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1.
Nat Immunol ; 14(4): 327-36, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23455675

RESUMO

During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-κB, AP-1, IRF3, IRF5 and IRF7. Activation resulted in the production of proinflammatory cytokines, modulation of natural killer stress ligands and induction of an antiviral state. Intracellular antibody signaling was abrogated by genetic deletion of TRIM21 and was restored by ectopic expression of TRIM21. The sensing of antibodies by TRIM21 was stimulated after infection by DNA or RNA nonenveloped viruses or intracellular bacteria. Thus, the antibody-TRIM21 detection system provides potent, comprehensive activation of the innate immune system independently of known pattern-recognition receptors.


Assuntos
Anticorpos Antivirais/imunologia , Espaço Intracelular/imunologia , Espaço Intracelular/metabolismo , Receptores Fc/metabolismo , Ribonucleoproteínas/imunologia , Transdução de Sinais , Vírus/imunologia , Adenoviridae/imunologia , Animais , Anticorpos Antivirais/química , Anticorpos Antivirais/metabolismo , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Bactérias/imunologia , Linhagem Celular , Reações Cruzadas , Citocinas/biossíntese , Humanos , Mediadores da Inflamação/metabolismo , Fatores Reguladores de Interferon/metabolismo , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores de Reconhecimento de Padrão/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo , Fator de Transcrição AP-1/metabolismo
2.
PLoS Pathog ; 18(10): e1010882, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36191037

RESUMO

COVID-19 vaccines are playing a vital role in controlling the COVID-19 pandemic. As SARS-CoV-2 variants encoding mutations in the surface glycoprotein, Spike, continue to emerge, there is increased need to identify immunogens and vaccination regimens that provide the broadest and most durable immune responses. We compared the magnitude and breadth of the neutralizing antibody response, as well as levels of Spike-reactive memory B cells, in individuals receiving a second dose of BNT162b2 at a short (3-4 week) or extended interval (8-12 weeks) and following a third vaccination approximately 6-8 months later. We show that whilst an extended interval between the first two vaccinations can greatly increase the breadth of the immune response and generate a higher proportion of Spike reactive memory B cells, a third vaccination leads to similar levels between the two groups. Furthermore, we show that the third vaccine dose enhances neutralization activity against omicron lineage members BA.1, BA.2 and BA.4/BA.5 and this is further increased following breakthrough infection during the UK omicron wave. These findings are relevant for vaccination strategies in populations where COVID-19 vaccine coverage remains low.


Assuntos
COVID-19 , Vacinas Virais , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Glicoproteínas de Membrana/genética , Pandemias , SARS-CoV-2/genética , Vacinação
3.
J Infect Dis ; 226(2): 357-365, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35184187

RESUMO

BACKGROUND: Cytomegalovirus (CMV) is an important opportunistic pathogen after transplantation. Some virological variation in transplant recipients is explained by donor and recipient CMV serostatus, but not all. Circadian variability of herpesviruses has been described, so we investigated the effect of time of day of transplantation on posttransplant CMV viremia. METHODS: We performed a retrospective analysis of 1517 patients receiving liver or kidney allografts at a single center from 2002 to 2018. All patients were given preemptive therapy with CMV viremia monitoring after transplantation. Circulatory arrest and reperfusion time of donor organ were categorized into 4 periods. Patients were divided into serostatus groups based on previous CMV infection in donor and recipient. CMV viremia parameters were compared between time categories for each group. Factor analysis of mixed data was used to interrogate this complex data set. RESULTS: Live-donor transplant recipients were less likely to develop viremia than recipients of deceased-donor organs (48% vs 61%; P < .001). After controlling for this, there was no evidence of time of day of transplantation affecting CMV parameters in any serostatus group, by logistic regression or factor analysis of mixed data. DISCUSSION: We found no evidence for a circadian effect of transplantation on CMV viremia, but these novel results warrant confirmation by other centers.


Assuntos
Infecções por Citomegalovirus , Transplante de Órgãos , Antivirais/uso terapêutico , Ritmo Circadiano , Citomegalovirus , Humanos , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos , Carga Viral , Viremia/etiologia
4.
PLoS Pathog ; 11(10): e1005253, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26506431

RESUMO

Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and from innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection and degradation of viral genomes before their replication. TRIM21 triggers an initial wave of cytokine transcription that is antibody, rather than pathogen, driven. This early response is augmented by a second transcriptional program, determined by the nature of the infecting virus. In this second response, TRIM21-induced exposure of the viral genome promotes sensing of DNA and RNA viruses by cGAS and RIG-I. This mechanism allows early detection of an infection event and drives an inflammatory response in mice within hours of viral challenge.


