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1.
PLoS Pathog ; 16(12): e1008893, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33326490

RESUMO

Bacterial bloodstream infections (BSI) are a major health concern and can cause up to 40% mortality. Pseudomonas aeruginosa BSI is often of nosocomial origin and is associated with a particularly poor prognosis. The mechanism of bacterial persistence in blood is still largely unknown. Here, we analyzed the behavior of a cohort of clinical and laboratory Pseudomonas aeruginosa strains in human blood. In this specific environment, complement was the main defensive mechanism, acting either by direct bacterial lysis or by opsonophagocytosis, which required recognition by immune cells. We found highly variable survival rates for different strains in blood, whatever their origin, serotype, or the nature of their secreted toxins (ExoS, ExoU or ExlA) and despite their detection by immune cells. We identified and characterized a complement-tolerant subpopulation of bacterial cells that we named "evaders". Evaders shared some features with bacterial persisters, which tolerate antibiotic treatment. Notably, in bi-phasic killing curves, the evaders represented 0.1-0.001% of the initial bacterial load and displayed transient tolerance. However, the evaders are not dormant and require active metabolism to persist in blood. We detected the evaders for five other major human pathogens: Acinetobacter baumannii, Burkholderia multivorans, enteroaggregative Escherichia coli, Klebsiella pneumoniae, and Yersinia enterocolitica. Thus, the evaders could allow the pathogen to persist within the bloodstream, and may be the cause of fatal bacteremia or dissemination, in particular in the absence of effective antibiotic treatments.


Assuntos
Infecções Bacterianas/sangue , Infecções Bacterianas/imunologia , Ativação do Complemento/imunologia , Acinetobacter baumannii/crescimento & desenvolvimento , Acinetobacter baumannii/patogenicidade , Bacteriemia/sangue , Bacteriemia/imunologia , Bacteriemia/microbiologia , Bactérias , Burkholderia/crescimento & desenvolvimento , Burkholderia/patogenicidade , Proteínas do Sistema Complemento/imunologia , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Humanos , Klebsiella pneumoniae/crescimento & desenvolvimento , Klebsiella pneumoniae/patogenicidade , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/patogenicidade , Yersinia enterocolitica/crescimento & desenvolvimento , Yersinia enterocolitica/patogenicidade
2.
Nat Rev Rheumatol ; 16(10): 581-589, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32733003

RESUMO

Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Trombose/imunologia , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/imunologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/patologia , Coagulação Intravascular Disseminada/virologia , Fibrinogênio/análise , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Pandemias , Troca Plasmática/métodos , Contagem de Plaquetas/métodos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Fatores de Risco , Trombose/tratamento farmacológico , Trombose/patologia , Trombose/virologia , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/virologia
4.
PLoS Pathog ; 16(8): e1008754, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776975

RESUMO

Arbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. We also describe a transcriptomic response associated to apoptosis, blood-feeding and lipid metabolism. The three viruses differentially regulate components of Toll, Immune deficiency (IMD) and c-Jun N- terminal Kinase (JNK) pathways. However, silencing of the Toll and IMD pathway components showed variable effects on SG infection by each virus. In contrast, regulation of the JNK pathway produced consistent responses in both SGs and midgut. Infection by the three viruses increased with depletion of the activator Kayak and decreased with depletion of the negative regulator Puckered. Virus-induced JNK pathway regulates the complement factor, Thioester containing protein-20 (TEP20), and the apoptosis activator, Dronc, in SGs. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. Upon infection in SGs, TEP20 induces antimicrobial peptides (AMPs), while Dronc is required for apoptosis independently of TEP20. In conclusion, we revealed the broad antiviral function of JNK pathway in SGs and showed that it is mediated by a TEP20 complement and Dronc-induced apoptosis response. These results expand our understanding of the immune arsenal that blocks arbovirus transmission.


