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1.
Trends Immunol ; 43(4): 322-335, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35074254

RESUMEN

Bacillus Calmette-Guérin (BCG) is an attenuated Mycobacterium bovis strain used as a vaccine to prevent Mycobacterium tuberculosis (M. tb) infection. Its ability to potentiate the immune response induced by other vaccines and to promote nonspecific immunomodulatory effects has been described. These effects can be triggered by epigenetic reprogramming and metabolic shifts on innate immune cells, a phenomenon known as trained immunity. The induction of trained immunity may contribute to explain why BCG vaccination effectively decreases disease symptoms caused by pathogens different from M. tb. This article explains the importance of BCG immunization and the possible mechanisms associated with the induction of trained immunity, which might be used as a strategy for rapid activation of the immune system against unrelated pathogens.


Asunto(s)
Mycobacterium bovis , Mycobacterium tuberculosis , Vacuna BCG , Humanos , Inmunidad , Vacunación
2.
Immunology ; 173(3): 481-496, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39161170

RESUMEN

Acute respiratory infections are the leading cause of death and illness in children under 5 years old and represent a significant burden in older adults. Primarily caused by viruses infecting the lower respiratory tract, symptoms include cough, congestion, and low-grade fever, potentially leading to bronchiolitis and pneumonia. Messenger ribonucleic acid (mRNA)-based vaccines are biopharmaceutical formulations that employ mRNA molecules to induce specific immune responses, facilitating the expression of viral or bacterial antigens and promoting immunization against infectious diseases. Notably, this technology had significant relevance during the COVID-19 pandemic, as these formulations helped to limit SARS-CoV-2 virus infections, hospitalizations, and deaths. Importantly, mRNA vaccines promise to be implemented as new alternatives for fighting other respiratory viruses, such as influenza, human respiratory syncytial virus, and human metapneumovirus. This review article analyzes mRNA-based vaccines' main contributions, perspectives, challenges, and implications against respiratory viruses.


Asunto(s)
Infecciones del Sistema Respiratorio , Vacunas de ARNm , Humanos , Infecciones del Sistema Respiratorio/prevención & control , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/inmunología , Desarrollo de Vacunas , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Vacunas Sintéticas/inmunología , Vacunas Virales/inmunología , Animales , Vacunas contra la COVID-19/inmunología , ARN Mensajero/genética , ARN Mensajero/inmunología
3.
J Infect Dis ; 228(7): 857-867, 2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37572355

RESUMEN

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.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , Virión , Inmunoglobulina G , Anticuerpos Antivirales , Anticuerpos Neutralizantes , Vacunación
4.
Clin Infect Dis ; 75(1): e594-e602, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-35255140

RESUMEN

BACKGROUND: Inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been widely implemented in low- and middle-income countries. However, immunogenicity in immunocompromised patients has not been established. Herein, we aimed to evaluate immune response to CoronaVac vaccine in these patients. METHODS: This prospective cohort study included 193 participants with 5 different immunocompromising conditions and 67 controls, receiving 2 doses of CoronaVac 8-12 weeks before enrollment. The study was conducted between May and August 2021, at Red de Salud UC-CHRISTUS, Santiago, Chile. Neutralizing antibody (NAb) positivity, total anti-SARS-CoV-2 immunoglobulin G antibody (TAb) concentrations, and T-cell responses were determined. RESULTS: NAb positivity and median neutralizing activity were 83.1% and 51.2% for the control group versus 20.6% and 5.7% (both P < .001) in the solid organ transplant group, 41.5% and 19.2% (both P < .0001) in the autoimmune rheumatic diseases group, 43.3% (P < .001) and 21.4% (P<.01 or P = .001) in the cancer with solid tumors group, 45.5% and 28.7% (both P < .001) in the human immunodeficiency virus (HIV) infection group, 64.3% and 56.6% (both differences not significant) in the hematopoietic stem cell transplant group, respectively. TAb seropositivity was also lower for the solid organ transplant (20.6%; P < .0001), rheumatic diseases (61%; P < .001), and HIV groups (70.9%; P = .003), compared with the control group (92.3%). On the other hand, the number of interferon γ spot-forming T cells specific for SARS-CoV-2 tended to be lower in all immunocompromising conditions but did not differ significantly between groups. CONCLUSIONS: Diverse immunocompromising conditions markedly reduce the humoral response to CoronaVac vaccine. These findings suggest that a boosting vaccination strategy should be considered in these vulnerable patients. CLINICAL TRIALS REGISTRATION: NCT04888793.


