Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.

A gut microbial factor modulates locomotor behaviour in Drosophila.

While research into the biology of animal behaviour has primarily focused on the central nervous system, cues from peripheral tissues and the environment have been implicated in brain development and function1. There is emerging evidence that bidirectional communication between the gut and the brain affects behaviours including anxiety, cognition, nociception and social interaction1-9. Coordinated locomotor behaviour is critical for the survival and propagation of animals, and is regulated by internal and external sensory inputs10,11. However, little is known about how the gut microbiome influences host locomotion, or the molecular and cellular mechanisms involved. Here we report that germ-free status or antibiotic treatment results in hyperactive locomotor behaviour in the fruit fly Drosophila melanogaster. Increased walking speed and daily activity in the absence of a gut microbiome are rescued by mono-colonization with specific bacteria, including the fly commensal Lactobacillus brevis. The bacterial enzyme xylose isomerase from L. brevis recapitulates the locomotor effects of microbial colonization by modulating sugar metabolism in flies. Notably, thermogenetic activation of octopaminergic neurons or exogenous administration of octopamine, the invertebrate counterpart of noradrenaline, abrogates the effects of xylose isomerase on Drosophila locomotion. These findings reveal a previously unappreciated role for the gut microbiome in modulating locomotion, and identify octopaminergic neurons as mediators of peripheral microbial cues that regulate motor behaviour in animals.

Infused ice can multiply IceCube's sensitivity.

The IceCube Neutrino Observatory is the world's largest neutrino detector with a cubic-kilometer instrumented volume at the South Pole. It is preparing for a major upgrade that will significantly increase its sensitivity. A promising technological innovation investigated for this upgrade is wavelength shifting optics. Augmenting sensors with such optics could increase the photo-collection area of IceCube's digital optical modules, and shift the incoming photons' wavelength to where these modules are the most sensitive. Here we investigate the use of IceCube's drill holes as wavelength shifting optics. We calculate the sensitivity enhancement due to increasing the ice's refractive index in the holes, and infusing wavelength-shifting substrate into the ice. We find that, with adequate wavelength-shifter infusion, every ~0.05 increase in the ice's refractive index will increase IceCube's photon sensitivity by 100%, opening the possibility for the substantial, cost-effective expansion of IceCube's reach.

Environmental Stress Causes Lethal Neuro-Trauma during Asymptomatic Viral Infections.

Asymptomatic infections often proceed undetected, yet can still prime the host to be sensitive to secondary environmental stress. While the mechanisms underlying disease caused by asymptomatic infections are unknown, it is believed that productive pathogen replication is required. We report that the environmental stress of carbon dioxide (CO2) anesthesia converts an asymptomatic rhabdovirus infection in Drosophila to one that is lethal. This lethality results from a pool of infectious virus in glial cells and is regulated by the antiviral RNAi pathway of the host. CO2 sensitivity is caused by the fusogenic activity of the viral glycoprotein, which results in fusion of neurons and glia. Expression of the viral glycoprotein, but not a fusion defective mutant, is sufficient to cause CO2 sensitivity, which can occur even in the absence of productive viral replication. These findings highlight how viral proteins, independent of pathogen replication, may predispose hosts to life-threatening environmental stress.