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2.
Cell Rep ; 38(10): 110503, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35235832

RESUMO

Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.


Assuntos
COVID-19 , Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais , Metiltransferases , Subfamília C de Receptores Semelhantes a Lectina de Células NK , RNA Helicases , SARS-CoV-2 , Proteínas não Estruturais Virais , COVID-19/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/imunologia , Metiltransferases/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Peptídeos/metabolismo , RNA Helicases/imunologia , Proteínas não Estruturais Virais/imunologia , Antígenos HLA-E
3.
Vaccines (Basel) ; 10(3)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35334989

RESUMO

Heterologous primary immunization against SARS-CoV-2 is part of applied recommendations. However, little is known about duration of immune responses after heterologous vaccine regimens. To evaluate duration of immune responses after primary vaccination with homologous adeno-vectored ChAdOx1 nCoV-19 vaccine (ChAd) or heterologous ChAd/BNT162b2 mRNA vaccine (BNT), anti-spike-IgG and SARS-CoV-2 VOC-neutralizing antibody responses were measured in 354 healthcare workers (HCW) at 2 weeks, 3 months, 5 months and 6 months after the second vaccine dose. T-cell responses were investigated using a whole blood interferon gamma (IFN-γ) release assay 2 weeks and 3 months post second vaccine dose. Two hundred and ten HCW immunized with homologous BNT were enrolled for comparison of antibody responses. In study participants naïve to SARS-CoV-2 prior to vaccination, heterologous ChAd/BNT resulted in 6-fold higher peak anti-spike IgG antibody titers compared to homologous ChAd vaccination. The half-life of antibody titers was 3.1 months (95% CI 2.8-3.6) following homologous ChAd vaccination and 1.9 months (95% CI 1.7-2.1) after heterologous vaccination, reducing the GMT difference between the groups to 3-fold 6 months post vaccination. Peak T-cell responses were stronger in ChAd/BNT vaccinees, but no significant difference was observed 3 months post vaccination. SARS-CoV-2 infection prior to vaccination resulted in substantially higher peak GMTs and IFN-γ levels and enhanced SARS-CoV-2 specific antibody and T cell responses over time. Heterologous primary SARS-CoV-2 immunization with ChAd and BNT elicits a stronger initial immune response compared to homologous vaccination with ChAd. However, although the differences in humoral responses remain over 6 months, the difference in SARS-CoV-2 specific T cell responses are no longer significant three months after vaccination.

4.
Int J Infect Dis ; 113: 127-135, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34653656

RESUMO

OBJECTIVES: To investigate the risk of haematologic and solid organ malignancies in patients with haemorrhagic fever with renal syndrome (HFRS) compared with the general population. METHODS: This propensity-score-matched cohort study was conducted using data collected from the Korean national health insurance service (NHIS) between January 2003 and December 2017. The HFRS cohort included 5888 newly diagnosed cases of HFRS, and 412,804 general participants from the NHIS database were included as the control cohort. The incidence rate of malignancies was assessed and compared between the HFRS and control cohorts. RESULTS: There were 64 cases of haematologic malignancy in 236,286 person-years of observation, and 1245 cases of solid organ cancer in 209,333 person-years. The risks of haematologic malignancy and solid organ cancer were significantly higher in the HFRS cohort [adjusted hazards ratio (aHR) 4.10, 95% confidence interval (CI) 2.36-7.14] than the control cohort [aHR 2.97, 95% CI 2.60-3.38). In subgroup analysis, the HFRS cohort was associated with high hazard ratios for leukaemia and non-Hodgkin lymphoma. The HFRS cohort also had increased aHRs for all types of solid organ cancer. CONCLUSIONS: Patients with HFRS are at increased risk of both haematologic and solid organ malignancies compared with the general population, and this increased proportionally over time. Careful monitoring for malignancy after the onset of HFRS may be necessary.


