Brain Memory Signals Appear to Regulate Metabolism

 Rhythmic brain signals that help encode memories also appear to influence blood sugar levels and may regulate the timing of the release of hormones, early, pre-clinical research shows.

"Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism," senior author György Buzsáki, MD, PhD, professor, Department of Neuroscience and Physiology, NYU Grossman School of Medicine and NYU Langone Health in New York City, said in a news release.

"Evidence suggests that the brain evolved, for reasons of efficiency, to use the same signals to achieve two very different functions in terms of memory and hormonal regulation," added corresponding author David Tingley, PhD, a post-doctoral scholar in Buzsáki's lab.

Additional research may also reveal devices or therapies that can adjust the brain signals to lower blood sugar and improve memory, the researchers say.

The study was published online August 11 in Nature.

It's recently been discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles. This firing pattern is called a "sharp wave ripple" for the shape it takes when captured graphically by electroencephalogram.

In their study, Buzsáki, Tingley, and colleagues observed that clusters of sharp wave ripples recorded from the hippocampus of rats were "reliably" and rapidly, followed by decreases in blood sugar concentrations in the animals.

"This correlation was not dependent on circadian, ultradian, or meal-triggered fluctuations, it could be mimicked with optogenetically induced ripples in the hippocampus, but not in the parietal cortex, and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum (LS), the major conduit between the hippocampus and hypothalamus," the researchers report.

These observations suggest that hippocampal sharp wave ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well as other hormones by the pituitary gland, the researchers note.

As sharp wave ripples mostly occur during non-rapid eye movement sleep, the impact of sleep disturbance on sharp wave ripples may provide a mechanistic link between poor sleep and high blood sugar levels seen in type 2 diabetes, they suggest.

"There are a couple of experimental studies showing that if you deprive a young healthy person for 48 hours from sleep, their glucose tolerance resembles that of a diabetic person, Buzsáki noted in an interview with Medscape Medical News.

Moving forward, the researchers will seek to extend their theory that several hormones could be affected by nightly sharp wave ripples.

The research was funded by National Institutes of Health. The authors have disclosed no relevant financial relationships.

Nature. Published online August 11, 2021. Abstract

https://www.medscape.com/viewarticle/956562

Enhancing innate immunity against virus in times of COVID-19

 Désirée Larenas-Linnemanna *, Noel Rodríguez-Pérezb , Alfredo Arias-Cruzc , María Virginia Blandón-Vijila , Blanca E. Del Río-Navarrod , Alan Estrada-Cardonae , José E. Geredaf , Jorge A. Luna-Pechg , Elsy Maureen Navarrete-Rodríguezd , Ernesto Onuma-Takaneh , César Fireth Pozo-Beltráni and María Isabel Rojo-Gutiérrezj

DOI: http://doi.org/10.1016/j.waojou.2020.100476

PDF: https://www.worldallergyorganizationjournal.org/article/S1939-4551(20)30379-3/pdf

ABSTRACT

 Introduction: In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. 

Methods: Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Nonspecific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc). 

Results: For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence. 

Conclusion: Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.

https://www.worldallergyorganizationjournal.org/article/S1939-4551(20)30379-3/pdf

3 Doses of mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients

 DOI: 10.1056/NEJMc2108861

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMc2108861?articleTools=true

TO THE EDITOR:

A weak immune response to two doses of vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in recipients of solid-organ transplants.1,2 Severe cases of coronavirus disease 2019 (Covid-19) have also been reported in transplant recipients who had received two doses of vaccine.3 These reports prompted the French National Authority for Health to recommend the use of a third dose in immunosuppressed patients.4 Here, we report the humoral response in a group of 101 consecutive solid-organ transplant recipients (mean [±SD] age, 58±2 years; 69% were men) who were given three doses of the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). The group included 78 kidney-transplant recipients, 12 liver-transplant recipients, 8 lung-transplant or heart-transplant recipients, and 3 pancreas-transplant recipients. The first two doses were given 1 month apart, and the third dose was administered 61±1 days after the second dose. The time between transplantation and the initiation of vaccination was 97±8 months. Immunosuppression was due to the use of glucocorticoids (in 87% of patients), calcineurin inhibitors (in 79% of patients), mycophenolic acid (in 63% of patients), mammalian target of rapamycin inhibitors (in 30% of patients), and belatacept (in 12% of patients). The levels of antibodies to SARS-CoV-2 spike protein were assessed in all the patients with the use of the Wantai enzyme-linked immunosorbent assay (Beijing Wantai Biological Pharmacy Enterprise).5 Antibody titers are expressed as the ratio of the sample signal to a calibrator-assigned cutoff signal (the signal-to-cutoff ratio). According to French law, because this was an anonymous retrospective study, institutional review board approval was not required.