Asunto(s)
COVID-19 , Enfermedades Reumáticas , Vacunas Virales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Chile/epidemiología , Humanos , Inmunidad , Huésped Inmunocomprometido , Estudios Prospectivos , SARS-CoV-2 , Vacunas de Productos Inactivados
5.
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
6.
Clin Exp Immunol ; 210(1): 68-78, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-36036806

RESUMEN

Lower respiratory tract infections (LRTIs) produced by viruses are the most frequent cause of morbidity and mortality in children younger than 5 years of age. The immune response triggered by viral infection can induce a strong inflammation in the airways and cytokines could be considered as biomarkers for disease severity as these molecules modulate the inflammatory response that defines the outcome of patients. Aiming to predict the severity of disease during respiratory tract infections, we conducted a 1-year follow-up observational study in infants who presented upper or lower respiratory tract infections caused by seasonal respiratory viruses. At the time of enrollment, nasopharyngeal swabs (NPS) were obtained from infants to measure mRNA expression and protein levels of IL-3, IL-8, IL-33, and thymic stromal lymphopoietin. While all cytokines significantly increased their protein levels in infants with upper and lower respiratory tract infections as compared to control infants, IL-33 and IL-8 showed a significant increase in respiratory syncytial virus (RSV)-infected patients with LRTI as compared to patients with upper respiratory tract infection. We also found higher viral loads of RSV-positive samples with a greater IL-8 response at the beginning of the symptoms. Data obtained in this study suggest that both IL-8 and IL-33 could be used as biomarkers for clinical severity for infants suffering from LRTIs caused by the RSV.


Asunto(s)
Infecciones por Virus Sincitial Respiratorio , Infecciones del Sistema Respiratorio , Virus , Humanos , Lactante , Niño , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Interleucina-33 , Interleucina-3 , Interleucina-8 , Virus Sincitiales Respiratorios , Citocinas , Índice de Severidad de la Enfermedad , Biomarcadores , ARN Mensajero
7.
Crit Rev Food Sci Nutr ; 62(6): 1466-1479, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33226264

RESUMEN

Adequate iodine nutrition is crucial for all mammals by playing his starring role as a component of thyroid hormones, which are key regulators of cellular processes for life such as differentiation, growth, function, and metabolism. Deficiency or excess of iodine in the diet are worldwide highly frequent conditions that are responsible of health problems like hypothyroidism, hypothyroxinemia, goiter, thyroiditis, hyperthyroidism, and autoimmune thyroid diseases among others. The incorporation of iodine in salt or other nutrients resolved the consequences of severe iodine deficiency like goiter, cretinism. However, this strategy in several countries led to other ailments like Hashimoto autoimmune thyroiditis, hyperthyroidism, and hypothyroidism. The goal of this review is to analyze and discuss the different aspects of iodine nutrition for human health comprising its biological role through thyroid hormones, pathogen control, and the regulation of the intestinal microbiota.


Asunto(s)
Bocio , Hipertiroidismo , Hipotiroidismo , Yodo , Animales , Humanos , Micronutrientes
8.
Int J Mol Sci ; 23(18)2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36142624

RESUMEN

Cutaneous lupus erythematosus (CLE) is an autoimmune disorder like systemic lupus erythematosus (SLE). Both SLE and CLE characterize autoantibody secretion and immune cell recruitment. In particular, CLE can be divided into three more frequent types, varying in the severity of the skin lesions they present. The role of type I IFN was shown to be one of the leading causes of the development of this pathology in the skin. Different treatments have been developed and tested against these different variants of CLE to decrease the increasing levels of CLE in humans. In this article, a literature revision discussing the similarities between SLE and CLE is carried out. In addition, new advances in understanding the development of CLE and the leading treatments being evaluated in animal models and clinical trials are reviewed.


