RESUMEN
COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, CCP characteristics that promote SARS-CoV-2 control are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing (ID50 ≤ 1:250), but moderate to high Fc-effector activity, in contrast to those with poor Fc function, delay mortality and/or improve survival of SARS-CoV-2-challenged K18-hACE2 mice. The impact of innate immune cells on CCP efficacy depended on their residual neutralizing activity. Fractionation of a selected CCP revealed that IgG and Ig(M + A) were required during therapy, but the IgG fraction alone sufficed during prophylaxis. Finally, despite reduced neutralization, ancestral SARS-CoV-2-elicited CCPs significantly delayed Delta and Beta-induced mortality suggesting that Fc-effector functions contribute to immunity against VOCs. Thus, Fc activity of CCPs provide a second line of defense when neutralization is compromised and can serve as an important criterion for CCP selection.
Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Ratones , COVID-19/terapia , Sueroterapia para COVID-19 , Resultado del Tratamiento , Inmunoglobulina GRESUMEN
Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.
Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , COVID-19/terapia , Animales , Anticuerpos Antivirales/química , Citotoxicidad Celular Dependiente de Anticuerpos , COVID-19/mortalidad , COVID-19/prevención & control , COVID-19/transmisión , Modelos Animales de Enfermedad , Epítopos , Humanos , Inmunización Pasiva/mortalidad , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/metabolismo , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Ratones , Unión Proteica , Conformación Proteica , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sueroterapia para COVID-19RESUMEN
Neutralizing antibodies (NAbs) are effective in treating COVID-19, but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment during prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. Real-time imaging revealed that the virus spread sequentially from the nasal cavity to the lungs in mice and thereafter systemically to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days. In addition to direct neutralization, depletion studies indicated that Fc effector interactions of NAbs with monocytes, neutrophils, and natural killer cells were required to effectively dampen inflammatory responses and limit immunopathology. Our study highlights that both Fab and Fc effector functions of NAbs are essential for optimal in vivo efficacy against SARS-CoV-2.
Asunto(s)
Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Encéfalo/patología , COVID-19/inmunología , Pulmón/patología , SARS-CoV-2/fisiología , Testículo/patología , Enzima Convertidora de Angiotensina 2/genética , Animales , Anticuerpos Neutralizantes/genética , Anticuerpos Antivirales/genética , Encéfalo/virología , COVID-19/terapia , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Luciferasas/genética , Mediciones Luminiscentes , Pulmón/virología , Masculino , Ratones , Ratones Transgénicos , Testículo/virologíaRESUMEN
Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.
Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , VIH-1/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos CD4/química , Antígenos CD4/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Línea Celular , Epítopos/inmunología , Femenino , Glicoproteínas/química , Glicoproteínas/inmunología , Células HEK293 , Infecciones por VIH/virología , VIH-1/química , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Células Asesinas Naturales/inmunología , Masculino , Ratones , Ratones SCID , Modelos Animales , Conformación Proteica , Replicación Viral/efectos de los fármacos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/químicaRESUMEN
Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. We could visualize virus spread sequentially from the nasal cavity to the lungs and thereafter systemically to various organs including the brain, which culminated in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days. In addition to direct Fab-mediated neutralization, Fc effector interactions of NAbs with monocytes, neutrophils and natural killer cells were required to effectively dampen inflammatory responses and limit immunopathology. Our study highlights that both Fab and Fc effector functions of NAbs are essential for optimal in vivo efficacy against SARS-CoV-2.
RESUMEN
We used unbiased metagenomic next-generation sequencing to diagnose a fatal case of meningoencephalitis caused by St. Louis encephalitis virus in a patient from California in September 2016. This case is associated with the recent 2015-2016 reemergence of this virus in the southwestern United States.
Asunto(s)
Bronconeumonía/diagnóstico , Virus de la Encefalitis de San Luis/genética , Encefalitis de San Luis/diagnóstico , Genoma Viral , Linfoma de Células del Manto/diagnóstico , Metagenoma , Anciano , Bronconeumonía/patología , California , Virus de la Encefalitis de San Luis/clasificación , Virus de la Encefalitis de San Luis/aislamiento & purificación , Encefalitis de San Luis/líquido cefalorraquídeo , Encefalitis de San Luis/patología , Encefalitis de San Luis/virología , Resultado Fatal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfoma de Células del Manto/patología , Masculino , Filogenia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
St. Louis encephalitis virus infection was detected in summer 2015 in southern California after an 11-year absence, concomitant with an Arizona outbreak. Sequence comparisons showed close identity of California and Arizona isolates with 2005 Argentine isolates, suggesting introduction from South America and underscoring the value of continued arbovirus surveillance.