RESUMO
Despite SARS-CoV-2 being a "novel" virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (ß-CoVs), and FcγR activation. Analysis of IgG targeting ß-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2'FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2'FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2'FP ratios. These findings suggest that HR2/S2'FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Imunoglobulina G , Estações do Ano , Glicoproteína da Espícula de CoronavírusRESUMO
The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Convalescença , Células Matadoras Naturais/imunologia , Pacientes Ambulatoriais , SARS-CoV-2/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/sangue , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/metabolismoRESUMO
Andes virus, an orthohantavirus endemic to South America, causes severe hantavirus cardiopulmonary syndrome associated with human-to-human transmission. No approved treatments or vaccines against this virus are available. We show that a combined treatment with 2 monoclonal antibodies protected Syrian hamsters when administered at midstage or late-stage disease.
Assuntos
Infecções por Hantavirus , Orthohantavírus , Animais , Anticorpos Monoclonais/uso terapêutico , Cricetinae , Infecções por Hantavirus/tratamento farmacológico , Humanos , Mesocricetus , América do SulRESUMO
Background: New World Hantaviruses (NWHs) are the etiological agent underlying hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with high mortality rates in humans. In Panama, infections with Choclo Orthohantavirus (CHOV) cause a much milder illness characterized by higher seroprevalence and lower mortality rates. To date, the cytokine profiles and antibody responses associated with this milder form of HCPS have not been defined. Therefore, in this study, we examined immune serological profiles associated with CHOV infections. Methods: For this retrospective study, sera from fifteen individuals with acute CHOV-induced HCPS, were analyzed alongside sera from fifteen convalescent phase individuals and thirty-three asymptomatic, CHOV-seropositive individuals. Cytokine profiles were analyzed by multiplex immunoassay. Antibody subclasses, binding, and neutralization against CHOV-glycoprotein (CHOV-GP) were evaluated by ELISA, and flow cytometry. Results: High titers of IFNγ, IL-4, IL-8, and IL-10 serum cytokines were found in the acute individuals. Elevated IL-4 serum levels were found in convalescent and asymptomatic seropositive individuals. High titers of IgG1 subclass were observed across the three cohorts analyzed. Neutralizing antibody response against CHOV-GP was detectable in few acute individuals but was strong in both convalescent and asymptomatic seropositive individuals. Conclusion: A Th1/Th2 cytokine signature is characteristic during acute mild HCPS caused by CHOV infection. High expression of Th2 and IL-8 cytokines are correlated with clinical parameters in acute mild HCPS. In addition, a strong IL-4 signature is associated with different cohorts, including asymptomatic individuals. Furthermore, asymptomatic individuals presented high titers of neutralizing antibodies.
Assuntos
Anticorpos Antivirais , Citocinas , Infecções por Hantavirus , Imunoglobulina G , Orthohantavírus , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Orthohantavírus/imunologia , Orthohantavírus/metabolismo , Infecções por Hantavirus/sangue , Infecções por Hantavirus/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Hantavirus cardiopulmonary syndrome (HCPS) caused by Andes orthohantavirus (ANDV) in South America is a public health threat due to the significant rate of mortality and the lack of a specific treatment. Interestingly, the virus does not produce cytopathic effect, thereby the strong antiviral immune response is suspected to contribute to pathogenesis, hence is important to understand the balance between protective and harmfully immunity. CD4+ T regulatory cells (Treg) are essential to control an exacerbated immune response. In human ANDV infection, little is known about CD4+ Treg cells, which may be involved in control immunopathology associated to the infection. In this report, we characterize the phenotype of memory CD4+ Tregs in a HCPS survivor's cohort. Based on the expression of CXCR3, CCR4, and CCR6, we identified different Th-like Treg populations in ANDV survival's PBMCs. In addition, the effect of ANDV-glycoprotein virus like particles (VLP) was determined. We demonstrated that memory CD4+ Treg from HCPS present a specific phenotype, showing higher frequency of PD-1 compared to healthy donors (HD). In addition, it was observed a decrease in the frequency of Th1-like memory CD4+ Treg in HCPS, important to highlight that this signature could be preserved even years after resolution of infection. Moreover, to gain insight in the mechanism involved, we evaluated whether ANDV-glycoprotein (GP) VLP could modulate CD4+ Treg. Interestingly, ANDV-GP VLP induced a decrease in the frequency of CXCR3 (Th1-like) and an increase in CCR4 (Th2-like) memory CD4+ Treg in both HD and HCPS PBMCs, indicating that ANDV-GP could specifically act over CXCR3 and CCR4 in CD4+ Treg. This report contributes to the study of human CD4+ Treg cells in ANDV infection.
Assuntos
Infecções por Hantavirus , Orthohantavírus , Glicoproteínas , Humanos , Fenótipo , Linfócitos T ReguladoresRESUMO
Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV-glycoprotein (GP) Abs. ANDV-GP-specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por Hantavirus/tratamento farmacológico , Infecções por Hantavirus/prevenção & controle , Orthohantavírus/fisiologia , Proteínas Recombinantes/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Linfócitos B/efeitos dos fármacos , Glicoproteínas/imunologia , Células HEK293 , Orthohantavírus/efeitos dos fármacos , Infecções por Hantavirus/sangue , Infecções por Hantavirus/imunologia , Humanos , Memória Imunológica/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , SobreviventesRESUMO
Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-beta peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients.