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1.
Nat Microbiol ; 9(9): 2383-2394, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39179693

RESUMO

Severe coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral divergence were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titres and decreased morbidity compared with the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but dissemination from the CNS to the lung required the intact FCS. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization.


Assuntos
COVID-19 , Sistema Nervoso Central , Pulmão , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Tropismo Viral , Animais , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Camundongos , COVID-19/virologia , Pulmão/virologia , Pulmão/patologia , Sistema Nervoso Central/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Furina/metabolismo , Furina/genética , Virulência , Humanos , Mutação , Evolução Molecular , Feminino , Modelos Animais de Doenças
2.
J Immunol ; 213(5): 612-618, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39007643

RESUMO

Breast milk confers multiple benefits to the neonate, including passive immunity against multiple microorganisms via Abs. However, it remains unclear whether breast milk-derived Abs affect vaccine-induced immunity in the neonate. We evaluated in C57BL/6 and BALB/c mice whether breastfeeding from an mRNA-SARS-CoV-2-vaccinated dam affects vaccine-induced immunity in neonate mice. Using an experimental model that allows the distinction of maternal Abs and neonate Abs based on their allotype, we show that breastfeeding from an immune dam is associated with reduced vaccine immunity in the neonate. Importantly, mice that breastfed from an immune dam showed reduced numbers of plasma cells after vaccination, relative to mice that breastfed from a naive dam. Our subsequent studies using an mRNA-luciferase reporter system show that passive transfer of Abs through breastfeeding accelerates the clearance of vaccine Ag in suckling mice, resulting in reduced Ag availability. Altogether, maternal Abs transferred through breast milk can protect against infectious microorganisms, but they may also interfere with the neonate's response to vaccination by accelerating the clearance of vaccine Ag. These findings are important for understanding the effects of maternal Abs on the neonate's response to vaccines and may provide insights for improving neonatal vaccines.


Assuntos
Animais Recém-Nascidos , Imunidade Materno-Adquirida , Camundongos Endogâmicos BALB C , Leite Humano , Animais , Camundongos , Feminino , Imunidade Materno-Adquirida/imunologia , Leite Humano/imunologia , Animais Lactentes/imunologia , Camundongos Endogâmicos C57BL , Vacinação , Humanos , Aleitamento Materno
3.
J Clin Invest ; 134(15)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38861331

RESUMO

Viral vectors are being used for the treatment of cancer. Yet, their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1-/- mice and MyD88-/- mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single-cell RNA sequencing analyses, antibody blockade experiments, and knockout models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.


Assuntos
Vetores Genéticos , Interferon Tipo I , Vírus da Coriomeningite Linfocítica , Camundongos Knockout , Animais , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Interferon Tipo I/imunologia , Interferon Tipo I/genética , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Humanos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/terapia , Neoplasias Experimentais/patologia , Proteínas de Homeodomínio
4.
bioRxiv ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38496467

RESUMO

mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccinated mice with an mRNA vaccine encoding the SARS-CoV-2 spike antigen like the Moderna and Pfizer-BioNTech vaccines, followed by administration of 4-1BB costimulatory antibodies at various times post-vaccination. Administering 4-1BB costimulatory antibodies during the priming phase did not enhance immune responses. However, administering 4-1BB costimulatory antibodies after 96 hours elicited a significant improvement in CD8 T cell responses, leading to enhanced protection against breakthrough infections. A similar improvement in immune responses was observed with multiple mRNA vaccines, including vaccines against common cold coronavirus, human immunodeficiency virus (HIV), and arenavirus. These findings demonstrate a time-dependent effect by 4-1BB costimulation and provide insights for developing improved mRNA vaccines.

5.
bioRxiv ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38106001

RESUMO

Viral vectors are being used for the treatment of cancer. Yet their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this novel vector results in improved tumor control and survival. Importantly, r3LCMV also improved tumor control in immunodeficient Rag1-/- mice. Single cell RNA-Seq analyses, antibody blockade experiments, and KO models revealed a critical role for host IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by a replication-attenuated LCMV vector and unveil mechanisms underlying its antitumoral efficacy.

6.
Res Sq ; 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37790412

RESUMO

Severe COVID-19 and post-acute sequelae of SARS-CoV-2 infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here, we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral diversity were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the Spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titers and decreased morbidity compared to the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but this required reversion of the FCS deletion. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization with possible implications for the treatment of neuroinvasive COVID-19.

7.
Cell Rep ; 42(3): 112167, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36857186

RESUMO

mRNA vaccines are effective in preventing severe COVID-19, but breakthrough infections, emerging variants, and waning immunity warrant the use of boosters. Although mRNA boosters are being implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we report that lower antibody levels before boost are associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the immunogenicity of mRNA vaccines. Our studies in mice show that pre-existing antibodies accelerate the clearance of vaccine antigen via Fc-dependent mechanisms, limiting the amount of antigen available to prime B cell responses after mRNA boosters. These data demonstrate a "tug of war" between pre-existing antibody responses and de novo B cell responses following mRNA vaccination, and they suggest that transient downmodulation of antibody effector function may improve the efficacy of mRNA boosters.


Assuntos
Vacina BNT162 , COVID-19 , Animais , Humanos , Camundongos , COVID-19/prevenção & controle , Imunização Secundária , Anticorpos , RNA Mensageiro/genética , Vacinas de mRNA , Anticorpos Antivirais , Anticorpos Neutralizantes
8.
J Clin Invest ; 132(23)2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36219482

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19.


Assuntos
Anticorpos Monoclonais , COVID-19 , Nucleocapsídeo , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais , COVID-19/terapia , Vacinas contra COVID-19 , Nucleocapsídeo/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia
9.
Front Immunol ; 13: 908707, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958615

RESUMO

T cell-based therapies have been widely explored for the treatment of cancer and chronic infection, but B cell-based therapies have remained largely unexplored. To study the effect of B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer of virus-specific B cells resulted in increase in antibody titers and reduction of viral loads. Importantly, the efficacy of B cell therapy was partly dependent on antibody effector functions, and was improved by co-transferring virus-specific CD4 T cells. These findings provide a proof-of-concept that adoptive B cell therapy can be effective for the treatment of chronic infections, but provision of virus-specific CD4 T cells may be critical for optimal virus neutralization.


Assuntos
Coriomeningite Linfocítica , Animais , Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia Adotiva , Coriomeningite Linfocítica/terapia , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos C57BL
10.
bioRxiv ; 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35794898

RESUMO

mRNA vaccines have shown high efficacy in preventing severe COVID-19, but breakthrough infections, emerging variants and waning antibody levels have warranted the use of boosters. Although mRNA boosters have been widely implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we observed that lower antibody levels before boost were associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the boosting capacity of mRNA vaccines. Mechanistic studies in mice show that pre-existing antibodies significantly limit antigen expression and priming of B cell responses after mRNA vaccination. Furthermore, we demonstrate that the relative superiority of an updated Omicron vaccine over the original vaccine is critically dependent on the serostatus of the host. These data demonstrate that pre-existing immunity dictates responses to mRNA vaccination, elucidating specific circumstances when updated SARS-CoV-2 vaccines confer superior protection to original vaccines.

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