Assuntos
Febre Hemorrágica com Síndrome Renal , Neoplasias , China , Estudos de Coortes , Febre Hemorrágica com Síndrome Renal/complicações , Febre Hemorrágica com Síndrome Renal/epidemiologia , Humanos , Incidência , Neoplasias/epidemiologia , Neoplasias/etiologia , Modelos de Riscos Proporcionais
5.
EBioMedicine ; 70: 103523, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34391088

RESUMO

BACKGROUND: Recent reports demonstrate robust serological responses to a single dose of messenger RNA (mRNA) vaccines in individuals previously infected with SARS-CoV-2. Data on immune responses following a single-dose adenovirus-vectored vaccine expressing the SARS-CoV-2 spike protein (ChAdOx1 nCoV-19) in individuals with previous SARS-CoV-2 infection are however limited, and current guidelines recommend a two-dose regimen regardless of preexisting immunity. METHODS: We compared RBD-specific IgG and RBD-ACE2 blocking antibodies against SARS-CoV-2 wild type and variants of concern following two doses of the mRNA vaccine BNT162b2 in SARS-CoV-2 naïve healthcare workers (n=65) and a single dose of the adenovector vaccine ChAdOx1 nCoV-19 in 82 healthcare workers more than (n=45) and less than (n=37) 11 months post mild SARS-CoV-2 infection at time of vaccination. FINDINGS: The post-vaccine levels of RBD-specific IgG and neutralizing antibodies against the SARS-CoV-2 wild type and variants of concern including Delta lineage 1.617.2 were similar or higher in participants receiving a single dose of ChAdOx1 nCoV-19 vaccine post SARS-CoV-2 infection (both more than and less than 11 months post infection) compared to SARS-CoV-2 naïve participants who received two doses of BNT162b2 vaccine. INTERPRETATION: Our data support that a single dose ChAdOx1 nCoV-19 vaccine that is administered up to at least 11 months post SARS-CoV-2 infection serves as an effective immune booster. This provides a possible rationale for a single-dose vaccine regimen. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Vacina BNT162 , ChAdOx1 nCoV-19 , Feminino , Pessoal de Saúde , Humanos , Imunização Secundária/métodos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos
6.
Clin Transl Immunology ; 10(7): e1313, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34277007

RESUMO

OBJECTIVE: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms are not fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction. METHODS: We performed a comprehensive characterisation of longitudinal antiviral B-cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP) and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells. RESULTS: We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27-IgD- B cells and CD27-/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection. CONCLUSION: Our findings demonstrate that thrombocytopenia and kidney dysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus-infected individuals have significantly elevated levels of extracellular ATP in circulation.

7.
Cell Rep Med ; 2(3): 100220, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33763658

RESUMO

Hantaviruses are zoonotic RNA viruses that cause severe acute disease in humans. Infected individuals have strong inflammatory responses that likely cause immunopathology. Here, we studied the response of mucosal-associated invariant T (MAIT) cells in peripheral blood of individuals with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala orthohantavirus, a hantavirus endemic in Europe. We show that MAIT cell levels decrease in the blood during HFRS and that residual MAIT cells are highly activated. This activation correlates with HFRS severity markers. In vitro activation of MAIT cells by hantavirus-exposed antigen-presenting cells is dependent on type I interferons (IFNs) and independent of interleukin-18 (IL-18). These findings highlight the role of type I IFNs in virus-driven MAIT cell activation and suggest a potential role of MAIT cells in the disease pathogenesis of viral infections.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Infecções por Hantavirus/imunologia , Febre Hemorrágica com Síndrome Renal/imunologia , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/imunologia , Virus Puumala/patogenicidade , Adulto , Anticorpos Antivirais/sangue , Células Apresentadoras de Antígenos/virologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Células Endoteliais/imunologia , Células Endoteliais/virologia , Feminino , Regulação da Expressão Gênica , Infecções por Hantavirus/genética , Infecções por Hantavirus/patologia , Infecções por Hantavirus/virologia , Febre Hemorrágica com Síndrome Renal/genética , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Imunofenotipagem , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/virologia , Células T Invariantes Associadas à Mucosa/virologia , Virus Puumala/imunologia , Índice de Gravidade de Doença
8.
J Immunol ; 205(9): 2437-2446, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32878912

