RESUMO
While the COVID-19 pandemic is causing important loss of life, knowledge of the effects of the causative SARS-CoV-2 virus on human cells is currently limited. Investigating protein-protein interactions (PPIs) between viral and host proteins can provide a better understanding of the mechanisms exploited by the virus and enable the identification of potential drug targets. We therefore performed an in-depth computational analysis of the interactome of SARS-CoV-2 and human proteins in infected HEK 293 cells published by Gordon et al. (Nature2020, 583, 459-468) to reveal processes that are potentially affected by the virus and putative protein binding sites. Specifically, we performed a set of network-based functional and sequence motif enrichment analyses on SARS-CoV-2-interacting human proteins and on PPI networks generated by supplementing viral-host PPIs with known interactions. Using a novel implementation of our GoNet algorithm, we identified 329 Gene Ontology terms for which the SARS-CoV-2-interacting human proteins are significantly clustered in PPI networks. Furthermore, we present a novel protein sequence motif discovery approach, LESMoN-Pro, that identified 9 amino acid motifs for which the associated proteins are clustered in PPI networks. Together, these results provide insights into the processes and sequence motifs that are putatively implicated in SARS-CoV-2 infection and could lead to potential therapeutic targets.
Assuntos
Betacoronavirus , Infecções por Coronavirus , Interações Hospedeiro-Patógeno/genética , Pandemias , Pneumonia Viral , Mapas de Interação de Proteínas , Algoritmos , Motivos de Aminoácidos , Betacoronavirus/química , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , COVID-19 , Análise por Conglomerados , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Ontologia Genética , Células HEK293 , Humanos , Anotação de Sequência Molecular , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/fisiologia , Proteínas/química , Proteínas/classificação , Proteínas/genética , Proteínas/metabolismo , SARS-CoV-2 , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
Trogocytosis modulates immune responses, with still unclear underlying molecular mechanisms. Using leukemia mouse models, we found that lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer (NK) and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 on the surface of NK cells, rather than being endogenously expressed, was derived entirely from leukemia cells in a SLAM receptor-dependent fashion. PD-1 acquired via trogocytosis actively suppressed NK cell antitumor immunity. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where NK cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on NK and cytotoxic T cells, reveal the immunoregulatory effect of membrane transfer occurring when immune cells contact tumor cells.
Assuntos
Leucemia , Neoplasias , Animais , Linfócitos T CD8-Positivos , Humanos , Células Matadoras Naturais , Leucemia/metabolismo , Camundongos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.