Asunto(s)
Lupus Eritematoso Cutáneo , Lupus Eritematoso Sistémico , Animales , Humanos , Lupus Eritematoso Cutáneo/patología , Lupus Eritematoso Cutáneo/terapia , Piel/patología
9.
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
10.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-34360716

RESUMEN

Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.


Asunto(s)
Factor 1 Inducible por Hipoxia/metabolismo , Consumo de Oxígeno , Virosis/metabolismo , Replicación Viral , Virus/metabolismo , Hipoxia de la Célula , Humanos , Virosis/patología
11.
Mol Med ; 26(1): 35, 2020 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-32303184

RESUMEN

Human respiratory syncytial virus (hRSV) is the most important etiological agent causing hospitalizations associated with respiratory diseases in children under 5 years of age as well as the elderly, newborns and premature children are the most affected populations. This viral infection can be associated with various symptoms, such as fever, coughing, wheezing, and even pneumonia and bronchiolitis. Due to its severe symptoms, the need for mechanical ventilation is not uncommon in clinical practice. Additionally, alterations in the central nervous system -such as seizures, encephalopathy and encephalitis- have been associated with cases of hRSV-infections. Furthermore, the absence of effective vaccines or therapies against hRSV leads to elevated expenditures by the public health system and increased mortality rates for the high-risk population. Along these lines, vaccines and therapies can elicit different responses to this virus. While hRSV vaccine candidates seek to promote an active immune response associated with the achievement of immunological memory, other therapies -such as the administration of antibodies- provide a protective environment, although they do not trigger the activation of the immune system and therefore do not promote an immunological memory. An interesting approach to vaccination is the use of virus-neutralizing antibodies, which inhibit the entry of the pathogen into the host cells, therefore impairing the capacity of the virus to replicate. Currently, the most common molecule targeted for antibody design against hRSV is the F protein of this virus. However, other molecular components of the virus -such as the G or the N hRSV proteins- have also been explored as potential targets for the control of this disease. Currently, palivizumab is the only monoclonal antibody approved for human use. However, studies in humans have shown a protective effect only after the administration of at least 3 to 5 doses, due to the stability of this vaccine. Furthermore, other studies suggest that palivizumab only has an effectiveness close to 50% in high-risk infants. In this work, we will review different strategies addressed for the use of antibodies in a prophylactic or therapeutic context and their ability to prevent the symptoms caused by hRSV infection of the airways, as well as in other tissues such as the CNS.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Desarrollo de Medicamentos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitial Respiratorio Humano/inmunología , Anticuerpos Monoclonales/administración & dosificación , Desarrollo de Medicamentos/métodos , Humanos , Programas de Inmunización , Inmunización Pasiva , Inmunoglobulina A Secretora/inmunología , Inmunoglobulina G/inmunología , Premedicación , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/virología
12.
Infect Immun ; 87(5)2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30804104

RESUMEN

Carbapenem-resistant Klebsiella pneumoniae sequence type 258 (CRKP-ST258) can cause chronic infections in lungs and airways, with repeated episodes of bacteremia. In this report we addressed whether the recruitment of myeloid cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) modulates the clearance of CKRP-ST258 in the lungs and establishes bacterial persistence. Our data demonstrate that during pneumonia caused by a clinical isolate of CRKP-ST258 (KP35) there is an early recruitment of monocyte-myeloid-derived suppressor cells (M-MDSCs) and neutrophils that actively produce IL-10. However, M-MDSCs were the cells that sustained the production of IL-10 over the time of infection evaluated. Using mice unable to produce IL-10 (IL-10-/-), we observed that the production of this cytokine during the infection caused by KP35 is important to control bacterial burden, to prevent lung damage, to modulate cytokine production, and to improve host survival. Importantly, intranasal transfer of bone marrow-derived M-MDSCs from mice able to produce IL-10 at 1 day prior to infection improved the ability of IL-10-/- mice to clear KP35 in the lungs, decreasing their mortality. Altogether, our data demonstrate that IL-10 produced by M-MDSCs is required for bacterial clearance, reduction of lung tissue damage, and host survival during KP35 pneumonia.


Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos/inmunología , Interleucina-10/inmunología , Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/inmunología , Células Supresoras de Origen Mieloide/inmunología , Factores de Virulencia/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL
13.
J Immunol ; 199(1): 212-223, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28566367

RESUMEN

Human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in children. The development of novel prophylactic and therapeutic antiviral drugs against hRSV is imperative to control the burden of disease in the susceptible population. In this study, we examined the effects of inducing the activity of the host enzyme heme oxygenase-1 (HO-1) on hRSV replication and pathogenesis on lung inflammation induced by this virus. Our results show that after hRSV infection, HO-1 induction with metalloporphyrin cobalt protoporphyrin IX significantly reduces the loss of body weight due to hRSV-induced disease. Further, HO-1 induction also decreased viral replication and lung inflammation, as evidenced by a reduced neutrophil infiltration into the airways, with diminished cytokine and chemokine production and reduced T cell function. Concomitantly, upon cobalt protoporphyrin IX treatment, there is a significant upregulation in the production of IFN-α/ß mRNAs in the lungs. Furthermore, similar antiviral and protective effects occur by inducing the expression of human HO-1 in MHC class II+ cells in transgenic mice. Finally, in vitro data suggest that HO-1 induction can modulate the susceptibility of cells, especially the airway epithelial cells, to hRSV infection.


Asunto(s)
Hemo-Oxigenasa 1/metabolismo , Pulmón/inmunología , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/fisiología , Animales , Línea Celular , Citocinas/biosíntesis , Citocinas/inmunología , Replicación del ADN , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Hemo-Oxigenasa 1/genética , Humanos , Interferón-alfa/biosíntesis , Interferón-alfa/inmunología , Interferón beta/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Protoporfirinas/administración & dosificación , Protoporfirinas/farmacología , Infecciones por Virus Sincitial Respiratorio/inmunología , Linfocitos T/inmunología , Acoplamiento Viral , Internalización del Virus , Replicación Viral
14.
Microbiol Immunol ; 62(11): 711-719, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30357922

RESUMEN

Protein subunit vaccines are often preferred because of their protective efficacy and safety. Lactic acid bacteria expressing heterologous antigens constitute a promising approach to vaccine development. However, their safety in terms of toxicity and bacterial clearance must be evaluated. Anti-Streptococcus pyogenes (S. pyogenes) vaccines face additional safety concerns because they may elicit autoimmune responses. The assessment of toxicity, clearance and autoimmunity of an anti-streptococcal vaccine based on Lactococcus lactis (L. lactis) expressing 10 different M protein fragments from S. pyogenes (L. lactis-Mx10) is here reported. Clearance of L. lactis from the oropharynges of immunocompetent mice and mice devoid of T/B lymphocytes mice was achieved without using antibiotics. The absence of autoimmune responses against human tissues was demonstrated with human brain, heart and kidney. Assessment of toxicity showed that leucocyte counts and selected serum biochemical factors were not affected in L. lactis-Mx10-immunized mice. In contrast, mice immunized with L. lactis wild type vector (L. lactis-WT) showed increased neutrophil and monocyte counts and altered histopathology of lymph nodes, lungs and nasal epithelium. Two days after immunization, L. lactis-Mx10-immunized and L. lactis-WT-immunized mice weighed significantly less than unimmunized mice. However, both groups of immunized mice recovered their body weights by Day 6. Our results demonstrate that L. lactis-WT, but not the vaccine L. lactis-Mx10, induces alterations in certain hematologic and histopathological variables. We consider these data a major contribution to data on L. lactis as a bacterial vector for vaccine delivery.