Figure 1.Immunogenicity.

The prevalence of anti–SARS-CoV-2 antibodies was 0% (95% confidence interval [CI], 0 to 4; 0 of 101 patients) before the first dose, 4% (95% CI, 1 to 10; 4 of 101 patients) before the second dose, 40% (95% CI, 31 to 51; 40 of 99 patients) before the third dose, and 68% (95% CI, 58 to 77; 67 of 99 patients) 4 weeks after the third dose (Figure 1). Among the 59 patients who had been seronegative before the third dose, 26 (44%) were seropositive at 4 weeks after the third dose (mean [±SD] signal-to-cutoff ratio, 690±293). All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later; their antibody titers increased from 36±12 before the third dose to 2676±350 1 month after the third dose (P<0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower estimated glomerular filtration rate than patients who had an antibody response (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). As of this writing, Covid-19 had not developed in any of the patients after they received the three vaccine doses. No serious adverse events were reported after the administration of the third dose, and no acute rejection episodes occurred.

This study showed that administration of a third dose of the BNT162b2 vaccine to solid-organ transplant recipients significantly improved the immunogenicity of the vaccine, with no cases of Covid-19 reported in any of the patients. However, a large proportion of the patients remain at risk for Covid-19. Barrier measures should be maintained, and vaccination of the relatives of these patients should be encouraged.

Nassim Kamar, M.D., Ph.D.
Florence Abravanel, Pharm.D., Ph.D.
Olivier Marion, M.D.
Chloé Couat, M.Sc.
Jacques Izopet, Pharm.D., Ph.D.
Arnaud Del Bello, M.D.
Toulouse University Hospital, Toulouse, France
kamar.n@chu-toulouse.fr

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on June 23, 2021, at NEJM.org.

https://www.nejm.org/doi/full/10.1056/NEJMc2108861

Cross-reactive antibodies against human, animal coronaviruses suggest future diagnostics

 

Shelley Klompus1,2,#, 

Sigal Leviatan1,2,#, 

1. View ORCID ProfileThomas Vogl1,2,#,*, 
2. View ORCID ProfileRoei D. Mazor3,#, 
3. View ORCID ProfileIris N. Kalka1,2, 
4. View ORCID ProfileLiat Stoler-Barak
5. 1. DOI: 10.1126/sciimmunol.abe9950
   2. 1. PDF: 
   https://immunology.sciencemag.org/content/6/61/eabe9950/tab-pdf

   Abstract

   The spillover of animal coronaviruses (aCoVs) to humans has caused SARS, MERS, and COVID-19. While antibody responses displaying cross-reactivity between SARS-CoV-2 and seasonal/common cold human coronaviruses (hCoVs) have been reported, potential cross-reactivity with aCoVs and the diagnostic implications are incompletely understood. Here, we probed for antibody binding against all seven hCoVs and 49 aCoVs represented as 12,924 peptides within a phage-displayed antigen library. Antibody repertoires of 269 recovered COVID-19 patients showed distinct changes compared to 260 unexposed pre-pandemic controls, not limited to binding of SARS-CoV-2 antigens but including binding to antigens from hCoVs and aCoVs with shared motifs to SARS-CoV-2. We isolated broadly reactive monoclonal antibodies from recovered COVID-19 patients that bind a shared motif of SARS-CoV-2, hCoV-OC43, hCoV-HKU1, and several aCoVs, demonstrating that interspecies cross-reactivity can be mediated by a single immunoglobulin. Employing antibody binding data against the entire CoV antigen library allowed accurate discrimination of recovered COVID-19 patients from unexposed individuals by machine learning. Leaving out SARS-CoV-2 antigens and relying solely on antibody binding to other hCoVs and aCoVs achieved equally accurate detection of SARS-CoV-2 infection. The ability to detect SARS-CoV-2 infection without knowledge of its unique antigens solely from cross-reactive antibody responses against other hCoVs and aCoVs suggests a potential diagnostic strategy for the early stage of future pandemics. Creating regularly updated antigen libraries representing the animal coronavirome can provide the basis for a serological assay already poised to identify infected individuals following a future zoonotic transmission event.