Assuntos
Aedes/imunologia , Apoptose , Febre de Chikungunya/imunologia , Proteínas do Sistema Complemento/imunologia , Dengue/imunologia , Sistema de Sinalização das MAP Quinases , Glândulas Salivares/imunologia , Infecção por Zika virus/imunologia , Aedes/virologia , Animais , Febre de Chikungunya/metabolismo , Febre de Chikungunya/prevenção & controle , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Proteínas do Sistema Complemento/metabolismo , Dengue/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/imunologia , Feminino , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos Vetores/imunologia , Insetos Vetores/virologia , Glândulas Salivares/virologia , Transcriptoma , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
6.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604797

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
7.
PLoS One ; 15(6): e0234934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569286

RESUMO

BACKGROUND: Studies on adriamycin mice model suggest complement system is activated and together with IgM contributes to the glomerular injury of primary focal segmental glomerulosclerosis (FSGS). We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes. Here we examined the plasma and urinary complement profile of patients with primary FSGS, aiming to investigate the complement participation in FSGS pathogenesis. METHODS: Seventy patients with biopsy-proven primary FSGS were enrolled. The plasma and urinary levels of C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb were determined by commercial ELISA kits. RESULTS: The levels of C3a, C5a and C5b-9 in plasma and urine of FSGS patients were significantly higher than those in normal controls. The plasma and urinary levels of C5b-9 were positively correlated with urinary protein, renal dysfunction and interstitial fibrosis. The plasma C5a levels were positively correlated with the proportion of segmental sclerotic glomeruli. The urinary levels of Bb were elevated, positively correlated with C3a and C5b-9 levels, renal dysfunction, and interstitial fibrosis. The plasma C1q level was significantly decreased, and negatively correlated with urinary protein excretion. Urinary Bb level was a risk factor for no remission (HR = 3.348, 95% CI 1.264-8.870, P = 0.015) and ESRD (HR = 2.323, 95% CI 1.222-4.418, P = 0.010). CONCLUSION: In conclusion, our results identified the systemic activation of complement in human primary FSGS, possibly via the classical and alternative pathway. The activation of complement system was partly associated with the clinical manifestations, kidney pathological damage, and renal outcomes.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento , Glomerulosclerose Segmentar e Focal/imunologia , Glomérulos Renais , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/urina , Feminino , Humanos , Glomérulos Renais/imunologia , Glomérulos Renais/lesões , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Sci Rep ; 10(1): 7787, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385381

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.


Assuntos
Proteínas Sanguíneas , Proteínas do Sistema Complemento/imunologia , Haptoglobinas/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Estresse Oxidativo , Proteômica , Transdução de Sinais , Idoso , Biomarcadores , Estudos de Casos e Controles , Proteínas do Sistema Complemento/metabolismo , Biologia Computacional/métodos , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Proteoma , Proteômica/métodos , Curva ROC
10.
Cell Host Microbe ; 27(6): 863-869, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32464098

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has had devastating global impacts and will continue to have dramatic effects on public health for years to come. A better understanding of the immune response to SARS-CoV-2 will be critical for the application and development of therapeutics. The degree to which the innate immune response confers protection or induces pathogenesis through a dysregulated immune response remains unclear. In this review, we discuss what is known about the role of the innate immune system during SARS-CoV-2 infection, suggest directions for future studies, and evaluate proposed COVID-19 immunomodulating therapeutics.


Assuntos
Infecções por Coronavirus/imunologia , Imunidade Inata , Pneumonia Viral/imunologia , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Citocinas/imunologia , Humanos , Células Matadoras Naturais/imunologia , Células Mieloides/imunologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia
12.
PLoS One ; 15(4): e0231655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32325480

RESUMO

Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Quimiocina CCL20/imunologia , Proteínas do Sistema Complemento/imunologia , Doenças do Complexo Imune/tratamento farmacológico , Doenças do Complexo Imune/imunologia , Imunoconjugados/uso terapêutico , Animais , Anticorpos Monoclonais/toxicidade , Doença Crônica , Cristalização , Determinação de Ponto Final , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Macaca fascicularis
13.
Pathologe ; 41(3): 238-247, 2020 May.
Artigo em Alemão | MEDLINE | ID: mdl-32240352