Asunto(s)
Administración Intranasal/métodos , Antígenos Bacterianos/inmunología , Lactococcus lactis/inmunología , Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas/inmunología , Streptococcus pyogenes/inmunología , Vacunación/métodos , Vacunas Atenuadas/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/genética , Autoinmunidad/inmunología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/inmunología , Encéfalo/inmunología , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunización , Riñón/inmunología , Lactococcus lactis/genética , Pulmón/microbiología , Pulmón/patología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Miocardio/inmunología , Mucosa Nasal/patología , Infecciones Estreptocócicas/inmunología , Vacunas Estreptocócicas/administración & dosificación , Vacunas Estreptocócicas/genética , Vacunas Estreptocócicas/toxicidad , Streptococcus pyogenes/genética , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética
15.
Microbiol Immunol ; 62(6): 395-404, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29704396

RESUMEN

Streptococcus pyogenes (group A Streptococcus) causes diseases ranging from mild pharyngitis to severe invasive infections. The N-terminal fragment of streptococcal M protein elicits protective antibodies and is an attractive vaccine target. However, this N- terminal fragment is hypervariable: there are more than 200 different M types. In this study, an intranasal live bacterial vaccine comprising 10 strains of Lactococcus lactis, each expressing one N-terminal fragment of M protein, has been developed. Live bacterial-vectored vaccines cost less to manufacture because the processes involved are less complex than those required for production of protein subunit vaccines. Moreover, intranasal administration does not require syringes or specialized personnel. Evaluation of individual vaccine types (M1, M2, M3, M4, M6, M9, M12, M22, M28 and M77) showed that most of them protected mice against challenge with virulent S. pyogenes. All 10 strains combined in a 10-valent vaccine (M×10) induced serum and bronchoalveolar lavage IgG titers that ranged from three- to 10-fold those of unimmunized mice. After intranasal challenge with M28 streptococci, survival of M×10-immunized mice was significantly higher than that of unimmunized mice. In contrast, when mice were challenged with M75 streptococci, survival of M×10-immunized mice did not differ significantly from that of unimmunized mice. Mx-10 immunized mice had significantly less S. pyogenes in oropharyngeal washes and developed less severe disease symptoms after challenge than did unimmunized mice. Our L. lactis-based vaccine may provide an alternative solution to development of broadly protective group A streptococcal vaccines.


Asunto(s)
Administración Intranasal/métodos , Antígenos Bacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Portadoras/inmunología , Lactococcus lactis/inmunología , Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas/inmunología , Streptococcus pyogenes/inmunología , Vacunación/métodos , Vacunas Atenuadas/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/clasificación , Antígenos Bacterianos/metabolismo , Proteínas de la Membrana Bacteriana Externa/clasificación , Proteínas de la Membrana Bacteriana Externa/metabolismo , Peso Corporal , Proteínas Portadoras/clasificación , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Femenino , Inmunidad , Inmunización , Inmunoglobulina G/sangre , Lactococcus lactis/patogenicidad , Ratones , Ratones Endogámicos BALB C , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Vacunas Estreptocócicas/administración & dosificación , Resultado del Tratamiento , Vacunas Atenuadas/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología
16.
Clin Microbiol Rev ; 29(4): 795-818, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27413096

RESUMEN

Globally, as a leading agent of acute respiratory tract infections in children <5 years of age and the elderly, the human metapneumovirus (HMPV) has gained considerable attention. As inferred from studies comparing vaccinated and experimentally infected mice, the acquired immune response elicited by this pathogen fails to efficiently clear the virus from the airways, which leads to an exaggerated inflammatory response and lung damage. Furthermore, after disease resolution, there is a poor development of T and B cell immunological memory, which is believed to promote reinfections and viral spread in the community. In this article, we discuss the molecular mechanisms that shape the interactions of HMPV with host tissues that lead to pulmonary pathology and to the development of adaptive immunity that fails to protect against natural infections by this virus.


Asunto(s)
Inmunidad Adaptativa , Metapneumovirus/inmunología , Metapneumovirus/fisiología , Infecciones por Paramyxoviridae/inmunología , Infecciones por Paramyxoviridae/patología , Infecciones del Sistema Respiratorio/patología , Animales , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Humanos , Ratones , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología
17.
Proc Natl Acad Sci U S A ; 111(31): E3214-23, 2014 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-25056968

RESUMEN

Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Membrana Celular/metabolismo , Sinapsis Inmunológicas/inmunología , Nucleoproteínas/metabolismo , Virus Sincitial Respiratorio Humano/inmunología , Proteínas Virales/metabolismo , Animales , Brefeldino A/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Comunicación Celular , Línea Celular , Membrana Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/metabolismo , Antígenos de Histocompatibilidad/inmunología , Humanos , Sinapsis Inmunológicas/efectos de los fármacos , Membrana Dobles de Lípidos/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Péptidos/inmunología , Transporte de Proteínas/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Replicación Viral/efectos de los fármacos
18.
Immunology ; 149(1): 1-12, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26938875

RESUMEN

Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases.


Asunto(s)
Presentación de Antígeno , Hemo-Oxigenasa 1/metabolismo , Enfermedades del Sistema Inmune/tratamiento farmacológico , Tolerancia Inmunológica , Inflamación/metabolismo , Linfocitos T/inmunología , Animales , Monóxido de Carbono/metabolismo , Diseño de Fármacos , Humanos , Inmunomodulación , Activación de Linfocitos
19.
Eur J Immunol ; 45(12): 3269-88, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26461179

RESUMEN

Heme-oxygenase 1 (HO-1) prevents T cell-mediated inflammatory disease by producing carbon monoxide (CO) and impairing DC immunogenicity. However, the cellular mechanisms causing this inhibition are unknown. Here, we show that CO impairs mitochondrial function in DCs by reducing both the mitochondrial membrane potential and ATP production, and resembling the effect of a nonlethal dose of a classical mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Moreover, both CO and CCCP reduced cargo transport, endosome-to-lysosome fusion, and antigen processing, dampening the production of peptide-MHC complexes on the surface of DCs. As a result, the inhibition of naive CD4(+) T-cell priming was observed. Furthermore, mitochondrial dysfunction in DCs also significantly reduced CD8(+) T cell-dependent type 1 diabetes onset in vivo. These results showed for the first time that CO interferes with T-cell priming by blocking an unknown mitochondria-dependent antigen-processing pathway in mature DC. Interestingly, other immune functions in DCs such as antigen capture, cytokine secretion, costimulation, and cell survival relied on glycolysis, suggesting that oxidative phosphorylation might only play a key role for the maturation of antigen-containing endosomes. In conclusion, CO produced by HO-1 impairs antigen-dependent inflammation by regulating DC immunogenicity by a mitochondria-dependent mechanism.


Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Monóxido de Carbono/farmacología , Células Dendríticas/inmunología , Endosomas/fisiología , Mitocondrias/fisiología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Hemo-Oxigenasa 1/fisiología , Humanos
20.
Eur J Immunol ; 45(6): 1680-95, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25763996

RESUMEN

Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.


Asunto(s)
Citocinas/metabolismo , Metapneumovirus/fisiología , Infecciones por Paramyxoviridae/metabolismo , Infecciones por Paramyxoviridae/virología , Neumonía Viral/metabolismo , Neumonía Viral/virología , Transducción de Señal , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Línea Celular , Citocinas/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/virología , Expresión Génica , Humanos , Interleucina-33 , Interleucina-8/genética , Interleucina-8/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Metapneumovirus/efectos de los fármacos , Ratones , Neutrófilos/inmunología , Neutrófilos/metabolismo , Ligando OX40/antagonistas & inhibidores , Ligando OX40/genética , Ligando OX40/metabolismo , Infecciones por Paramyxoviridae/tratamiento farmacológico , Infecciones por Paramyxoviridae/genética , Infecciones por Paramyxoviridae/patología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/genética , Neumonía Viral/patología , Receptores de Citocinas/antagonistas & inhibidores , Receptores de Citocinas/deficiencia , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Replicación Viral , Linfopoyetina del Estroma Tímico
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