The COVID-19 Research Rundown

The grim COVID-19 pandemic shows no sign of stopping, with the Delta variant bringing new waves of infections across the world. Thankfully, the vaccination efforts are running on full throttle leading to rarer cases of adverse effects, at least amongst the vaccinated crowds (1). And now that the Pfizer mRNA vaccine has been approved by the FDA, there are not many excuses left to not be vaccinated.

On the other hand, scientists continue to extensively research meticulous aspects of the virus, revealing discoveries that are relevant to biologists and/or the public. Here, we have compiled a rundown of recent COVID19 news & research articles.

Delta & its superpower

The Delta Variant has dominated the COVID cases across the world and is still spreading rapidly. Its mutations make it 40% more efficient than the alpha variant and various studies may have figured out the secret in the change of functions that arose due to some of these mutations. The prefusion form of spike protein consists of two regions that need to be cleaved for infection to be initiated (2). One of these sites, the furin cleavage site, as the name suggests, is cut off by the protein furin in the host cells. This site gets cleaved as soon as new virions are produced, leading to pre-activated virions, ready to infect surrounding cells.

In the delta variant, this Furin site has a mutation in one single amino acid, and that makes all the difference. This change (P681R: Proline at position 681 gets replaced by Arginine) can drastically improve the infectivity of the spike protein. Moreover, this mutation also leads to infected cells fusing with non-infected cells more effectively, which further adds to its viciousness. This may not be the only secret behind Delta’s superpower but is currently one of the best bets (3).

How aging makes us prone to adverse COVID-19 effects?

Senolytics- drugs that kill senescent cells, specifically- are turning out to be a potential therapeutic against COVID-19. Our cells stop dividing after a point, as a mechanism to avoid cancer, and are said to be senescent. Around the same time, they also start secreting pro-inflammatory cytokines to signal the immune system to clear the senescent cells out. As we grow older, the immune cells (that are also aging) cannot meet the demand against the sheer number of senescent cells popping up in every tissue. Hence, they are not cleared efficiently and their default pro-inflammatory phenotype remains unhindered leading to many chronic illnesses associated with aging.

Camell et al showed that senescent cells react to pathogenic molecules (eg. TLR stimulators) more violently as compared to normal cells (4). Their hyperinflammatory state also affects the cells around them – driving secondary senescence, lowering the viral immune responses, and upregulating proteins (like ACE2) that help SARS-CoV-2 to invade. Due to these mechanisms, older mice were more susceptible to developing viral infections and subsequently dying. The solution is clear: using Senolytics. By administering Senolytics, older mice had a higher chance of recovery from the viral infections and escaping death. Hence, through this study, the researchers suggest using Senolytics in older people to alleviate COVID19 symptoms. Clinical trials are now underway.

With increase in age, the expression of ACE2 (amongst other proteins) is increased in lung epithelial cells (5). Additionally, scientists observed frequent apoptosis of infected lung epithelial cells in younger populations preventing mass production of new virions. This apoptosis efficiency is reduced in older populations.

Individuals with deleterious genes & autoantibodies- a newly discovered target

The immune attack against the incoming coronavirus involves activation of receptors (like toll-like receptors or TLRs) that sense pathogenic proteins and in turn releases lots of cytokines. Massive cohort studies recognized that populations of people with errors in a gene coding for TLR3 and TLR7 are vulnerable to severe COVID-19-induced pneumonia (6,7).

A similar study recognized that the presence of autoantibodies against Type 1 IFNs, especially IFNα and IFNω occurred in 13% of the critical COVID-19 patients (8). Type 1 IFNs are the immune system’s main weapons against viral infections and are also activated by TLR stimulation. These autoantibodies directly inhibit the activity of IFNs and in turn, lead to severe cases of COVID-19. The authors also showed how these autoantibodies increased with age, pointing to yet another reason why the elderly is much more susceptible.

The researchers recommended special attention to populations with autoantibodies – priority vaccination and immediate hospitalization on infection; screening plasma for autoantibodies before administration; and treatment with IFNβ in specific cases.

Intranasal Route-For the Win

Oral and intranasal vaccines tend to serve better against SARS-CoV-2 since they lead to the production of antibodies specialized for the mucosal membranes called IgAs. Transmissibility of the virus is dramatically reduced when IgAs are part of the antibody repertoire because the body is responding at the very early stage of disease and in the virus entry point: the respiratory pathways.

Researchers at Washington University, St. Louis have been studying a chimpanzee adenovirus-vectored vaccine that expresses the prefusion spike protein on its surface. In their most recent study, they show that administration of this vaccine not only checks all the boxes in producing long-lived & robust humoral, cellular and mucosal immunity, but the vaccine also is effective against newer variants of the virus – something that the current vaccines are having trouble with (9). Moreover, only a single intranasal vaccination can induce this protection. Clinical trials are now underway.

In a pilot study carried out on a small cohort of patients in Brazil, administration of intranasal anti-CD3 antibodies led to reduced IL-6 and CRP (C-reactive protein) in blood accompanied with markedly better lung pathology (10). Anti-CD3 when given through the mucosa can stimulate regulatory T cells which increase IL-10 production and could be the reason for alleviating COVID19 symptoms. Although, large-scale studies & better molecular insights are necessary for this novel treatment to gain more traction.

*

The exponential amount of knowledge gained about SARS-CoV-2 in less than 2 years since the outbreak is nothing less than a scientific miracle. We are still far from overcoming it but closer to getting there than any other diseases in the past. Getting vaccinated and following CDC mandates is the best we can do as citizens to support healthcare officials and scientists. 

Sources:

REFERENCES

1. Covid: CDC study shows unvaccinated people 29 times more likely to be hospitalized (cnbc.com)

2. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells: Molecular Cell

3. The mutation that helps Delta spread like wildfire (nature.com)

4. Senolytics reduce coronavirus-related mortality in old mice | Science (sciencemag.org)

5. An intranasal vaccine durably protects against SARS-CoV-2 variants in mice: Cell Reports

6. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 | Science (sciencemag.org)

7. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19 | Science Immunology (sciencemag.org)

8. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths | Science Immunology (sciencemag.org)

9. An intranasal vaccine durably protects against SARS-CoV-2 variants in mice – ScienceDirect

10. Frontiers | Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study | Immunology (frontiersin.org)

Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.

Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.

Check out Antibuddies’ blog post “The COVID-19 research rundown”.

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