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific Abs are typically a major predictor of protective immunity, yet human B cell and Ab responses during COVID-19 are not fully understood. In this study, we analyzed Ab-secreting cell and Ab responses in 20 hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19 and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific Ab-secreting cells in all 20 COVID-19 patients using a multicolor FluoroSpot Assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing Abs by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG, and IgM Ab levels positively correlated with SARS-CoV-2-neutralizing Ab titers, suggesting that SARS-CoV-2-specific Ab levels may reflect the titers of neutralizing Abs in COVID-19 patients during the acute phase of infection. Last, we showed that IL-6 and C-reactive protein serum concentrations were higher in patients who were hospitalized for longer, supporting the recent observations that IL-6 and C-reactive protein could be used as markers for COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in 20 COVID-19 patients, with a focus on B cell and Ab responses, and describes tools to study immune responses to SARS-CoV-2 infection and vaccination.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Hospitalização , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/virologia , Proteínas do Nucleocapsídeo de Coronavírus , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Interleucina-6/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Proteínas do Nucleocapsídeo/imunologia , Pandemias , Fosfoproteínas , Pneumonia Viral/virologia , SARS-CoV-2 , Suécia/epidemiologia
9.
PLoS Pathog ; 16(2): e1008297, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032391

RESUMO

Hantaviruses, zoonotic RNA viruses belonging to the order Bunyavirales, cause two severe acute diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavirus-infected patients show strong cytotoxic lymphocyte responses and hyperinflammation; however, infected cells remain mostly intact. Hantaviruses were recently shown to inhibit apoptosis in infected cells. By inhibiting granzyme B- and TRAIL-mediated apoptosis, hantaviruses specifically and efficiently inhibit cytotoxic lymphocyte-mediated killing of infected cells. Hantaviruses also strongly inhibit apoptosis triggered intrinsically; i.e., initiated through intracellular activation pathways different from those used by cytotoxic lymphocytes. However, insights into the latter mechanisms are currently largely unknown. Here, we dissected the mechanism behind how hantavirus infection, represented by the HFRS-causing Hantaan virus and the HPS-causing Andes virus, results in resistance to staurosporine-induced apoptosis. Less active caspase-8 and caspase-9, and consequently less active caspase-3, was observed in infected compared to uninfected staurosporine-exposed cells. While staurosporine-exposed uninfected cells showed massive release of pro-apoptotic cytochrome C into the cytosol, this was not observed in infected cells. Further, hantaviruses prevented activation of BAX and mitochondrial outer membrane permeabilization (MOMP). In parallel, a significant increase in levels of the pro-survival factor BCL-2 was observed in hantavirus-infected cells. Importantly, direct inhibition of BCL-2 by the inhibitor ABT-737, as well as silencing of BCL-2 by siRNA, resulted in apoptosis in staurosporine-exposed hantavirus-infected cells. Overall, we here provide a tentative mechanism by which hantaviruses protect infected cells from intrinsic apoptosis at the mitochondrial level by inducing an increased expression of the pro-survival factor BCL-2, thereby preventing MOMPs and subsequent activation of caspases. The variety of mechanisms used by hantaviruses to ensure survival of infected cells likely contribute to the persistent infection in natural hosts and may play a role in immunopathogenesis of HFRS and HPS in humans.


Assuntos
Apoptose , Febre Hemorrágica com Síndrome Renal/metabolismo , Potencial da Membrana Mitocondrial , Membranas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Regulação para Cima , Células A549 , Caspases/genética , Caspases/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Febre Hemorrágica com Síndrome Renal/patologia , Humanos , Membranas Mitocondriais/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
Cell Rep ; 28(8): 2124-2139.e6, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31433987

RESUMO

Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.


