COVID-19 Pathology Sheds Further Light on Balance between Neutrophil Proteases and Their Inhibitors.

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the concomitant release of granule contents that damage surrounding tissues into sharp focus. Neutrophil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. Interestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promotes lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) and increases the risk of allergic responses. Recent observations point to the fact that reduced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19.

Effect of Ayurvedic Intervention as an adjunct therapy in Post COVID-19 Mucormycosis (PCM): A non-randomized parallel group study.

Background: The Ayurveda therapy is often used as an adjunct to conventional allopathic treatments for management of chronic disorders including life threatening infections such as post COVID-19 Mucormycosis (PCM). Aims/objectives: The aim of the current study is to evaluate the role of adjunct Ayurveda therapy (AAT + CAT) over conventional Allopathic therapy (CAT) in the prevention of progression of oral/orbital/neural extension of PCM. Material and methods: A non-randomised parallel group interventional study was on a sample of 92 cases of PCM, sorted into two groups i.e. group A (n = 46; AAT + CAT) and group B (n = 46; CAT/controls). The group A received AAT (lab-tested standardised regimen) while simultaneously receiving conventional antifungal measures (or CAT). The outcomes assessed were clinical symptomatic grading score, Nasal endoscopic examination for patency of sinuses, Progression or extension of disease from sinuses to maxilla, orbit and brain, need of additional surgical interventions and antifungal medication after study period, adverse drug reactions and mortality. Results: The group A (AAT + CAT)) had shown extension free PCM in 86.96% (n = 40) as opposed to 41.3% (n = 19) in group B (CAT), No surgical interventions were needed in 89.13% (n = 41) in group A vs. 60.87% (n = 28) in group B. Around 69.5% (n = 32) in group A vs. 4.37% (n = 2) in group B did not need antifungal medication. The safety of both arms of the therapy has been determined by liver function and renal profile which are with in normal range in both groups. Conclusion: Adjunct Ayurveda therapy (given along with routine medical therapy) for PCM showed a better cure and reduced disease progression after a trial period of 45 days and in the extended observational period of three months. AAT + CAT regimen is not only therapeutically effective, but also safe and economical option to consider for PCM.

The importance of pets during a global pandemic: See spot play

This chapter discusses my personal experiences as a clinician who contracted COVID-19, as a director of a nonprofit animal sanctuary, and as a clinician working in animal-assisted therapy (AAT) who has had to modify her treatment model in consideration of the quarantine health mandates. Although the human-animal bond has long been acknowledged as an effective treatment model, it is still considered a burgeoning field. The current health crisis has brought the benefits of the human-animal bond to the forefront of public perception. Both zooeyia (the benefits of the human-animal bond) and zoonosis (diseases transmitted by animals) will be discussed, as well as adaptations to AAT to work with clients remotely during quarantine regulations. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Investigating the Link between Alpha-1 Antitrypsin and Human Neutrophil Elastase in Bronchoalveolar Lavage Fluid of COVID-19 Patients.

Neutrophils play a pathogenic role in COVID-19 by releasing Neutrophils Extracellular Traps (NETs) or human neutrophil elastase (HNE). Given that HNE is inhibited by α1-antitrypsin (AAT), we aimed to assess the content of HNE, α1-antitrypsin (AAT) and HNE-AAT complexes (the AAT/HNE balance) in 33 bronchoalveolar lavage fluid (BALf) samples from COVID-19 patients. These samples were submitted for Gel-Electrophoresis, Western Blot and ELISA, and proteins (bound to AAT or HNE) were identified by Liquid Chromatography-Mass Spectrometry. NETs' release was analyzed by confocal microscopy. Both HNE and AAT were clearly detectable in BALf at high levels. Contrary to what was previously observed in other settings, the formation of HNE-AAT complex was not detected in COVID-19. Rather, HNE was found to be bound to acute phase proteins, histones and C3. Due to the relevant role of NETs, we assessed the ability of free AAT to bind to histones. While confirming this binding, AAT was not able to inhibit NET formation. In conclusion, despite the finding of a high burden of free and bound HNE, the lack of the HNE-AAT inhibitory complex in COVID-19 BALf demonstrates that AAT is not able to block HNE activity. Furthermore, while binding to histones, AAT does not prevent NET formation nor their noxious activity.

