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- Alzheimer's Disease
- COVID-19/Coronavirus
Spike and Nsp6 Are Key Determinants of SARS-CoV-2 Omicron BA.1 Attenuation
Chen et al., Nature. 2023.
https://pubmed.ncbi.nlm.nih.gov/36630998/
The ability of the SARS-CoV-2 virus to mutate and create variants of concern demands new vaccines to control the COVID-19 pandemic. The SARS-CoV-2 Omicron variant was shown to be more immune evasive and less virulent than current major variants. The spike (S) protein in this variant carries many mutations that drive these phenotypes. Researchers generated a chimeric recombinant SARS-CoV-2 virus encoding the S gene of Omicron (BA.1 lineage) in an ancestral SARS-CoV-2 isolate and compared it with the naturally circulating Omicron variant. The Omicron S-bearing virus escaped vaccine-induced humoral immunity, owing to mutations in the receptor-binding motif. The recombinant virus replicated efficiently in distal lung cell lines and in K18-hACE2 mice. Moreover, mutations induced in non-structural protein 6 (nsp6) in addition to the S protein were sufficient to restate the attenuated phenotype of Omicron. These findings indicate that the pathogenicity of Omicron is determined by mutations both inside and outside of the S gene. Supported by ORIP (S10OD026983, S10OD030269).
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.
Chronic TREM2 Activation Exacerbates Aβ-Associated Tau Seeding and Spreading
Jain et al., Journal of Experimental Medicine. 2023.
Using a mouse model for amyloidosis in which Alzheimer’s Disease (AD)–associated tau is injected into the brain to induce amyloid β (Aβ)–dependent tau seeding/spreading, investigators found that chronic administration of an activating triggering receptor expressed on myeloid cells 2 (TREM2) antibody increases microglial activation of dystrophic neurites surrounding Aβ plaques (NP) but increases NP-tau pathology and neuritic dystrophy without altering Aβ plaque burden. These data suggest that sustained microglial activation through TREM2 that does not result in strong myeloid removal might exacerbate Aβ-induced tau pathology, which could have important clinical implications. Supported by ORIP (S10OD021629) and NIA.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.
SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19
Beckman et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111573
SARS-CoV-2 causes brain fog and other neurological complications in some patients. It has been unclear whether SARS-CoV-2 infects the brain directly or whether central nervous system sequelae result from systemic inflammatory responses triggered in the periphery. Using a rhesus macaque model, researchers detected SARS-CoV-2 in the olfactory cortex and interconnected regions 7 days after infection, demonstrating that the virus enters the brain through the olfactory nerve. Neuroinflammation and neuronal damage were more severe in elderly monkeys with type 2 diabetes. The researchers found that in aged monkeys, SARS-CoV-2 traveled farther along nerve pathways to regions associated with Alzheimer's disease. Supported by ORIP (P51OD011107) and NIA.
Distinct Sensitivities to SARS-CoV-2 Variants in Vaccinated Humans and Mice
Walls et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111299
Emergence of SARS-CoV-2 variants necessitates real-time evaluation of their impact on serum neutralizing activity, as a proxy for vaccine efficacy, to inform public health policies and guide vaccine development. The investigators report that vaccinated female BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses toward the SARS-CoV-2 Beta and Gamma variants of concern, compared with humans of both sexes and male nonhuman primates (i.e., rhesus and pigtail macaques). This finding was consistent across several vaccine modalities, doses, antigens, and assays, suggesting caution should be exercised when interpreting serum neutralizing data obtained from mice. Supported by ORIP (P51OD010425, U42OD011123) and NIAID.
Wastewater Sequencing Reveals Early Cryptic SARS-CoV-2 Variant Transmission
Karthikeyan et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-05049-6
The investigators explored the use of SARS-CoV-2 RNA concentration in wastewater as a practical approach to estimate community prevalence of COVID-19, detect emerging variants, and track regional infection dynamics. Two obstacles must be overcome to leverage wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. The investigators developed and deployed improved virus concentration protocols and deconvolution software to fully resolve multiple virus strains from wastewater. Results indicate that emerging variants of concern were detected up to 14 days earlier in wastewater samples, and multiple instances of virus spread that were not captured by clinical genomic surveillance were identified by wastewater-based genomic surveillance. The study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission. The work suggests a critical, urgently needed methodology for early detection of emerging variants and early public health interventions. Supported by ORIP (S10OD026929), and NIAID.
Durable Protection Against the SARS-CoV-2 Omicron Variant Is Induced by an Adjuvanted Subunit Vaccine
Arunachalam et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abq4130
Additional SARS-CoV-2 vaccines are needed, owing to waning immunity to the original vaccines and the emergence of variants of concern. A recent study in male rhesus macaques demonstrated durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, an oil-in-water emulsion containing α‑tocopherol. Two immunizations with the vaccine resulted in durable immunity, without cross-reactivity. Further boosting with a version of the vaccine containing the Beta variant or the ancestral RBD elicited cross-reactive immune responses that conferred protection against Omicron challenge. Supported by ORIP (P51OD011104), NCI, and NIAID.
Mosaic RBD Nanoparticles Protect Against Challenge by Diverse Sarbecoviruses in Animal Models
Cohen et al., Science. 2022.
https://www.doi.org/10.1126/science.abq0839
Two animal coronaviruses from the SARS-like betacoronavirus (sarbecovirus) lineage—SARS-CoV and SARS-CoV-2—have caused epidemics or pandemics in humans during the past 20 years. New SARS-CoV-2 variants have prolonged the COVID-19 pandemic, and the discovery of diverse sarbecoviruses in bats raises the possibility of another coronavirus pandemic. Vaccines and therapeutics are needed to protect against both SARS-CoV-2 variants and zoonotic sarbecoviruses with the potential to infect humans. The authors designed mosaic-8 nanoparticles (SARS-CoV-2 and seven animal sarbecoviruses) that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. Their results of immune responses elicited by mosaic-8 RBD nanoparticles in mice and macaques suggest that mosaic nanoparticles could protect against both SARS-CoV-2 variants and zoonotic sarbecoviruses with the potential to infect humans. Supported by ORIP (P40OD012217, U42OD021458, S10OD028685) and NIAID.
Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters
Mulka et al., The American Journal of Pathology. 2022.
https://www.doi.org/10.1016/j.ajpath.2021.10.009
To catalyze SARS-CoV-2 research, disease progression was characterized in a robust model. Male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 to track clinical, pathology, virology, and immunology outcomes. Inoculated animals lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses dominated in the lung. These lesions resolved over time. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19. Supported by ORIP (T32OD011089).