Assuntos
Regulação para Baixo , Infecções por Hantavirus/metabolismo , Infecções por Hantavirus/patologia , Orthohantavírus/fisiologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Células A549 , Adolescente , Adulto , Idoso , Morte Celular , Membrana Celular/metabolismo , Citoproteção , Feminino , Células Endoteliais da Veia Umbilical Humana/virologia , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Frações Subcelulares/metabolismo , Ubiquitinação/efeitos dos fármacos , Adulto Jovem
11.
Sci Rep ; 9(1): 834, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696898

RESUMO

Orthohantaviruses, previously known as hantaviruses, are zoonotic viruses that can cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) in humans. The HPS-causing Andes virus (ANDV) and the HFRS-causing Hantaan virus (HTNV) have anti-apoptotic effects. To investigate if this represents a general feature of orthohantaviruses, we analysed the capacity of six different orthohantaviruses - belonging to three distinct phylogroups and representing both pathogenic and non-pathogenic viruses - to inhibit apoptosis in infected cells. Primary human endothelial cells were infected with ANDV, HTNV, the HFRS-causing Puumala virus (PUUV) and Seoul virus, as well as the putative non-pathogenic Prospect Hill virus and Tula virus. Infected cells were then exposed to the apoptosis-inducing chemical staurosporine or to activated human NK cells exhibiting a high cytotoxic potential. Strikingly, all orthohantaviruses inhibited apoptosis in both settings. Moreover, we show that the nucleocapsid (N) protein from all examined orthohantaviruses are potential targets for caspase-3 and granzyme B. Recombinant N protein from ANDV, PUUV and the HFRS-causing Dobrava virus strongly inhibited granzyme B activity and also, to certain extent, caspase-3 activity. Taken together, this study demonstrates that six different orthohantaviruses inhibit apoptosis, suggesting this to be a general feature of orthohantaviruses likely serving as a mechanism of viral immune evasion.


Assuntos
Apoptose/imunologia , Vírus Hantaan/imunologia , Evasão da Resposta Imune/imunologia , Orthohepadnavirus/imunologia , Virus Puumala/imunologia , Vírus Seoul/imunologia , Células A549 , Caspase 3/imunologia , Linhagem Celular Tumoral , Células Endoteliais/virologia , Granzimas/imunologia , Orthohantavírus/imunologia , Síndrome Pulmonar por Hantavirus/patologia , Síndrome Pulmonar por Hantavirus/virologia , Febre Hemorrágica com Síndrome Renal/patologia , Febre Hemorrágica com Síndrome Renal/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Células K562 , Células Matadoras Naturais/virologia , Nucleocapsídeo/genética , Nucleocapsídeo/imunologia , Orthohepadnavirus/classificação , Orthohepadnavirus/genética
12.
J Infect Dis ; 219(11): 1832-1840, 2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-30698699

RESUMO

BACKGROUND: Hantavirus pulmonary syndrome (HPS) is caused by Andes virus (ANDV) and related hantaviruses in the Americas. Despite a fatality rate of 40%, the pathogenesis of HPS is poorly understood and factors associated with severity, fatality, and survival remain elusive. METHODS: Ninety-three ANDV-infected HPS patients, of whom 34 had a fatal outcome, were retrospectively studied. Serum levels of cytokines and other inflammation-associated markers were analyzed using multiplex immunoassay and enzyme-linked immunosorbent assay. Associations with disease severity, fatal outcome, and survival were identified using logistic regression. RESULTS: HPS patients exhibited increased serum levels of markers associated with inflammation, intestinal damage, and microbial translocation compared to controls. Patients with fatal outcome displayed higher levels of interleukin (IL) 6, IL-10, interferon-γ, soluble tumor necrosis factor-related apoptosis-inducing ligand, and intestinal fatty acid-binding protein (I-FABP) than survivors. Levels of complement factor 5/5a were higher in survivors compared with fatal cases. IL-6 and I-FABP, the latter a marker for intestinal damage, were by multivariate analyses identified as independent markers associated with disease severity (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.01-5.01) and fatal outcome (OR, 1.64; 95% CI, 1.01-2.64), respectively. CONCLUSIONS: HPS patients displayed a multifaceted, systemic inflammatory response, with IL-6 and I-FABP as independent markers of disease severity and fatality, respectively.


