Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.

BACKGROUND AND PURPOSE: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections. EXPERIMENTAL APPROACH: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models. KEY RESULTS: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage. CONCLUSION AND IMPLICATIONS: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Moving between experiences and new psychoanalytic frontiers

This article aims to dialogue with psychoanalysis in a frontier zone to show how a fundamental concept, such as the unconscious, has been transformed and expanded throughout the history of the psychoanalytic movement. Also, in the border area, we highlight Freud's thinking when he analyzes the civilization and its discontents, indicating that, considering the Covid-19 pandemic, we believe that we are living under the same aegis of the three sources of suffering mentioned in that work. Issues such as our own helplessness and our patients' helplessness, the impossibility of maintaining the traditional asymmetry, as well as the necessary adaptations to non-face-to-face sessions, are some of the topics addressed. We present theoretical perspectives that examine the mental state produced by the "overlapping worlds phenomenon", when the material brought to the session touches elements common to the lives of both patient and analyst. Clinical vignettes are introduced to illustrate this phenomenon Another frontier is also presented, which its heuristic value concerns the support of the articulator of uncertainty, understood as what presents itself as the new, the unpredictable, and its status and contribution to the psychoanalytic theory. The article ends by presenting a vivid picture of the reactions of patients and analysts, the framework and the analytical fields, from the beginning of the pandemic to the present moment. (PsycInfo Database Record (c) 2022 APA, all rights reserved) (Portuguese) O presente artigo visa dialogar com a psicanalise em zona de fronteira, refletindo sobre alguns temas como, por exemplo, o conceito de inconsciente e o quanto este foi se transformando e sendo ampliado ao longo da historia do movimento psicanalitico. Tambem em zona de fronteira, destacamos o pensamento de Freud quando analisa O malestar na civilizacao, indicando que, face aos acontecimentos atuais e na vigencia da pandemia Covid-19, acreditamos estar vivendo sob a egide das mesmas tres fontes de sofrimento citadas naquela obra. Questoes como o nosso proprio desamparo e o de nossos pacientes, a impossibilidade de manter a tradicional assimetria e as adaptacoes necessarias as sessoes nao presenciais sao alguns dos temas abordados. Sao apresentadas perspectivas teoricas que examinam o estado mental produzido pelo fenomeno dos mundos superpostos quando o material trazido a sessao apresenta elementos comuns a vida de ambos, paciente e analista. Vinhetas clinicas sao relatadas para ilustrar esse fenomeno acontecendo no tempo presente. Tambem e apresentada outra fronteira, cujo valor heuristico diz respeito a sustentacao do articulador incerteza, entendido como aquilo que se apresenta como o novo, o imprevisivel, e qual o seu estatuto e contribuicao para a teoria psicanalitica. O artigo finaliza apresentando um quadro vivido sobre as reacoes de pacientes e analistas, sobre o enquadre e sobre os campos analiticos desde o inicio da pandemia ate o momento atual. (PsycInfo Database Record (c) 2022 APA, all rights reserved) (Spanish) Este articulo tiene como objetivo dialogar con el psicoanalisis en territorio de frontera, reflexionando sobre algunos temas como, por ejemplo, el concepto de inconsciente y cuanto ha ido cambiando y ampliandose a lo largo de la historia del movimiento psicoanalitico. Tambien en territorio fronterizo, destacamos el pensamiento de Freud al analizar el malestar en la cultura, indicando que, dados los acontecimientos actuales y la pandemia del Covid-19, creemos que vivimos bajo la egida de las mismas tres fUentes de sufrimiento mencionadas en aquella obra. Cuestiones como nuestro propio desamparo y el de nuestros pacientes, la imposibilidad de mantener la tradicional asimetria y las adaptaciones necesarias a las sesiones no presenciales son algunos de los temas tratados. Se presentan perspectivas teoricas que examinan el estado mental producido por el "fenomeno de los mundos superpuestos" cuando el material traido a la sesion presenta elementos comunes a la vida tanto del paciente como del analista. Se relatan vinetas clinicas para ilustrar ese fenomeno que tiene lugar en el tiempo presente. Tambien se presenta otra frontera, cuyo valor heuristico concierne a la sustentacion del articulador incertidumbre, entendido como lo que se presenta como lo nuevo, lo impredecible, y cual es su estatuto y contribucion a la teoria psicoanalitica. El articulo finaliza presentando un cuadro vivido de las reacciones de pacientes y analistas, sobre el encuadre y los campos analiticos desde el inicio de la pandemia hasta el momento presente. (PsycInfo Database Record (c) 2022 APA, all rights reserved)