-α levels negatively correlated with white blood cells during defervescence in severe dengue patients. Furthermore, previous serologic status of patients to DENV did not influence type I IFN production.Conclusions: The distinct type I IFN profile in children with dengue and severe dengue, as well as its association with viral load, cytokine production and laboratory manifestations indicate differences in innate and adaptive immune responses that should be investigated further in order to unveil the association of immunological and physiological pathways that underlie in DENV infection.Fil: Talarico, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Byrne, Alana Brooke. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Amarilla, Sara. Instituto de Medicina Tropical; Paraguay. Universidad Nacional de Asunción; ParaguayFil: Lovera, Dolores. Universidad Nacional de Asunción; Paraguay. Instituto de Medicina Tropical; ParaguayFil: Vázquez, Cynthia. Laboratorio Central de Salud Pública; ParaguayFil: Chamorro, Gustavo. Laboratorio Central de Salud Pública; ParaguayFil: Acosta, Patricio Leandro. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferretti, Adrián. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Caballero, Mauricio Tomás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Arbo, Antonio. Instituto de Medicina Tropical; Paraguay. Universidad Nacional de Asunción; ParaguayFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentin

Distinct Immune Phenotypes and Cytokine Profiles in Children with Differing Severity of COVID-19

Background: Coronavirus disease 2019 (COVID-19) is usually mild and self-limited in children. However, a few Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections in children may progress to severe disease with respiratory distress or can result in a multisystem inflammatory syndrome (MIS-C) associated with COVID-19. The immune mechanisms for these differential clinical outcomes are largely unknown. Methods: A prospective cohort study was performed to analyze the laboratory parameters, antibody response, immune phenotypes and cytokine profiles of 51 children with different clinical presentations of COVID-19. Results: We found that the absolute lymphocyte counts gradually decreased with disease severity. Furthermore, SARS-CoV-2 IgG levels in the acute phase and convalescence were not significantly different in patients with different disease severity. A decrease in CD3+, CD4+and CD8+T cells was observed as disease severity increased. Both CD4+and CD8+T cells were activated in children with COVID-19, but no difference in the percentage of HLADR+-expressing cells was detected across the severity groups. In contrast, MIS-C patients exhibited augmented exhausted effector memory CD8+T cells. Interestingly, the cytokine profile in sera of moderate/severe and MIS-C patients revealed an increase in anti-inflammatory IL-1RA and a suppression of tumor necrosis factor-α, RANTES, eotaxin and PDGF-BB. MIS-C patients also exhibited augmented IL-1β. Conclusions: We report distinct immune profiles dependent on severity in pediatric COVID-19 patients. Further investigation in a larger population will help unravel the immune mechanisms underlying pediatric COVID-19.Fil: Talarico, Laura Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Toledano, Analia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Contrini, María Marta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Torrado, Lidia E.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Martínez, María Paula. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Gaillard, María Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Caratozzolo, Ana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Byrne, Alana Brooke. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Bonnin, Florencia Agustina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Tineo, María Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Yfran, Eduardo Walter. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Acosta, Patricio Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Lopez, Eduardo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentin