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1.
EBioMedicine ; 91: 104563, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37099842

RESUMEN

BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , COVID-19/prevención & control , Pandemias , SARS-CoV-2 , Vacunas de Productos Inactivados , Anticuerpos Antivirales , Anticuerpos Neutralizantes
2.
mBio ; 13(6): e0131122, 2022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36383021

RESUMEN

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.


Asunto(s)
COVID-19 , SARS-CoV-2 , Adolescente , Humanos , Niño , Preescolar , Anticuerpos Neutralizantes , Vacunas de Productos Inactivados , Anticuerpos Antivirales
3.
Elife ; 112022 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-36226829

RESUMEN

Background: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. Methods: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. Results: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4+ T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion. Conclusions: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. Funding: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial number: NCT04651790.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Esquemas de Inmunización , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Inmunidad Humoral , Interferones , Leucocitos Mononucleares , SARS-CoV-2
4.
mBio ; 13(4): e0142322, 2022 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-35946814

RESUMEN

CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.


Asunto(s)
COVID-19 , Vacunas Virales , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T
5.
Antioxidants (Basel) ; 11(6)2022 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-35739937

RESUMEN

An important virulence trait of Salmonella enterica serovar Typhimurium (S. Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fe2+, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during S. Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent S. Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of S. Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of S. Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled S. Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to Salmonella infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner.

6.
Front Immunol ; 13: 877533, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35572549

RESUMEN

Infectious diseases are one of the leading causes of morbidity and mortality worldwide, affecting high-risk populations such as children and the elderly. Pathogens usually activate local immune responses at the site of infection, resulting in both protective and inflammatory responses, which may lead to local changes in the microbiota, metabolites, and the cytokine environment. Although some pathogens can disseminate and cause systemic disease, increasing evidence suggests that local infections can affect tissues not directly invaded. In particular, diseases occurring at distal mucosal barriers such as the lung and the intestine seem to be linked, as shown by epidemiological studies in humans. These mucosal barriers have bidirectional interactions based mainly on multiple signals derived from the microbiota, which has been termed as the gut-lung axis. However, the effects observed in such distal places are still incompletely understood. Most of the current research focuses on the systemic impact of changes in microbiota and bacterial metabolites during infection, which could further modulate immune responses at distal tissue sites. Here, we describe how the gut microbiota and associated metabolites play key roles in maintaining local homeostasis and preventing enteric infection by direct and indirect mechanisms. Subsequently, we discuss recent murine and human studies linking infectious diseases with changes occurring at distal mucosal barriers, with particular emphasis on bacterial and viral infections affecting the lung and the gastrointestinal tract. Further, we discuss the potential mechanisms by which pathogens may cause such effects, promoting either protection or susceptibility to secondary infection.


Asunto(s)
Enfermedades Transmisibles , Microbioma Gastrointestinal , Microbiota , Neumonía , Anciano , Animales , Bacterias/metabolismo , Niño , Humanos , Ratones
7.
medRxiv ; 2022 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-35441179

RESUMEN

Background: CoronaVac ® is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac ® , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac ® on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile. Methods: Volunteers immunized with two doses of CoronaVac ® in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose. Findings: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 + T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron. Interpretation: Our results show that a booster dose of CoronaVac ® increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac ® is active against VOC, suggesting an effective protection.

8.
Front Microbiol ; 13: 798853, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35154050

RESUMEN

Neutrophils are innate immune cells that play an essential role during the clearance of pathogens that can release chromatin structures coated by several cytoplasmatic and granular antibacterial proteins, called neutrophil extracellular traps (NETs). These supra-molecular structures are produced to kill or immobilize several types of microorganisms, including bacteria and viruses. The contribution of the NET release process (or NETosis) to acute inflammation or the prevention of pathogen spreading depends on the specific microorganism involved in triggering this response. Furthermore, studies highlight the role of innate cells different from neutrophils in triggering the release of extracellular traps during bacterial infection. This review summarizes the contribution of NETs during bacterial and viral infections, explaining the molecular mechanisms involved in their formation and the relationship with different components of such pathogens.