Assuntos
Biomarcadores/metabolismo , Síndrome Pulmonar por Hantavirus/sangue , Síndrome Pulmonar por Hantavirus/metabolismo , Adulto , Citocinas/sangue , Citocinas/metabolismo , Feminino , Orthohantavírus/patogenicidade , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença
13.
PLoS One ; 11(2): e0149354, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26907493

RESUMO

Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS), a severe acute disease with a 40% case fatality rate. Humans are infected via inhalation, and the lungs are severely affected during HPS, but little is known regarding the effects of ANDV-infection of the lung. Using a 3-dimensional air-exposed organotypic human lung tissue model, we analyzed progeny virus production and cytokine-responses after ANDV-infection. After a 7-10 day period of low progeny virus production, a sudden peak in progeny virus levels was observed during approximately one week. This peak in ANDV-production coincided in time with activation of innate immune responses, as shown by induction of type I and III interferons and ISG56. After the peak in ANDV production a low, but stable, level of ANDV progeny was observed until 39 days after infection. Compared to uninfected models, ANDV caused long-term elevated levels of eotaxin-1, IL-6, IL-8, IP-10, and VEGF-A that peaked 20-25 days after infection, i.e., after the observed peak in progeny virus production. Notably, eotaxin-1 was only detected in supernatants from infected models. In conclusion, these findings suggest that ANDV replication in lung tissue elicits a late proinflammatory immune response with possible long-term effects on the local lung cytokine milieu. The change from an innate to a proinflammatory response might be important for the transition from initial asymptomatic infection to severe clinical disease, HPS.


Assuntos
Citocinas/metabolismo , Infecções por Hantavirus , Pulmão , Modelos Biológicos , Orthohantavírus/fisiologia , Pneumonia Viral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Replicação Viral , Linhagem Celular , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/virologia , Infecções por Hantavirus/metabolismo , Infecções por Hantavirus/patologia , Infecções por Hantavirus/virologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Síndrome
14.
J Gen Virol ; 95(Pt 11): 2356-2364, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25013204

RESUMO

Hantaviruses are zoonotic viruses that cause life-threatening diseases when transmitted to humans. Severe hantavirus infection is manifested by impairment of renal function, pulmonary oedema and capillary leakage. Both innate and adaptive immune responses contribute to the pathogenesis, but the underlying mechanisms are not fully understood. Here, we showed that galectin-3-binding protein (Gal-3BP) was upregulated as a result of hantavirus infection both in vitro and in vivo. Gal-3BP is a secreted glycoprotein found in human serum, and increased Gal-3BP levels have been reported in chronic viral infections and in several types of cancer. Our in vitro experiments showed that, whilst Vero E6 cells (an African green monkey kidney cell line) constitutively expressed and secreted Gal-3BP, this protein was detected in primary human cells only as a result of hantavirus infection. Analysis of Gal-3BP levels in serum samples of cynomolgus macaques infected experimentally with hantavirus indicated that hantavirus infection induced Gal-3BP also in vivo. Finally, analysis of plasma samples collected from patients hospitalized because of acute hantavirus infection showed higher Gal-3BP levels during the acute than the convalescent phase. Furthermore, the Gal-3BP levels in patients with haemorrhagic fever with renal syndrome correlated with increased complement activation and with clinical variables reflecting the severity of acute hantavirus infection.


Assuntos
Antígenos de Neoplasias/biossíntese , Biomarcadores Tumorais/biossíntese , Proteínas de Transporte/biossíntese , Galectina 3/metabolismo , Glicoproteínas/biossíntese , Infecções por Hantavirus/metabolismo , Doença Aguda , Animais , Antígenos de Neoplasias/sangue , Antígenos Virais/metabolismo , Biomarcadores Tumorais/sangue , Proteínas de Transporte/sangue , Chlorocebus aethiops , Ativação do Complemento , Feminino , Glicoproteínas/sangue , Infecções por Hantavirus/imunologia , Infecções por Hantavirus/virologia , Febre Hemorrágica com Síndrome Renal/imunologia , Febre Hemorrágica com Síndrome Renal/metabolismo , Febre Hemorrágica com Síndrome Renal/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Macaca fascicularis , Masculino , Virus Puumala , Distribuição Tecidual , Células Vero
15.
Clin Infect Dis ; 59(8): 1130-2, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24965350

RESUMO

Hemorrhagic fever with renal syndrome (HFRS) is a severe acute disease. Although long-term consequences to public health have been reported, no association with cancer is known. We examined the risk of cancer development after HFRS in the Swedish population between 1997 and 2011 (n = 6582) and report a 73% increased risk for lymphoma.