Assuntos
RNA Helicases DEAD-box/fisiologia , Genoma Viral , Nucleotidiltransferases/fisiologia , Fagocitose , Ribonucleoproteínas/fisiologia , Viroses/imunologia , Infecções por Adenovirus Humanos/imunologia , Animais , Proteína DEAD-box 58 , Células HeLa , Humanos , Imunidade Inata , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Picornaviridae/imunologia , Receptores Imunológicos , Rhinovirus
5.
Proc Natl Acad Sci U S A ; 111(37): 13463-8, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25169018

RESUMO

IgA is the most prevalent antibody type on mucosal surfaces and the second most prevalent antibody in circulation, yet its role in immune defense is not fully understood. Here we show that IgA is carried inside cells during virus infection, where it activates intracellular virus neutralization and innate immune signaling. Cytosolic IgA-virion complexes colocalize with the high-affinity antibody receptor tripartite motif-containing protein 21 (TRIM21) and are positive for lysine-48 ubiquitin chains. IgA neutralizes adenovirus infection in a TRIM21- and proteasome-dependent manner in both human and mouse cells. Translocated IgA also potently activates NF-κB signaling pathways in cells expressing TRIM21, whereas viral infection in the absence of antibody or TRIM21 is undetected. TRIM21 recognizes an epitope in IgG Fc that is not conserved in IgA; however, fluorescence anisotropy experiments demonstrate that direct binding to IgA is maintained. We use molecular modeling to show that TRIM21 forms a nonspecific hydrophobic seal around a ß-loop structure that is present in IgG, IgM, and IgA, explaining how TRIM21 achieves such remarkable broad antibody specificity. The findings demonstrate that the antiviral protection afforded by IgA extends to the intracellular cytosolic environment.


Assuntos
Infecções por Adenoviridae/imunologia , Anticorpos Neutralizantes/metabolismo , Imunidade Inata , Imunoglobulina A/metabolismo , Testes de Neutralização , Adenosina Trifosfatases/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Citocinas/metabolismo , Células HeLa , Humanos , Imunoglobulina A/sangue , Imunoglobulina M/metabolismo , Espaço Intracelular/metabolismo , Camundongos , Modelos Moleculares , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo , Proteína com Valosina , Replicação Viral
6.
Oxf Open Immunol ; 4(1): iqac012, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36844257

RESUMO

Neutralizing monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein have been developed for the treatment of COVID-19. Whilst antibody therapy has been shown to reduce the risk of COVID-19-associated hospitalization and death, there is limited understanding of the endogenous immunity to SARS-CoV-2 generated in mAb-treated patients and therefore ongoing susceptibility to future infections. Here we measure the endogenous antibody response in SARS-CoV-2-infected individuals treated with REGN-COV2 (Ronapreve). We show that in the majority of unvaccinated, delta-infected REGN-COV2-treated individuals, an endogenous antibody response is generated, but, like untreated, delta-infected individuals, there was a limited neutralization breadth. However, some vaccinated individuals who were seronegative at SARS-CoV-2 infection baseline and some unvaccinated individuals failed to produce an endogenous immune response following infection and REGN-COV2 treatment demonstrating the importance of mAb therapy in some patient populations.

7.
BMJ ; 378: e072410, 2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902115

RESUMO

OBJECTIVE: To characterise the clinical features of monkeypox infection in humans. DESIGN: Descriptive case series. SETTING: A regional high consequences infectious disease centre with associated primary and secondary care referrals, and affiliated sexual health centres in south London between May and July 2022. PARTICIPANTS: 197 patients with polymerase chain reaction confirmed monkeypox infection. RESULTS: The median age of participants was 38 years. All 197 participants were men, and 196 identified as gay, bisexual, or other men who have sex with men. All presented with mucocutaneous lesions, most commonly on the genitals (n=111 participants, 56.3%) or in the perianal area (n=82, 41.6%). 170 (86.3%) participants reported systemic illness. The most common systemic symptoms were fever (n=122, 61.9%), lymphadenopathy (114, 57.9%), and myalgia (n=62, 31.5%). 102/166 (61.5%) developed systemic features before the onset of mucocutaneous manifestations and 64 (38.5%) after (n=4 unknown). 27 (13.7%) presented exclusively with mucocutaneous manifestations without systemic features. 71 (36.0%) reported rectal pain, 33 (16.8%) sore throat, and 31 (15.7%) penile oedema. 27 (13.7%) had oral lesions and 9 (4.6%) had tonsillar signs. 70/195 (35.9%) participants had concomitant HIV infection. 56 (31.5%) of those screened for sexually transmitted infections had a concomitant sexually transmitted infection. Overall, 20 (10.2%) participants were admitted to hospital for the management of symptoms, most commonly rectal pain and penile swelling. CONCLUSIONS: These findings confirm the ongoing unprecedented community transmission of monkeypox virus among gay, bisexual, and other men who have sex with men seen in the UK and many other non-endemic countries. A variable temporal association was observed between mucocutaneous and systemic features, suggesting a new clinical course to the disease. New clinical presentations of monkeypox infection were identified, including rectal pain and penile oedema. These presentations should be included in public health messaging to aid early diagnosis and reduce onward transmission.