   
   
   https://immunology.sciencemag.org/content/6/61/eabe9950

Protective heterologous T cell immunity in COVID-19 induced by MMR, DPT vaccine antigens

 

• Vijayashree Mysore
• Xavier Cullere
• Matthew L. Settles
• Andrew H. Lichtman #
• Lara Jehi #
• Tanya N. Mayadas

DOI:https://doi.org/10.1016/j.medj.2021.08.004

PDF: https://www.cell.com/action/showPdf?pii=S2666-6340%2821%2900289-0

SUMMARY

BACKGROUND

T cells control viral infection and promote vaccine durability and in COVID-19 associate with mild disease. We investigated whether prior Measles-Mumps-Rubella (MMR) or Tetanus-Diptheria-Pertussis (Tdap) vaccination elicit cross-reactive T cells that mitigate COVID-19.

METHODS

Antigen presenting cells (APC) loaded ex vivo with SARS-CoV-2, MMR or Tdap antigens and autologous T cells from COVID-19 convalescent and uninfected individuals, and COVID-19 mRNA vaccinated donors were co-cultured and T cell activation and phenotype were detected by IFN-γ ELISpot assays and flow cytometry. ELISA assays and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and scRNA-seq identified cross-reactive T cells and their transcriptional profile. A propensity-weighted analysis of COVID-19 patients estimated the effects of MMR and Tdap vaccination on COVID-19 outcomes.

FINDINGS

High correlation was observed between T cell responses to SARS-CoV-2 (Spike-S1 and Nucleocapsid) and MMR and Tdap proteins in COVID-19 convalescent and vaccinated individuals. The overlapping T cell population contained an effector memory T cell subset (TEMRA) implicated in protective, anti-viral immunity and their detection required APC-derived IL-15, known to sensitize T cells to activation. Cross-reactive TCR repertoires detected in antigen-experienced T cells recognizing SARS-CoV-2, MMR and Tdap epitopes had TEMRA features. Indices of disease severity were reduced in MMR or Tdap vaccinated individuals by 32-38% and 20-23% respectively, among COVID-19 patients.

CONCLUSIONS

Tdap and MMR memory T cells reactivated by SARS-CoV-2 may provide protection against severe COVID-19 disease.

FUNDING

National Institutes of Health (R01HL065095, R01AI152522, R01NS097719), donation from Barbara and Amos Hostetter and the Chleck Foundation.

https://www.cell.com/med/fulltext/S2666-6340(21)00289-0#%20

Promising inhibitors could lead to new antiviral drugs to treat COVID-19

 The rapid development of safe and effective COVID-19 vaccines has been a major step forward in helping bring the pandemic under control. But with the rise of variants and an uneven global distribution of vaccines, COVID-19 is a disease that will have to be managed for some time.

Antiviral drugs that target the way the virus replicates may be the best option for treating outbreaks of COVID-19 in unvaccinated and undervaccinated populations.

Using the Canadian Light Source (CLS), a national research facility at the University of Saskatchewan, researchers from the University of Alberta isolated promising inhibitors that could be used to treat COVID-19 infections. The scientists used the synchrotron at CLS remotely during the facility's special COVID-19 call for proposals, an initiative created to support research to help fight the pandemic.

"With the help of the CLS and the multiple teams here at the U of A, including our lab and the Young lab in the Department of Biochemistry, the Vederas lab in the Department of Chemistry and the Tyrrell team in the Department of Medical Microbiology and Immunology, we've been very efficient at developing a group of inhibitors that is very promising," said Joanne Lemieux, a professor in the U of A's Faculty of Medicine & Dentistry.

The synchrotron creates light millions of times brighter than the sun that helps researchers to find very detailed information about their samples. Lemieux and colleagues used the CMCF beamline at the CLS to search for molecules that could stop SARS-CoV-2—the virus that causes COVID-19—from replicating inside human cells.