Assuntos
Febre Hemorrágica com Síndrome Renal/complicações , Linfoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Suécia/epidemiologia , Adulto Jovem
16.
J Virol ; 88(4): 2344-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24335294

RESUMO

How hantaviruses assemble and exit infected cells remains largely unknown. Here, we show that the expression of Andes (ANDV) and Puumala (PUUV) hantavirus Gn and Gc envelope glycoproteins lead to their self-assembly into virus-like particles (VLPs) which were released to cell supernatants. The viral nucleoprotein was not required for particle formation. Further, a Gc endodomain deletion mutant did not abrogate VLP formation. The VLPs were pleomorphic, exposed protrusions and reacted with patient sera.


Assuntos
Orthohantavírus/metabolismo , Virus Puumala/metabolismo , Proteínas do Envelope Viral/metabolismo , Vírion/metabolismo , Western Blotting , Reações Cruzadas/imunologia , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Orthohantavírus/genética , Humanos , Virus Puumala/genética , Vírion/genética
17.
J Virol ; 85(4): 1747-56, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21106742

RESUMO

Hantaviruses, the causative agents of two emerging diseases, are negative-stranded RNA viruses with a tripartite genome. We isolated two substrains from a parental strain of Puumala hantavirus (PUUV-Pa), PUUV-small (PUUV-Sm) and PUUV-large (PUUV-La), named after their focus size when titrated. The two isolates were sequenced; this revealed differences at two positions in the nucleocapsid protein and two positions in the RNA-dependent RNA polymerase, but the glycoproteins were identical. We also detected a 43-nucleotide deletion in the PUUV-La S-segment 5' noncoding region covering a predicted hairpin loop structure that was found to be conserved among all hantaviruses with members of the rodent subfamily Arvicolinae as their hosts. Stocks of PUUV-La showed a lower ratio of viral RNA to infectious particles than stocks of PUUV-Sm and PUUV-Pa, indicating that PUUV-La replicated more efficiently in alpha/beta interferon (IFN-α/ß)-defective Vero E6 cells. In Vero E6 cells, PUUV-La replicated to higher titers and PUUV-Sm replicated to lower titers than PUUV-Pa. In contrast, in IFN-competent MRC-5 cells, PUUV-La and PUUV-Sm replicated to similar levels, while PUUV-Pa progeny virus production was strongly inhibited. The different isolates clearly differed in their potential to induce innate immune responses in MRC-5 cells. PUUV-Pa caused stronger induction of IFN-ß, ISG56, and MxA than PUUV-La and PUUV-Sm, while PUUV-Sm caused stronger MxA and ISG56 induction than PUUV-La. These data demonstrate that the phenotypes of isolated hantavirus substrains can have substantial differences compared to each other and to the parental strain. Importantly, this implies that the reported differences in phenotypes for hantaviruses might depend more on chance due to spontaneous mutations during passage than inherited true differences between hantaviruses.


Assuntos
Células Epiteliais/virologia , Fibroblastos/virologia , Rim/virologia , Pulmão/virologia , Virus Puumala/classificação , Virus Puumala/fisiologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Chlorocebus aethiops , Humanos , Rim/citologia , Pulmão/citologia , Dados de Sequência Molecular , Mutação , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/genética , Fenótipo , Virus Puumala/genética , Virus Puumala/imunologia , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , Análise de Sequência de DNA , Especificidade da Espécie , Células Vero , Proteínas Virais/química , Proteínas Virais/genética , Replicação Viral
18.
J Virol ; 84(18): 9140-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20592090