RESUMO

Increasing interest in the role of the complement system in systemic and renal disease is based on new pathophysiological and therapeutic insights of the recent past and particularly in genetic analyses in children with atypical hemolytic uremic syndrome (aHUS). aHUS is the prototypical systemic disease associated with excessive activation of the alternative complement pathway and manifests in the kidney, but also in other organs as thrombotic microangiopathy (TMA). Pathomechanisms discovered to induce the overactivation of the alternative complement pathway in aHUS led to the first successful therapeutic application of a C5b9 inhibitor. This suppression of the terminal complement cascade succeeded in inhibiting local tissue damage. Thereafter, thanks to advanced modern technologies, further systemic and renal diseases associated with mutations or auto-antibodies targeting the complement pathway were identified. Hereby, disease onset is frequently associated with an additional trigger, e.g. infection or hormonal alterations/imbalances, against the background of a pre-existing predisposition of the patient.Due to the growing understanding of the regulation, and thus the possibility of therapeutic modulation of the different complement pathways, and due to the increasing availability of a variety of drugs inhibiting the complement system, interest in complement-mediated systemic and renal disease has been steadily increasing, making it a "hot-topic" in medicine in recent years.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Nefropatias/imunologia , Criança , Humanos , Microangiopatias Trombóticas/imunologia
15.
Immunol Cell Biol ; 98(4): 305-317, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32142167

RESUMO

Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.


Assuntos
Anticorpos Monoclonais/imunologia , Doenças Transmissíveis/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/metabolismo , Antígenos/imunologia , Antígenos/metabolismo , Autoanticorpos/efeitos adversos , Autoanticorpos/imunologia , Engenharia Biomédica , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/patologia , Doenças Transmissíveis/virologia , Complemento C1q/química , Complemento C1q/imunologia , Complemento C1q/metabolismo , Proteínas do Sistema Complemento/química , Proteínas do Sistema Complemento/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/química , Imunoglobulina G/imunologia , Imunoglobulina G/ultraestrutura , Neoplasias/patologia , Receptores Fc/imunologia , Receptores Fc/metabolismo
16.
Mol Immunol ; 121: 99-110, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199212

RESUMO

The complement cascade consists of cell bound and serum proteins acting together to protect the host from pathogens, remove cancerous cells and effectively links innate and adaptive immune responses. Despite its usefulness in microbial neutralization and clearance of cancerous cells, excessive complement activation causes an immune imbalance and tissue damage in the host. Hence, a series of complement regulatory proteins present at a higher concentration in blood plasma and on cell surfaces tightly regulate the cascade. The complement cascade can be initiated by B-1 B cell production of natural antibodies. Natural antibodies arise spontaneously without any known exogenous antigenic or microbial stimulus and protect against invading pathogens, clear apoptotic cells, provide tissue homeostasis, and modulate adaptive immune functions. Natural IgM antibodies recognize microbial and cancer antigens and serve as an activator of complement mediated lysis. This review will discuss advances in complement activation and regulation in bacterial and viral infections, and cancer. We will also explore the crosstalk of natural antibodies with bacterial populations and cancer.


Assuntos
Infecções Bacterianas/imunologia , Imunidade Humoral , Imunidade Inata , Neoplasias/imunologia , Viroses/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo , Evasão Tumoral
17.
J Leukoc Biol ; 108(1): 339-351, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32182389

RESUMO

The complement system is a collection of soluble and membrane-bound proteins that together act as a powerful amplifier of the innate and adaptive immune systems. Although its role in infection is well established, complement is becoming increasingly recognized as a key contributor to sterile inflammation, a chronic inflammatory process often associated with noncommunicable diseases. In this context, damaged tissues release danger signals and trigger complement, which acts on a range of leukocytes to augment and bridge the innate and adaptive immune systems. Given the detrimental effect of chronic inflammation, the complement system is therefore well placed as an anti-inflammatory drug target. In this review, we provide a general outline of the sterile activators, effectors, and targets of the complement system and a series of examples (i.e., hypertension, cancer, allograft transplant rejection, and neuroinflammation) that highlight complement's ability to bridge the 2 arms of the immune system.