9.
Clin Infect Dis ; 75(1): e792-e804, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34537835

RESUMEN

BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial. METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity. RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2. CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.


Asunto(s)
COVID-19 , Vacunas Virales , Adolescente , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Chile , Método Doble Ciego , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Persona de Mediana Edad , SARS-CoV-2 , Vacunas de Productos Inactivados/efectos adversos , Adulto Joven
10.
Front Immunol ; 12: 747830, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34858404

RESUMEN

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible of the current pandemic ongoing all around the world. Since its discovery in 2019, several circulating variants have emerged and some of them are associated with increased infections and death rate. Despite the genetic differences among these variants, vaccines approved for human use have shown a good immunogenic and protective response against them. In Chile, over 70% of the vaccinated population is immunized with CoronaVac, an inactivated SARS-CoV-2 vaccine. The immune response elicited by this vaccine has been described against the first SARS-CoV-2 strain isolated from Wuhan, China and the D614G strain (lineage B). To date, four SARS-CoV-2 variants of concern described have circulated worldwide. Here, we describe the neutralizing capacities of antibodies secreted by volunteers in the Chilean population immunized with CoronaVac against variants of concern Alpha (B.1.1.7), Beta (B.1.351) Gamma (P.1) and Delta (B.617.2). Methods: Volunteers enrolled in a phase 3 clinical trial were vaccinated with two doses of CoronaVac in 0-14 or 0-28 immunization schedules. Sera samples were used to evaluate the capacity of antibodies induced by the vaccine to block the binding between Receptor Binding Domain (RBD) from variants of concern and the human ACE2 receptor by an in-house ELISA. Further, conventional microneutralization assays were used to test neutralization of SARS-CoV-2 infection. Moreover, interferon-γ-secreting T cells against Spike from variants of concern were evaluated in PBMCs from vaccinated subjects using ELISPOT. Results: CoronaVac promotes the secretion of antibodies able to block the RBD of all the SARS-CoV-2 variants studied. Seropositivity rates of neutralizing antibodies in the population evaluated were over 97% for the lineage B strain, over 80% for Alpha and Gamma variants, over 75% for Delta variant and over 60% for the Beta variant. Geometric means titers of blocking antibodies were reduced when tested against SARS-CoV-2 variants as compared to ancestral strain. We also observed that antibodies from vaccinated subjects were able to neutralize the infection of variants D614G, Alpha, Gamma and Delta in a conventional microneutralization assay. Importantly, after SARS-CoV-2 infection, we observed that the blocking capacity of antibodies from vaccinated volunteers increased up to ten times for all the variants tested. We compared the number of interferon-γ-secreting T cells specific for SARS-CoV-2 Spike WT and variants of concern from vaccinated subjects and we did not detect significant differences. Conclusion: Immunization with CoronaVac in either immunization schedule promotes the secretion of antibodies able to block SARS-CoV-2 variants of concern and partially neutralizes SARS-CoV-2 infection. In addition, it stimulates cellular responses against all variants of concern.


Asunto(s)
Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Vacunas de Productos Inactivados/inmunología , Adolescente , Adulto , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/sangre , Humanos , Interferón gamma/inmunología , Persona de Mediana Edad , Pruebas de Neutralización , SARS-CoV-2/clasificación , Vacunación , Adulto Joven
11.
Front Immunol ; 12: 742914, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34659237

RESUMEN

Constant efforts to prevent infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are actively carried out around the world. Several vaccines are currently approved for emergency use in the population, while ongoing studies continue to provide information on their safety and effectiveness. CoronaVac is an inactivated SARS-CoV-2 vaccine with a good safety and immunogenicity profile as seen in phase 1, 2, and 3 clinical trials around the world, with an effectiveness of 65.9% for symptomatic cases. Although vaccination reduces the risk of disease, infections can still occur during or after completion of the vaccination schedule (breakthrough cases). This report describes the clinical and immunological profile of vaccine breakthrough cases reported in a clinical trial in progress in Chile that is evaluating the safety, immunogenicity, and efficacy of two vaccination schedules of CoronaVac (clinicaltrials.gov NCT04651790). Out of the 2,263 fully vaccinated subjects, at end of June 2021, 45 have reported symptomatic SARS-CoV-2 infection 14 or more days after the second dose (1.99% of fully vaccinated subjects). Of the 45 breakthrough cases, 96% developed mild disease; one case developed a moderate disease; and one developed a severe disease and required mechanical ventilation. Both cases that developed moderate and severe disease were adults over 60 years old and presented comorbidities. The immune response before and after SARS-CoV-2 infection was analyzed in nine vaccine breakthrough cases, revealing that six of them exhibited circulating anti-S1-RBD IgG antibodies with neutralizing capacities after immunization, which showed a significant increase 2 and 4 weeks after symptoms onset. Two cases exhibited low circulating anti-S1-RBD IgG and almost non-existing neutralizing capacity after either vaccination or infection, although they developed a mild disease. An increase in the number of interferon-γ-secreting T cells specific for SARS-CoV-2 was detected 2 weeks after the second dose in seven cases and after symptoms onset. In conclusion, breakthrough cases were mostly mild and did not necessarily correlate with a lack of vaccine-induced immunity, suggesting that other factors, to be defined in future studies, could lead to symptomatic infection after vaccination with CoronaVac.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Vacunas de Productos Inactivados/inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/patología , Chile , Comorbilidad , Femenino , Humanos , Esquemas de Inmunización , Inmunogenicidad Vacunal/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Interferón gamma/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Vacunación , Adulto Joven
12.
Front Microbiol ; 12: 647044, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34276584

RESUMEN

Salmonella enterica is a common source of food and water-borne infections, causing a wide range of clinical ailments in both human and animal hosts. Immunity to Salmonella involves an interplay between different immune responses, which are rapidly initiated to control bacterial burden. However, Salmonella has developed several strategies to evade and modulate the host immune responses. In this sense, the main knowledge about the pathogenicity of this bacterium has been obtained by the study of mouse models with non-typhoidal serovars. However, this knowledge is not representative of all the pathologies caused by non-typhoidal serovars in the human. Here we review the most important features of typhoidal and non-typhoidal serovars and the diseases they cause in the human host, describing the virulence mechanisms used by these pathogens that have been identified in different models of infection.

13.
Front Immunol ; 12: 638917, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33995357

RESUMEN

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.


Asunto(s)
Interleucina-10/metabolismo , Pulmón/patología , Neutrófilos/metabolismo , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/fisiología , Traslado Adoptivo , Animales , Antiinflamatorios , Células Cultivadas , Inmunidad Celular , Interleucina-10/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila
14.
medRxiv ; 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35441164

RESUMEN

Background: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile. Methods: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ). Findings: The recruitment of participants occurred between November 27 th , 2020, until January 9 th , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity. Interpretation: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens. Funding: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.

15.
Front Cell Infect Microbiol ; 10: 571771, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33282749

RESUMEN

Carbapenem-resistant Klebsiella pneumoniae ST258 (CRKP-ST258) are a global concern due to their rapid dissemination, high lethality, antibiotic resistance and resistance to components of the immune response, such as neutrophils. Neutrophils are major host mediators, able to kill well-studied and antibiotic-sensitive laboratory reference strains of K. pneumoniae. However, CRKP-ST258 are able to evade neutrophil phagocytic killing, persisting longer in the host despite robust neutrophil recruitment. Here, we show that neutrophils are unable to clear a CRKP-ST258 isolate (KP35). Compared to the response elicited by a prototypic K. pneumoniae ATCC 43816 (KPPR1), the neutrophil intracellular response against KP35 is characterized by equivalent production of reactive oxygen species (ROS) and myeloperoxidase content, but impaired phagosomal acidification. Our results ruled out that this phenomenon is due to a phagocytosis defect, as we observed similar efficiency of phagocytosis by neutrophils infected with KP35 or KPPR1. Genomic analysis of the cps loci of KPPR1 and KP35 suggest that the capsule composition of KP35 explain the high phagocytosis efficiency by neutrophils. Consistent with other reports, we show that KP35 did not induce DNA release by neutrophils and KPPR1 only induced it at 3 h, when most of the bacteria have already been cleared. l-arginine metabolism has been identified as an important modulator of the host immune response and positively regulate T cells, macrophages and neutrophils in response to microbes. Our data show that l-arginine supplementation improved phagosome acidification, increased ROS production and enhanced nitric oxide consumption by neutrophils in response to KP35. The enhanced intracellular response observed after l-arginine supplementation ultimately improved KP35 clearance in vitro. KP35 was able to dysregulate the intracellular microbicidal machinery of neutrophils to survive in the intracellular environment. This process, however, can be reversed after l-arginine supplementation.


Asunto(s)
Infecciones por Klebsiella , Klebsiella pneumoniae , Animales , Arginina , Carbapenémicos/farmacología , Ratones , Neutrófilos
16.
PLoS Pathog ; 15(12): e1008152, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31800631

RESUMEN

Pathogenicity island excision is a phenomenon that occurs in several Salmonella enterica serovars and other members of the family Enterobacteriaceae. ROD21 is an excisable pathogenicity island found in the chromosome of S. Enteritidis, S. Dublin and S. Typhi among others, which contain several genes encoding virulence-associated proteins. Excision of ROD21 may play a role in the ability of S. Enteritidis to cause a systemic infection in mice. Our previous studies have shown that Salmonella strains unable to excise ROD21 display a reduced ability to colonize the liver and spleen. In this work, we determined the kinetics of ROD21 excision in vivo in C57BL/6 mice and its effect on virulence. We quantified bacterial burden and excision frequency in different portions of the digestive tract and internal organs throughout the infection. We observed that the frequency of ROD21 excision was significantly increased in the bacterial population colonizing mesenteric lymph nodes at early stages of the infective cycle, before 48 hours post-infection. In contrast, excision frequency remained very low in the liver and spleen at these stages. Interestingly, excision increased drastically after 48 h post infection, when intestinal re-infection and mortality begun. Moreover, we observed that the inability to excise ROD21 had a negative effect on S. Enteritidis capacity to translocate from the intestine to deeper organs, which correlates with an abnormal transcription of invA in the S. Enteritidis strain unable to excise ROD21. These results suggest that excision of ROD21 is a genetic mechanism required by S. Enteritidis to produce a successful invasion of the intestinal epithelium, a step required to generate systemic infection in mice.


Asunto(s)
Islas Genómicas/genética , Mucosa Intestinal/microbiología , Salmonelosis Animal/microbiología , Salmonella enteritidis/genética , Salmonella enteritidis/patogenicidad , Animales , Ratones , Ratones Endogámicos C57BL , Virulencia/genética
17.
J Leukoc Biol ; 105(5): 857-872, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30480847

RESUMEN

An effective pathogen has the ability to evade the immune response. The strategies used to achieve this may be based on the direct action of virulence factors or on the induction of host factors. Myeloid-derived suppressor cells (MDSCs) are immune cells with an incredible ability to suppress the inflammatory response, which makes them excellent targets to be exploited by pathogenic bacteria, viruses, or parasites. In this review, we describe the origin and suppressive mechanisms of MDSCs, as well as their role in chronic bacterial, viral, and parasitic infections, where their expansion seems to be essential in the chronicity of the disease. We also analyze the disadvantages of current MDSC depletion strategies and the different in vitro generation methods, which can be useful tools for the deeper study of these cells in the context of microbial infections.


Asunto(s)
Infecciones Bacterianas/inmunología , Células de la Médula Ósea/inmunología , Citocinas/inmunología , Células Supresoras de Origen Mieloide/inmunología , Enfermedades Parasitarias/inmunología , Virosis/inmunología , Animales , Infecciones Bacterianas/genética , Infecciones Bacterianas/microbiología , Células de la Médula Ósea/microbiología , Enfermedad Crónica , Citocinas/genética , Expresión Génica , Humanos , Evasión Inmune , Inmunidad Innata , Linfocitos/inmunología , Linfocitos/microbiología , Monocitos/inmunología , Monocitos/microbiología , Células Supresoras de Origen Mieloide/microbiología , Neutrófilos/inmunología , Neutrófilos/microbiología , Enfermedades Parasitarias/genética , Enfermedades Parasitarias/microbiología , Transducción de Señal , Virosis/genética , Virosis/microbiología
18.
Front Immunol ; 9: 1956, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30258436

RESUMEN

Heme Oxygenase 1 (HMOX1) is an enzyme that catalyzes the reaction that degrades the heme group contained in several important proteins, such as hemoglobin, myoglobin, and cytochrome p450. The enzymatic reaction catalyzed by HMOX1 generates Fe2+, biliverdin and CO. It has been shown that HMOX1 activity and the by-product CO can downmodulate the damaging immune response in several models of intestinal inflammation as a result of pharmacological induction of HMOX1 expression and the administration of non-toxic amounts of CO. Inflammatory Bowel Diseases, which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), are one of the most studied ailments associated to HMOX1 effects. However, microbiota imbalances and infections are also important factors influencing the occurrence of acute and chronic intestinal inflammation, where HMOX1 activity may play a major role. As part of this article we discuss the immune modulatory capacity of HMOX1 during IBD, as well during the infections and interactions with the microbiota that contribute to this inflammatory disease.


Asunto(s)
Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Microbioma Gastrointestinal/inmunología , Hemo-Oxigenasa 1/inmunología , Intestinos/inmunología , Animales , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/patología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Intestinos/microbiología , Intestinos/patología
19.
Front Immunol ; 9: 1166, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29896196

RESUMEN

Chronic intestinal inflammations are triggered by genetic and environmental components. However, it remains unclear how specific changes in the microbiota, host immunity, or pathogen exposure could promote the onset and exacerbation of these diseases. Here, we evaluated whether Salmonella enterica serovar Typhimurium (S. Typhimurium) infection increases the susceptibility to develop intestinal inflammation in mice. Two mouse models were used to evaluate the impact of S. Typhimurium infection: the chemical induction of colitis by dextran sulfate sodium (DSS) and interleukin (IL)-10-/- mice, which develop spontaneous intestinal inflammation. We observed that S. Typhimurium infection makes DSS-treated and IL-10-/- mice more susceptible to develop intestinal inflammation. Importantly, this increased susceptibility is associated to the ability of S. Typhimurium to persist in liver and spleen of infected mice, which depends on the virulence proteins secreted by Salmonella Pathogenicity Island 2-encoded type three secretion system (TTSS-2). Although immunization with a live attenuated vaccine resulted in a moderate reduction of the IL-10-/- mice susceptibility to develop intestinal inflammation due to previous S. Typhimurium infection, it did not prevent bacterial persistence. Our results suggest that persistent S. Typhimurium infection may increase the susceptibility of mice to develop inflammation in the intestine, which could be associated with virulence proteins secreted by TTSS-2.


Asunto(s)
Proteínas Bacterianas/inmunología , Colitis/inmunología , Predisposición Genética a la Enfermedad , Interleucina-10/deficiencia , Intestinos , Proteínas de la Membrana/inmunología , Infecciones por Salmonella , Salmonella typhimurium , Animales , Proteínas Bacterianas/genética , Colitis/genética , Colitis/microbiología , Colitis/patología , Sulfato de Dextran/toxicidad , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/microbiología , Interleucina-10/inmunología , Intestinos/inmunología , Intestinos/patología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Infecciones por Salmonella/genética , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/patología , Salmonella typhimurium/inmunología , Salmonella typhimurium/patogenicidad , Factores de Virulencia/genética , Factores de Virulencia/inmunología
20.
Front Immunol ; 9: 74, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29441064

RESUMEN

Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn's disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC.


Asunto(s)
Fumar Cigarrillos , Gastroenteritis/etiología , Gastroenteritis/metabolismo , Animales , Autoinmunidad , Fumar Cigarrillos/efectos adversos , Susceptibilidad a Enfermedades , Gastroenteritis/diagnóstico , Gastroenteritis/epidemiología , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología
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