RESUMO

Type III interferons ([IFNs] IFN-lambda and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-alpha/beta). Like IFN-alpha/beta, IFN-lambda-expression can be induced by viruses, and it is believed that type I and III IFNs are regulated in the same manner. Hantaviruses are weak IFN-alpha/beta inducers and have surprisingly been shown to activate IFN-alpha/beta-independent IFN-stimulated gene (ISG) expression. Here, we show that in Hantaan virus (HTNV)-infected human epithelial A549 cells, induction of IFN-lambda1 preceded induction of MxA and IFN-beta by 12 and 24 h, respectively, and IFN-alpha was not induced at all. Furthermore, induction of IFN-lambda1 and MxA was observed in HTNV-infected African green monkey epithelial Vero E6 cells, a cell line that cannot produce type I IFNs, clearly showing that HTNV can induce IFN-lambda1 and ISGs in the complete absence of IFN-alpha/beta. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-lambda receptor, induction of MxA coincided in time with IFN-beta-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-lambda1 is dependent on replicating virus. Induction of both IFN-beta and IFN-lambda1 in A549 cells after poly(I:C)-stimulation was strongly inhibited in HTNV-infected cells, suggesting that HTNV can inhibit signaling pathways used to simultaneously activate types I and III IFNs. In conclusion, we show that HTNV can cause type I IFN-independent IFN-lambda1 induction and IFN-lambda1-specific ISG induction. Importantly, the results suggest the existence of specific signaling pathways that induce IFN-lambda1 without simultaneous type I IFN induction during virus infection.


Assuntos
Vírus Hantaan/imunologia , Interleucinas/biossíntese , Animais , Linhagem Celular , Chlorocebus aethiops , Células Epiteliais/imunologia , Células Epiteliais/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Interferon beta/imunologia , Interferon beta/metabolismo , Interferons , Interleucinas/imunologia , Transdução de Sinais
19.
PLoS One ; 3(4): e2032, 2008 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-18446221

RESUMO

Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5' triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5' triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5' monophosphate-specific exonuclease indicates that the RIG-I-activating 5' triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5' end as a strategy of viruses to evade the innate immune response.


Assuntos
RNA Helicases DEAD-box/imunologia , Genoma Viral/genética , Interferons/imunologia , Vírus de RNA/genética , Linhagem Celular , Proteína DEAD-box 58 , Humanos , Fosfatos , Vírus de RNA/patogenicidade , RNA Viral/genética , Receptores Imunológicos , Virulência
20.
Antivir Ther ; 13(1): 125-33, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18389907

RESUMO

BACKGROUND: Hantaviruses cause two severe and often fatal human diseases: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Presently, there is no effective prevention available for HFRS or HPS. Here, we studied the effect of passive immunization on the course of infection in cynomolgus macaques challenged with wild-type Puumala hantavirus (PUUV-wt). METHODS: A pool of serum drawn from previously PUUV-wt-infected monkeys was used for immunization; a pool of serum from the same monkeys that was obtained before infection was used as a control. Immunizations were administered 3 days before and 15 days after challenge with PUUV-wt. After challenge, monkeys were sampled once a week and analysed for PUUV-infection markers. RESULTS: All three monkeys treated with non-immune serum became positive for PUUV RNA in plasma and showed PUUV nucleocapsid-specific immunoglobin M (IgM) responses after challenge. In contrast, no PUUV RNA or anti-PUUV-specific IgM response was detected in the three passively immunized monkeys. As seen in PUUV-infected humans, the control monkeys showed a marked decrease in the amount of platelets and increased levels of creatinine, interleukin (1L)-6, IL-10, and tumour necrosis factor (TNF) after inoculation. In contrast, no marked changes in the amount of platelets were observed in the immunized monkeys and they did not show increased levels of creatinine, IL-6, IL-10 and TNF after virus challenge. CONCLUSION: The results show that passive immunization in monkeys, using serum from previously hantavirus-infected monkeys, can induce sterile protection and protect against pathogenesis. Convalescent-phase antibodies may represent a potential therapy that can induce immediate protection against HFRS and HPS.


Assuntos
Febre Hemorrágica com Síndrome Renal/imunologia , Imunização Passiva , Macaca fascicularis/imunologia , Macaca fascicularis/virologia , Virus Puumala/imunologia , Animais , Anticorpos Antivirais/sangue , Proteína C-Reativa/metabolismo , Creatinina/sangue , Citocinas/sangue , Óxido Nítrico/sangue , Fatores de Tempo , Viremia/imunologia
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