Cannabinoid CB2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer's Disease

The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer's disease. By using a novel mouse model (CB2EGFP/f/f), we studied the distribution of cannabinoid CB2 receptors in the 5xFAD mouse model of Alzheimer's disease (by generating 5xFAD/CB2EGFP/f/f mice) and explored the roles of CB2 receptors in microglial function. We used a novel selective and brain penetrant CB2 receptor agonist (RO6866945) as well as mice lacking the CB2 receptor (5xFAD/CB2-/-) for these studies. We found that CB2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB2 receptors as potential targets for the development of amyloid-modulating therapies.Funding The present work has been supported by a grant from Ministerio de Ciencia e Innovacion (ref PID2019-108992RB-I00 and ref PID2019-107548RB-I00) to JR and PG, respectively, by the Basque Government (ref IT1230-19) to PG, and the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin to CJH

Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein

SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. The SARS-CoV-2 spike (S) glycoprotein comprises a highly conserved free fatty acid binding pocket (FABP) with unknown function and evolutionary selection advantage1,2. Deciphering FABP impact on COVID-19 progression is challenged by the heterogenous nature and large molecular variability of live virus. Here we create synthetic minimal virions (MiniVs) of wild-type and mutant SARS-CoV-2 with precise molecular composition and programmable complexity by bottom-up assembly. MiniV-based systematic assessment of S free fatty acid (FFA) binding reveals that FABP functions as an allosteric regulatory site enabling adaptation of SARS-CoV-2 immunogenicity to inflammation states via binding of pro-inflammatory FFAs. This is achieved by regulation of the S open-to-close equilibrium and the exposure of both, the receptor binding domain (RBD) and the SARS-CoV-2 RGD motif that is responsible for integrin co-receptor engagement. We find that the FDA-approved drugs vitamin K and dexamethasone modulate S-based cell binding in an FABP-like manner. In inflammatory FFA environments, neutralizing immunoglobulins from human convalescent COVID-19 donors lose neutralization activity. Empowered by our MiniV technology, we suggest a conserved mechanism by which SARS-CoV-2 dynamically couples its immunogenicity to the host immune response

Supplementary Material for: Extreme Surgical Maneuvers in Fungal Endophthalmitis

<b><i>Purpose:</i></b> To present the different evolution of 2 cases of endophthalmitis caused by Fusarium solani, an aggressive filamentous fungus, depending on the medical and surgical treatment performed. <b><i>Methods:</i></b> We present 2 cases of endophthalmitis caused by Fusarium solani. Topical, intrastromal, intravitreal, and systemic antifungal treatment (natamycin, voriconazole, amphotericin B) failed in both cases. Corneal perforation took place in one of them, being unsuccessfully treated with cyanoacrylate and several amniotic membrane transplants. It became necessary to perform a hot penetrating keratoplasty (PK) in both patients. The lenses were removed, and the microbiological analysis showed their colonization by Fusarium solani. In one of the cases, a second PK and a more aggressive pars plana vitrectomy (PPV) were performed after corneal recurrence detected by confocal microscopy, as well as the following therapeutic intra- and postoperative maneuvers: anterior chamber washing with povidone-iodine 5% for 1 min; iridectomy of the infiltrated regions; aspiration of the fungal colonies with vitrector; several air/fluid/amphotericin/voriconazole exchanges during PPV; endodiathermy and endophotocoagulation of the chorioretinitis foci; and intrascleral angle injections of voriconazole and amphotericin. <b><i>Results:</i></b> These were the only cases of endophthalmitis caused by Fusarium attended to at our hospital during the last 10 years. In the case in which PPV was performed without those maneuvers, endophthalmitis rapidly recurred in a more aggressive way, so finally it became necessary to eviscerate the globe. On the other hand, in the patient who underwent PPV with the specific surgical maneuvers and postoperative procedures described above, we could preserve the eye and even a vision of hand motion without an intraocular lens. <b><i>Conclusions:</i></b> The main objectives of these surgical procedures are to control the fungal infection and to preserve the ocular globe. It is essential to eliminate all ocular structures (iris, lens, vitreous, etc.) affected by this strain of fungus in order to reduce the risk of recurrence. When indicated, early surgery with the appropriate maneuvers detailed above may make an evisceration unnecessary and even recover some visual acuity