Assuntos
Infecções por HIV , Mpox , Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Adulto , Surtos de Doenças , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Homossexualidade Masculina , Humanos , Londres/epidemiologia , Masculino , Mpox/complicações , Dor/complicações , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia
8.
Clin Infect Pract ; 9: 100059, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33521626

RESUMO

BACKGROUND: Venous thrombo-embolism is now well-recognised as a common complication of severe COVID-19 disease. Arterial thrombosis has been less well recognised, although it is increasingly reported, mostly in the context of myocardial infarction and stroke. CASE REPORT: A 63-year-old man developed a pale, cold foot with an absent dorsalis pedis pulse 7 days into his admission with COVID-19. A CT angiogram demonstrated a large thrombus in the lower thoracic aorta, which had not been present on CT pulmonary angiogram the preceding week, along with occlusion of both popliteal arteries. He was managed with therapeutic dose of low molecular weight heparin (LMWH) for 6 weeks. RESULTS: This case adds to the growing list of potential sites and consequences of thrombosis in COVID-19. CONCLUSION: This case underscores the urgent need for pathophysiological studies and clinical trials to target treatments and guidelines for thromboprophylaxis in COVID-19.

10.
J Leukoc Biol ; 96(2): 233-44, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24899588

RESUMO

Historically, once a cell became infected, it was considered to be beyond all help. By this stage, the invading pathogen had breached the innate defenses and was beyond the reach of the humoral arm of the adaptive immune response. The pathogen could still be removed by cell-mediated immunity (e.g., by NK cells or cytotoxic T lymphocytes), but these mechanisms necessitated the destruction of the infected cell. However, in recent years, it has become increasingly clear that many cells possess sensor and effector mechanisms for dealing with intracellular pathogens. Most of these mechanisms are not restricted to professional immune cells nor do they all necessitate the destruction of the host. In this review, we examine the strategies that cells use to detect and destroy pathogens once the cell membrane has been penetrated.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Membrana Celular/imunologia , Imunidade Celular , Imunidade Humoral , Infecções/imunologia , Células Matadoras Naturais/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Membrana Celular/patologia , Humanos , Infecções/patologia , Células Matadoras Naturais/patologia , Camundongos
11.
Science ; 345(6201): 1256070, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25190799

RESUMO

Pathogens traverse multiple barriers during infection, including cell membranes. We found that during this transition, pathogens carried covalently attached complement C3 into the cell, triggering immediate signaling and effector responses. Sensing of C3 in the cytosol activated mitochondrial antiviral signaling (MAVS)-dependent signaling cascades and induced proinflammatory cytokine secretion. C3 also flagged viruses for rapid proteasomal degradation, preventing their replication. This system could detect both viral and bacterial pathogens but was antagonized by enteroviruses, such as rhinovirus and poliovirus, which cleave C3 using their 3C protease. The antiviral rupintrivir inhibited 3C protease and prevented C3 cleavage, rendering enteroviruses susceptible to intracellular complement sensing. Thus, complement C3 allows cells to detect and disable pathogens that have invaded the cytosol.


Assuntos
Adenoviridae/imunologia , Infecções por Adenovirus Humanos/imunologia , Complemento C3/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Animais , Anticorpos Antivirais/imunologia , Citocinas/biossíntese , Citocinas/genética , Cães , Células HEK293 , Humanos , Fatores Reguladores de Interferon/metabolismo , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo
12.
PLoS One ; 5(1): e8902, 2010 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-20126656

RESUMO

Streptococcus pneumoniae is a common cause of infection in both HIV positive patients and those with complement deficiencies. We hypothesised that HIV positive individuals might exhibit reduced opsonisation of pneumococcus with complement due to reduced levels of S. pneumoniae specific IgG. We discovered no difference in C3 deposition on S. pneumoniae between HIV positive or negative individuals, and furthermore C3 deposition remained unchanged as HIV progressed towards AIDS. We found no correlation between C3 deposition on S. pneumoniae and CD4 cell count in HIV infected individuals. Hence we have demonstrated no failure of complement immunity in HIV positive patients.


Assuntos
Complemento C3b/metabolismo , Infecções por HIV/metabolismo , Streptococcus pneumoniae/metabolismo , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/microbiologia , Humanos , Masculino
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