Assuntos
Imunidade Adaptativa , Proteínas do Sistema Complemento/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/patologia , Imunidade Inata , Inflamação/imunologia , Animais , Rejeição de Enxerto/imunologia , Humanos
18.
Infect Immun ; 88(5)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32122944

RESUMO

The spirochete Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.


Assuntos
Proteínas de Bactérias/imunologia , Borrelia burgdorferi/imunologia , Fator H do Complemento/imunologia , Doença de Lyme/imunologia , Carrapatos/microbiologia , Animais , Anticorpos/imunologia , Sítios de Ligação/imunologia , Proteínas do Sistema Complemento/imunologia , Feminino , Humanos , Vacinas contra Doença de Lyme/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H
19.
Postgrad Med ; 132(2): 184-191, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32124678

RESUMO

Invasive meningococcal disease (IMD) is a potentially devastating infection associated with high mortality and long-term sequelae; however, vaccines are available to protect against the five common disease-causing serogroups (A, B, C, W, and Y). Because traditional field efficacy clinical trials were not feasible due to low IMD incidence that necessitates a very large number of participants, serum bactericidal antibody (SBA) assays using rabbit (rSBA) or human (hSBA) complement were established as in vitro surrogates of meningococcal vaccine efficacy and are now routinely used to support vaccine licensure. Specifically, rSBA assays have been used to evaluate responses to meningococcal capsular polysaccharide-protein conjugate vaccines against serogroups A, C, W, and Y; the accepted correlate of protection for rSBA assays is a titer ≥1:8. Importantly, because the bacterial capsular polysaccharide antigen is conserved across strains, only one test strain that expresses an invariant polysaccharide capsule for each serogroup is required to assess coverage. rSBA assays are unsuitable for subcapsular protein-based serogroup B (MenB) vaccines, and therefore, hSBA assays have been used for licensure; titers ≥1:4 are considered the correlate of protection against IMD for hSBA. In contrast to MenACWY vaccines, because bacterial surface proteins are antigenically variable, MenB vaccines must be tested with hSBA assays using multiple test strains that represent the antigenic diversity of disease-causing isolates. As this complexity regarding SBA assessment methods can make data interpretation difficult, herein we describe the use of hSBA assays to evaluate MenB vaccine efficacy and to support licensure. In addition, we highlight how the two recently approved MenB vaccines differ in their use of hSBA assays in clinical studies to demonstrate broad protection against MenB IMD.


Assuntos
Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/imunologia , Neisseria meningitidis Sorogrupo B/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas do Sistema Complemento/imunologia , Humanos , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/administração & dosagem , Coelhos
20.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012928

RESUMO

PEGylated nanomedicines are known to induce infusion reactions (IRs) that in some cases can be life-threatening. Herein, we report a case study in which a patient with rare mediastinal and intracardiac IgG4-related sclerosing disease received 8 treatments of intravenously administered PEGylated liposomal methylprednisolone-succinate (NSSL-MPS). Due to the ethical requirements to reduce IRs, the patient received a cocktail of premedication including low dose of steroids, acetaminophen and H2 blockers before each infusion. The treatment was well-tolerated in that IRs, complement activation, anti-PEG antibodies and accelerated blood clearance of the PEGylated drug were not detected. Prior to the clinical study, an in vitro panel of assays utilizing blood of healthy donors was used to determine the potential of a PEGylated drug to activate complement system, elicit pro-inflammatory cytokines, damage erythrocytes and affect various components of the blood coagulation system. The overall findings of the in vitro panel were negative and correlated with the results observed in the clinical phase.


Assuntos
Fatores Imunológicos/administração & dosagem , Lipossomos , Hemissuccinato de Metilprednisolona/administração & dosagem , Biomarcadores , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Lipossomos/química , Masculino , Hemissuccinato de Metilprednisolona/farmacocinética , Polietilenoglicóis/química
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