Les expériences de gain-de-fonction des virus pathogènes émergents1

Résumé Dans la nature, des virus adaptés à la transmission circulent dans les espèces animales (chauves-souris, oiseaux, rongeurs, primates, etc.). Le franchissement de la barrière des espèces peut se faire par contamination d'autres espèces animales, dont l'homme. Des manipulations génétiques ont été réalisées sur des virus sauvages pour faciliter le passage interespèces et augmenter la virulence virale. Le but était d'identifier les gènes critiques pour la pathogénicité. Ces manipulations ont été réalisées sur des agents pathogènes potentiellement épidémiques, comme Myxovirus influenzae de la grippe aviaire et les coronavirus des épidémies de SRAS et de MERS. Ces expériences dangereuses ont fait l'objet d'un moratoire aux États-Unis (2014-2017). Trois ans après l'émergence du Covid-19, l'origine du SARS-CoV2 d'emblée très contagieux reste un mystère. Il existe deux scénarios pour expliquer son émergence. Les partisans de l'origine naturelle avancent que le virus de la chauve-souris aurait pu infecter directement l'homme, se propageant silencieusement à un faible niveau chez l'homme pendant des années, sans éliminer l'existence d'hôtes intermédiaires non détectés. Cela n'explique pas l'origine à Wuhan, loin des réservoirs naturels de virus. Le site furin serait apparu spontanément à partir d'autres coronavirus. Le scénario alternatif est celui d'un accident de laboratoire à Wuhan, après des expériences de gain-de-fonction à partir d'un SARS-like CoV, voire même la survenue d'une contamination humaine par un virus CoV sauvage recuilli sur le terrain, lors de cultures cellulaires ou des tests sur les animaux à Wuhan. Summary In nature, viruses are well-adapted to transmission in wild animal species (bats, birds, rodents, primates...). The crossing of the species barrier can be done by contamination of other animal species, including humans. Genetic manipulations have been carried out on wild viruses to facilitate interspecies passage and increase viral virulence. The aim was to identify genes critical for pathogenicity. These manipulations have been performed on potentially epidemic pathogens, such as Myxovirus influenzae from avian influenza and coronaviruses from the SARS and MERS epidemics. These dangerous experiments were placed under a moratorium in the United States (2014-2017). Three years after the emergence of Covid-19, the origin of the highly contagious SARS-CoV2 remains a mystery. There are two scenarios to explain its emergence. Proponents of the natural origin argue that the bat virus could have directly infected humans, spreading silently at a low level in humans for years, without eliminating the possibility of undetected intermediate hosts. The furin site would have appeared spontaneously from other coronaviruses. However, this does not explain the specific origin in Wuhan, far from natural virus reservoirs. The alternative scenario is that of a laboratory accident in Wuhan, after gain-of-function experiments with an SARS-like CoV, or even the occurrence of human contamination by a wild CoV virus collected in the field, during cell cultures or animal tests in Wuhan.

Immunoregulatory role of nucleated erythroid cells

Nucleated erythroid cells (NEC) are the precursors of the most massive population of human cells – erythrocytes, for which functions of hemo- and immunoregulation have been shown at various stages of ontogenesis and in various organs and tissues of the human body. NEC perform this function by secreting cytokine proteins, growth factors, enzymes such as arginase-2, ROS, and by surface molecules PD-L1 and PD-L2. Their important regulatory role has been shown for the formation of fetoplacental immunosuppression, immunosuppression during pregnancy, suppression of the response against commensals in the gastrointestinal tract, in the pathogenesis of bacterial and viral infections in adults, in the pathogenesis of tumor growth and autoimmune diseases, as well as participation in the recognition of pathogen-associated molecular patterns using Toll-like receptors in fish and birds. Such qualities, together with their number and width of distribution, represent NEC as active participants in hemo- and immunoregulation, which makes it important to study their regulatory role in health and disease.

An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity.

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

Molecular Mechanisms of the Toll-Like Receptor, STING, MAVS, Inflammasome, and Interferon Pathways.

Pattern recognition receptors (PRRs) form the front line of defense against pathogens. Many of the molecular mechanisms that facilitate PRR signaling have been characterized in detail, which is critical for the development of accurate PRR pathway models at the molecular interaction level. These models could support the development of therapeutics for numerous diseases, including sepsis and COVID-19. This review describes the molecular mechanisms of the principal signaling interactions of the Toll-like receptor, STING, MAVS, and inflammasome pathways. A detailed molecular mechanism network is included as Data Set S1 in the supplemental material.

COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception-A Systematic Review.

Clinical reports of neurological manifestations associated with severe coronavirus disease 2019 (COVID-19), such as acute ischemic stroke (AIS), encephalopathy, seizures, headaches, acute necrotizing encephalitis, cerebral microbleeds, posterior reversible leukoencephalopathy syndrome, hemophagocytic lymphohistiocytosis, peripheral neuropathy, cranial nerve palsies, transverse myelitis, and demyelinating disorders, are increasing rapidly. However, there are comparatively few studies investigating the potential impact of immunological responses secondary to hypoxia, oxidative stress, and excessive platelet-induced aggregation on the brain. This scoping review has focused on the pathophysiological mechanisms associated with peripheral and consequential neural (central) inflammation leading to COVID-19-related ischemic strokes. It also highlights the common biological processes shared between AIS and COVID-19 infection and the importance of the recognition that severe respiratory dysfunction and neurological impairments associated with COVID and chronic inflammation [post-COVID-19 neurological syndrome (PCNS)] may significantly impact recovery and ability to benefit from neurorehabilitation. This study provides a comprehensive review of the pathobiology of COVID-19 and ischemic stroke. It also affirms that the immunological contribution to the pathophysiology of COVID-19 is predictive of the neurological sequelae particularly ischemic stroke, which makes it the expectation rather than the exception. This work is of fundamental significance to the neurorehabilitation community given the increasing number of COVID-related ischemic strokes, the current limited knowledge regarding the risk of reinfection, and recent reports of a PCNS. It further highlights the need for global collaboration and research into new pathobiology-based neurorehabilitation treatment strategies and more integrated evidence-based care.