The team found inhibitors that target a special kind of protein called a protease, which is used by the virus to make more copies of itself. Proteases act like an ax and help the virus chop up large proteins. Without this protein, the virus would be unable to multiply and harm human health.

"One of the inhibitors that we used as our benchmark starting point was one that was developed to treat a feline coronavirus," Lemieux said. "This was not an optimal inhibitor given the dosage for humans, which is why new derivatives needed to be made in order to provide patients with a lower dosage."

While COVID-19 and its cousins SARS and MERS cause serious respiratory diseases, coronaviruses are also responsible for a wide range of illnesses in humans and animals. Lemieux said the proteases are very similar among the different coronaviruses.

"It's likely that any antiviral that is developed for one coronavirus would also be a broad specificity inhibitor that could treat a variety of coronavirus infections, including those found in animals," Lemieux said.

Over the past decade, oral antiviral medication has become more accessible to patients in need. There are oral protease inhibitors that treat and manage symptoms for diseases like HIV and hepatitis C. The research team wants to help make SARS-CoV-2 inhibitors available in a pill form, which would make it easier to treat COVID-19.

Lemieux's team is not alone in their quest for antivirals that will help treat diseases like COVID-19. Pfizer, the pharmaceutical company behind the successful mRNA vaccine, is moving its antivirals to Phase 1 clinical trials. Lemieux sees this as a sign that her group has been headed in the right direction.

"With many people working around the world developing antivirals targeting proteases, there is very likely to be one or more antivirals on the market," Lemieux said. "This would enable ease of accessibility for people around the world, especially in regions or populations where vaccines are not an option."

The team's findings were recently published in the European Journal of Medicinal Chemistry.

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Antiviral used to treat cat coronavirus also works against SARS-CoV-2

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More information: Wayne Vuong et al, Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies, European Journal of Medicinal Chemistry (2021). DOI: 10.1016/j.ejmech.2021.113584

https://medicalxpress.com/news/2021-08-inhibitors-antiviral-drugs-covid-.html

Polio Vaccination Induces Humoral Immune Response That Cross Reacts With SARS-CoV-2

 Brittany A. Comunale1*, Lilly Engineer1,2, Yong Jiang3, John C. Andrews4, Qianna Liu3, Lyuqing Ji3, James T. Yurkovich5, Roderick A. Comunale4 and Qiyi Xie4

DOI:  https://doi.org/10.3389/fmed.2021.710010

PDF: https://www.frontiersin.org/articles/10.3389/fmed.2021.710010/pdf

Background: Millions have been exposed to SARS-CoV-2, but the severity of resultant infections has varied among adults and children, with adults presenting more serious symptomatic cases. Children may possess an immunity that adults lack, possibly from childhood vaccinations. This retrospective study suggests immunization against the poliovirus may provide an immunity to SARS-CoV-2.

Methods: Publicly available data were analyzed for possible correlations between national median ages and epidemiological outbreak patterns across 100 countries. Sera from 204 adults and children, who were immunized with the poliovirus vaccine, were analyzed using an enzyme-linked immunosorbent assay. The effects of polio-immune serum on SARS-CoV-2-induced cytopathology in cell culture were then evaluated.

Results: Analyses of median population age demonstrated a positive correlation between median age and SARS-CoV-2 prevalence and death rates. Countries with effective poliovirus immunization protocols and younger populations have fewer and less pathogenic cases of COVID-19. Antibodies to poliovirus and SARS-CoV-2 were found in pediatric sera and in sera from adults recently immunized with polio. Sera from polio-immunized individuals inhibited SARS-CoV-2 infection of Vero cell cultures. These results suggest the anti-D3-pol-antibody, induced by poliovirus vaccination, may provide a similar degree of protection from SARS-CoV-2 to adults as to children.

Conclusions: Poliovirus vaccination induces an adaptive humoral immune response. Antibodies created by poliovirus vaccination bind the RNA-dependent RNA polymerase (RdRp) protein of both poliovirus and SARS-CoV-2, thereby preventing SARS-CoV-2 infection. These findings suggest proteins other than “spike” proteins may be suitable targets for immunity and vaccine development.

https://www.frontiersin.org/articles/10.3389/fmed.2021.710010/full