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1.
EBioMedicine ; 91: 104563, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37099842

RESUMO

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.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , COVID-19/prevenção & controle , Pandemias , SARS-CoV-2 , Vacinas de Produtos Inativados , Anticorpos Antivirais , Anticorpos Neutralizantes
2.
Front Immunol ; 12: 638917, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995357

RESUMO

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.


Assuntos
Interleucina-10/metabolismo , Pulmão/patologia , Neutrófilos/metabolismo , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/fisiologia , Transferência Adotiva , Animais , Anti-Inflamatórios , Células Cultivadas , Imunidade Celular , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos
3.
Chest ; 160(5): 1624-1633, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33878342

RESUMO

BACKGROUND: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown. RESEARCH QUESTION: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients? METHODS: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer. RESULTS: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95% CI]: 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity was a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer. INTERPRETATION: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo.


Assuntos
Proteínas de Bactérias/metabolismo , Estado Terminal , Unidades de Terapia Intensiva/estatística & dados numéricos , Pulmão , Metaloendopeptidases/metabolismo , Mortalidade , Pneumonia Bacteriana , Infecções por Pseudomonas , Pseudomonas aeruginosa , Animais , Correlação de Dados , Estado Terminal/mortalidade , Estado Terminal/terapia , Demografia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Infecções por Pseudomonas/etiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/patogenicidade , Respiração Artificial/estatística & dados numéricos , Estados Unidos/epidemiologia , Fatores de Virulência
5.
Front Cell Infect Microbiol ; 10: 571771, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282749

RESUMO

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.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Animais , Arginina , Carbapenêmicos/farmacologia , Camundongos , Neutrófilos
6.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804104

RESUMO

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.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos/imunologia , Interleucina-10/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/imunologia , Células Supressoras Mieloides/imunologia , Fatores de Virulência/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL
7.
J Leukoc Biol ; 105(5): 857-872, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30480847

RESUMO

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.


Assuntos
Infecções Bacterianas/imunologia , Células da Medula Óssea/imunologia , Citocinas/imunologia , Células Supressoras Mieloides/imunologia , Doenças Parasitárias/imunologia , Viroses/imunologia , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Células da Medula Óssea/microbiologia , Doença Crônica , Citocinas/genética , Expressão Gênica , Humanos , Evasão da Resposta Imune , Imunidade Inata , Linfócitos/imunologia , Linfócitos/microbiologia , Monócitos/imunologia , Monócitos/microbiologia , Células Supressoras Mieloides/microbiologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Doenças Parasitárias/genética , Doenças Parasitárias/microbiologia , Transdução de Sinais , Viroses/genética , Viroses/microbiologia
8.
Front Microbiol ; 9: 2047, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30279680

RESUMO

Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokine produced during bacterial infection. Two related phenomena explain the importance of IL-10 production in this context: first, the wide range of cells able to produce this cytokine and second, the wide effects that it causes on target cells. In a previous report we described opposing roles of IL-10 production during bacterial infection. Overall, during infections caused by intracellular bacteria or by pathogens that modulate the inflammatory response, IL-10 production facilitates bacterial persistence and dissemination within the host. Whereas during infections caused by extracellular or highly inflammatory bacteria, IL-10 production reduces host tissue damage and facilitates host survival. Given that these data were obtained using antibiotic susceptible bacteria, the potential application of these studies to multi-drug resistant (MDR) bacteria needs to be evaluated. MDR bacteria can become by 2050 a major death cause worldwide, not only for its ability to resist antimicrobial therapy but also because the virulence of these strains is different as compared to antibiotic susceptible strains. Therefore, it is important to understand the interaction of MDR-bacteria with the immune system during infection. This review discusses the current data about the role of IL-10 during infections caused by major circulating antibiotic resistant bacteria. We conclude that the production of IL-10 improves host survival during infections caused by extracellular or highly inflammatory bacteria, however, it is detrimental during infections caused by intracellular bacteria or bacterial pathogens that modulate the inflammatory response. Importantly, during MDR-bacterial infections a differential IL-10 production has been described, compared to non-MDR bacteria, which might be due to virulence factors specific of MDR bacteria that modulate production of IL-10. This knowledge is important for the development of new therapies against infections caused by these bacteria, where antibiotics effectiveness is dramatically decreasing.

