Copy-editor: Rob Camp
2 March
Immunology
Paper of the Day
Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature, February 24, 2021. https://doi.org/10.1038/s41586-021-03298-5
Exercise will boost your immune system! What we all “knew” already, can now be explained. A specialized type of bone cell progenitor has been identified in the bone marrow and shown to support the generation of lymphocytes in response to movement. Bo Shen and colleagues have identified a role for movement in stimulating communication between one type of stromal cell and immune progenitors in mice, ultimately helping the animals to fight infection. The discovery that mechanosensitive osteogenic progenitors have a role in fighting infections is exciting.
Balz K, Kaushik A, Chen M, et al. Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Sci Rep February 25, 2021, 11, 4792. https://doi.org/10.1038/s41598-021-84320-8
Different systematic bioinformatic approaches were used to identify potentially cross-reactive allergen- and SARS-CoV-2-T cell epitopes. Numerous candidate epitope pairs were identified, highlighting an important role of MHC class I inhalant allergens. According to Kathrin Balz and colleagues, findings generate further hypotheses in how the adaptive immune system responds differentially with respect to the atopy status of the host. Their study warrants an immediate investigation of these predicted T cell epitopes to link their possible role in driving the immune response against SARS-CoV-2 and eventually shape the COVID-19 outcome.
Epidemiology
Lim T, Delorey M, Bestul N, et al. Changes in SARS CoV-2 Seroprevalence Over Time in Ten Sites in the United States, March – August, 2020. Clin Infect Dis. 2021 Feb 26:ciab185. PubMed: https://pubmed.gov/33639620. Full-text: https://doi.org/10.1093/cid/ciab185
In a well-designed large-scale seroprevalence study, Travis Lim and colleagues tested 78,990 specimens from ten US sites that experienced different epidemic curves, over multiple time points between March and August 2020. During this period, less than 10% of the population had detectable antibodies to SARS-CoV-2 at all sites except New York (23.2%) and Florida (13.3%).
Virology
Zhou D, Chan JF, Zhou B, et al. Robust SARS-CoV-2 Infection in Nasal Turbinates after Treatment with Systemic Neutralizing Antibodies. Cell Host Microbe February 24, 2021. Full-text: https://www.sciencedirect.com/science/article/pii/S1931312821000986?via%3Dihub
Viral infection in nasal turbinate may outcompete antibody treatment. Using a Syrian hamster model, the authors show that ZDY20, ZB8 and 2-15 (three of the most promising classes of RBD-specific human neutralizing Abs) prophylactic intraperitoneal or intranasal injection of individual HuNAb or DNA vaccination significantly reduced infection in the lungs but not in the nasal turbinates of hamsters intranasally challenged with SARS-CoV-2. Although post-challenge HuNAb therapy suppresses viral loads and lung damage, robust infection is observed in nasal turbinates treated within 1-3 days. This has significant implications for sub-protection, reinfection and vaccine.
Vaccines
Rinott E, Youngster I, Lewis YE. Reduction in COVID-19 Patients Requiring Mechanical Ventilation Following Implementation of a National COVID-19 Vaccination Program — Israel, December 2020–February 2021. MMWR Morb Mortal Wkly Rep, 26 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7009e3external icon.
Again, encouraging data from Israel. The percentage of COVID-19 patients aged ≥ 70 years requiring mechanical ventilation fluctuated during October–December 2020 but has considerably and consistently decreased after implementation of the vaccination campaign prioritizing older adults. The decline in the ratio of persons aged ≥ 70 years to those < 50 years requiring mechanical ventilation began around the time of start of administration of the second dose of vaccine (January 10, 2021).
Clinical
Cuevas AM, Clark JM, Potter JJ. Increased TLR/MyD88 signaling in patients with obesity: is there a link to COVID-19 disease severity? Int J Obes (Lond). 2021 Feb 26. PubMed: https://pubmed.gov/33637950. Full-text: https://doi.org/10.1038/s41366-021-00768-8
Why is obesity a risk factor for severe COVID-19? The authors review current knowledge and hypothesize that people with obesity, especially excess abdominal/visceral fat and associated metabolic complications, have over-expression of MyD88 in the adipose tissue and perhaps in other cells and tissues (like immune cells) that triggers an exaggerated inflammatory response of the immune system.
Severe COVID-19
Deinhardt-Emmer S, Böttcher S, Häring C, et al. SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction. J Virol 2021 Feb 26:JVI.00110-21. PubMed: https://pubmed.gov/33637603. Full-text: https://doi.org/10.1128/JVI.00110-21
To elucidate the viral effects on the barrier integrity and immune reactions, Stefanie Deinhardt-Emmer and colleagues from Jena, Germany used mono-cell culture systems and a complex human chip model composed of epithelial, endothelial, and mononuclear cells. SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including interferon expression. By contrast, the adjacent endothelial layer was not infected nor did it show productive viral replication or release of interferon. With prolonged infection, both cell types were damaged, and the barrier function was deteriorated, allowing the viral particles to have to carry too much.
Althaus K, Marini I, Zlamal J, et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood February 25, 2021, 137 (8): 1061–1071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791311/
Severe COVID-19 is associated with antibody-mediated up-regulation of platelet apoptosis. In addition, Karina Althaus and colleagues from Tübingen, Germany found a correlation between platelet apoptosis markers and SOFA score, plasma levels of D-dimer, and the incidence of thromboembolic complications in severe COVID-19 patients. These data indicate that platelet apoptosis may contribute to sustained inflammation and increased thromboembolic risk in COVID-19 patients and could potentially present a potential therapeutic target.
Treatment
Piepenbrink MS, Park JG, Oladunni FS, et al. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Reports February 24, 2021. DOI: https://doi.org/10.1016/j.xcrm.2021.100218
Antibodies delivered via inhalation for the prevention and treatment of SARS-CoV-2: Michael S. Pipenbrink from Birmingham, US shows that this works. Fully human monoclonal antibodies (hmAbs) potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, exhibited in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhaled treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung-deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration.
Bugin K, Woodcock J. Trends in COVID-19 therapeutic clinical trials. Nature Reviews Drug Discovery, 25 February 2021. https://www.nature.com/articles/d41573-021-00037-3
Janet Woodcock and Kevin Bugin have comprehensively assessed the ongoing COVID-19 therapeutic clinical development efforts worldwide. Surveying the clinical trial landscape, their most important finding is that the vast majority of trials of therapeutics for COVID-19 are not designed to yield actionable information; low randomization rates and underpowered outcome data render matters of safety and efficacy generally uninterpretable.
Milic J, Novella A, Meschiari M, et al. Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia. AIDS Res Hum Retroviruses. 2021 Feb 23. PubMed: https://pubmed.gov/33619997. Full-text: https://doi.org/10.1089/AID.2020.0305
The HIV protease inhibitor darunavir doesn’t work in COVID. Didn’t we know this already? In this retrospective study in HIV-negative patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy, patients on darunavir/c (c=cobicistat is a pharmacoenhancer) had higher rates of mortality (25% vs 10%, p < 0.0001) and of mechanical ventilation and death (37% vs. 25%, p = 0.03). Multiple serious interactions associated with darunavir/c were observed in the 19 patients who died. According to the authors, darunavir/c “should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials”. The question is: why did the authors study this now?