RESUMO
New therapies to treat or prevent viral infections are essential, as recently observed during the COVID-19 pandemic. Here, we propose a therapeutic strategy based on monoclonal antibodies that block the specific interaction between the host receptor Siglec-1/CD169 and gangliosides embedded in the viral envelope. Antibodies are an excellent option for treating infectious diseases based on their high specificity, strong targeting affinity, and relatively low toxicity. Through a process of humanization, we optimized monoclonal antibodies to eliminate sequence liabilities and performed biophysical characterization. We demonstrated that they maintain their ability to block viral entry into myeloid cells. These molecular improvements during the discovery stage are key if we are to maximize efforts to develop new therapeutic strategies. Humanized monoclonal antibodies targeting CD169 provide new opportunities in the treatment of infections caused by ganglioside-containing enveloped viruses, which pose a constant threat to human health. In contrast with current neutralizing antibodies that bind antigens on the infectious particle, our antibodies can prevent several types of enveloped viruses interacting with host cells because they target the host CD169 protein, thus becoming a potential pan-antiviral therapy.
Assuntos
Anticorpos Monoclonais Humanizados , Antivirais , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Animais , Tratamento Farmacológico da COVID-19 , Internalização do Vírus/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacosRESUMO
Sialic-acid-binding immunoglobulin-like lectins are cell surface immune receptors known as Siglecs that play a paramount role as modulators of immunity. In recent years, research has underscored how the underlaying biology of this family of receptors influences the outcome of viral infections. While Siglecs are needed to promote effective antiviral immune responses, they can also pave the way to viral dissemination within tissues. Here, we review how recent preclinical findings focusing on the interplay between Siglecs and viruses may translate into promising broad-spectrum therapeutic interventions or key biomarkers to monitor the course of viral infections.
Assuntos
Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Viroses , Humanos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Viroses/genéticaRESUMO
Several Ebola viruses cause outbreaks of lethal haemorrhagic fever in humans, but developing therapies tackle only Zaire Ebola virus. Dendritic cells (DCs) are targets of this infection in vivo. Here, we found that Ebola virus entry into activated DCs requires the sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169), which recognizes sialylated gangliosides anchored to viral membranes. Blockage of the Siglec-1 receptor by anti-Siglec-1 monoclonal antibodies halted Ebola viral uptake and cytoplasmic entry, offering cross-protection against other ganglioside-containing viruses such as human immunodeficiency virus type 1.
Assuntos
Anticorpos Monoclonais/farmacologia , Citoplasma/virologia , Ebolavirus/fisiologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Gangliosídeos/metabolismo , HIV-1/fisiologia , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Interferon-alfa/farmacologia , Lipopolissacarídeos/farmacologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Vírion/metabolismoAssuntos
Células Dendríticas/metabolismo , Células Dendríticas/virologia , SARS-CoV-2/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/virologia , Linhagem Celular , Humanos , Ácido N-Acetilneuramínico/metabolismo , Receptores de Coronavírus/metabolismoRESUMO
BACKGROUND: Chagas disease is caused by Trypanosoma cruzi, and humans acquire the parasite by exposure to contaminated feces from hematophagous insect vectors known as triatomines. Triatoma virus (TrV) is the sole viral pathogen of triatomines, and is transmitted among insects through the fecal-oral route and, as it happens with T. cruzi, the infected insects release the virus when defecating during or after blood uptake. METHODS: In this work, we analysed the occurrence of anti-TrV antibodies in human sera from Chagas disease endemic and non-endemic countries, and developed a mathematical model to estimate the transmission probability of TrV from insects to man, which ranged between 0.00053 and 0.0015. RESULTS: Our results confirm that people with Chagas disease living in Bolivia, Argentina and Mexico have been exposed to TrV, and that TrV is unable to replicate in human hosts. CONCLUSIONS: We presented the first experimental evidence of antibodies against TrV structural proteins in human sera.