9.
Biochem Biophys Rep ; 13: 12-16, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29226257

RESUMO

Interleukin-10 production and lung neutrophil infiltration are two essential components of the balanced immune response to pneumonia caused by Streptococcus pneumoniae. Here we describe the existence of two neutrophil subsets in lungs during experimental S. pneumoniae infection in mice, which have different size, granularity and expression of activation markers. During infection, both neutrophils subsets were increased in the lungs of IL-10 producing mice, however this increment was significantly higher in the absence of this cytokine. These results suggest that IL-10 is a key cytokine that regulates lung inflammation during bacterial infection caused by specific neutrophil subsets infiltrating the lungs.

10.
Front Immunol ; 8: 889, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28824622

RESUMO

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterium that produces disease in numerous hosts. In mice, oral inoculation is followed by intestinal colonization and subsequent systemic dissemination, which leads to severe pathogenesis without the activation of an efficient anti-Salmonella immune response. This feature suggests that the infection caused by S. Typhimurium may promote the production of anti-inflammatory molecules by the host that prevent efficient T cell activation and bacterial clearance. In this study, we describe the contribution of immune cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) to the systemic infection caused by S. Typhimurium in mice. We observed that the production of IL-10 was required by S. Typhimurium to cause a systemic disease, since mice lacking IL-10 (IL-10-/-) were significantly more resistant to die after an infection as compared to wild-type (WT) mice. IL-10-/- mice had reduced bacterial loads in internal organs and increased levels of pro-inflammatory cytokines in serum at 5 days of infection. Importantly, WT mice showed high bacterial loads in tissues and no increase of cytokines in serum after 5 days of S. Typhimurium infection, except for IL-10. In WT mice, we observed a peak of il-10 messenger RNA production in ileum, spleen, and liver after 5 days of infection. Importantly, the adoptive transfer of T or B cells from WT mice restored the susceptibility of IL-10-/- mice to systemic S. Typhimurium infection, suggesting that the generation of regulatory cells in vivo is required to sustain a systemic infection by S. Typhimurium. These findings support the notion that IL-10 production from lymphoid cells is a key process in the infective cycle of S. Typhimurium in mice due to generation of a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination.

11.
Cytokine Growth Factor Rev ; 32: 17-30, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27522641

RESUMO

Interleukin-10 (IL-10) is recognized as an anti-inflammatory cytokine that downmodulates inflammatory immune responses at multiple levels. In innate cells, production of this cytokine is usually triggered after pathogen recognition receptor (PRR) engagement by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patters (DAMPs), as well as by other soluble factors. Importantly, IL-10 is frequently secreted during acute bacterial infections and has been described to play a key role in infection resolution, although its effects can significantly vary depending on the infecting bacterium. While the production of IL-10 might favor host survival in some cases, it may also result harmful for the host in other circumstances, as it can prevent appropriate bacterial clearance. In this review we discuss the role of IL-10 in bacterial clearance and propose that this cytokine is required to recover from infection caused by extracellular or highly pro-inflammatory bacteria. Altogether, we propose that IL-10 drives excessive suppression of the immune response upon infection with intracellular bacteria or in non-inflammatory bacterial infections, which ultimately favors bacterial persistence and dissemination within the host. Thus, the nature of the bacterium causing infection is an important factor that needs to be taken into account when considering new immunotherapies that consist on the modulation of inflammation, such as IL-10. Indeed, induction of this cytokine may significantly improve the host's immune response to certain bacteria when antibiotics are not completely effective.


Assuntos
Infecções Bacterianas/imunologia , Interleucina-10/imunologia , Animais , Humanos , Imunidade Inata , Infecções Respiratórias/imunologia , Transdução de Sinais
12.
Immunology ; 146(1): 100-12, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26032199

RESUMO

Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inflammatory cytokine interleukin-10 (IL-10) is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10(-/-) mice). The IL-10(-/-) mice showed increased mortality, higher expression of pro-inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10(-/-) mice showed significantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inflammatory cytokines and the infiltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inflammation of tissues and to improve host survival, even though bacterial dissemination is less efficient in the absence of this cytokine.


Assuntos
Interleucina-10/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pneumonia Pneumocócica/imunologia , Streptococcus pneumoniae/imunologia , Animais , Carga Bacteriana/genética , Carga Bacteriana/imunologia , Encéfalo/microbiologia , Inflamação/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-1beta/biossíntese , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia Pneumocócica/mortalidade , Baço/microbiologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
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