Boosted Pro-Inflammatory Activity in Human PBMCs by Lipopolysaccharide and SARS-CoV-2 Spike Protein Is Regulated by α-1 Antitrypsin.

For the treatment of severe COVID-19, supplementation with human plasma-purified α-1 antitrypsin (AAT) to patients is currently considered. AAT inhibits host proteases that facilitate viral entry and possesses broad anti-inflammatory and immunomodulatory activities. Researchers have demonstrated that an interaction between SARS-CoV-2 spike protein (S) and lipopolysaccharides (LPS) enhances pro-inflammatory responses in vitro and in vivo. Hence, we wanted to understand the potential anti-inflammatory activities of plasma-derived and recombinant AAT (recAAT) in a model of human total peripheral blood mononuclear cells (PBMCs) exposed to a combination of CHO expressed trimeric spike protein and LPS, ex vivo. We confirmed that cytokine production was enhanced in PBMCs within six hours when low levels of LPS were combined with purified spike proteins ("spike"). In the presence of 0.5 mg/mL recAAT, however, LPS/spike-induced TNF-α and IL-1ß mRNA expression and protein release were significantly inhibited (by about 46-50%) relative to LPS/spike alone. Although without statistical significance, recAAT also reduced production of IL-6 and IL-8. Notably, under the same experimental conditions, the plasma-derived AAT preparation Respreeza (used in native and oxidized forms) did not show significant effects. Our findings imply that an early pro-inflammatory activation of human PBMCs is better controlled by the recombinant version of AAT than the human plasma-derived AAT used here. Considering the increasing clinical interest in AAT therapy as useful to ameliorate the hyper-inflammation seen during COVID-19 infection, different AAT preparations require careful evaluation.

Measuring Implicit Approach-Avoidance Tendencies towards Food Using a Mobile Phone outside the Lab.

Implicit ('unconscious') approach-avoidance tendencies towards stimuli can be measured using the Approach Avoidance Task (AAT). We recently expanded a toolbox for analyzing the raw data of a novel, mobile version of the AAT (mAAT), that asks participants to move their phone towards their face (pull) or away (push) in response to images presented on the phone. We here tested the mAAT reaction time and the mAAT distance in a study with 71 Dutch participants that were recruited online and performed an experiment without coming to the laboratory. The participants used both the mAAT and (explicit) rating scales to respond to photographic images of food. As hypothesized, the rated wanting, rated valence and mAAT reaction time indicated a preference for palatable over unpalatable food, and for Dutch over Asian food. Additionally, as expected, arousal was rated higher for unpalatable than for palatable food, and higher for Dutch than for Asian food. The mAAT distance indicated that the unpalatable food images were moved across larger distances, regardless of the movement direction (pull or push), compared to the palatable food images; and the Dutch food images were moved across larger distances than the Asian food images. We conclude that the mAAT can be used to implicitly probe approach-avoidance motivation for complex images in the food domain. The new measure of mAAT distance may be used as an implicit measure of arousal. The ratings and the mAAT measures do not reflect the exact same information and may complement each other. Implicit measures, such as mAAT variables, are particularly valuable when response biases that can occur when using explicit ratings are expected.

Do gene-environment interactions play a role in COVID-19 distribution? The case of Alpha-1 Antitrypsin, air pollution and COVID-19.

BACKGROUND: Gene-environment interactions are relevant for several respiratory diseases. This communication raises the hypothesis that the severity of COVID-19, a complex disease where the individual response to the infection may play a significant role, could partly result from a gene-environment interaction between air-pollution and Alpha-1 Antitrypsin (AAT) genes. METHODS: To evaluate the impact of the AAT and air pollution interaction on COVID-19, we introduced an AAT*air pollution global risk score summing together, in each country, an air pollution score (ozone, nitrogen dioxide and fine particulate matter) and an AAT score (which sums the ranked frequency of MZ, SZ, MS). We compared this global score with the ranking of European countries in terms of death number per million persons. RESULTS: The ranking of the AAT*air pollution global risk score matched the ranking of the countries in terms of the observed COVID-19 deaths per 1M inhabitants, namely in the case of the first European countries: Belgium, UK, Spain, Italy, Sweden, France. We observed parallelism between the number of COVID deaths and the AAT*air pollution global risk in Europe. AAT anti-protease, immune-modulating and coagulation-modulating activities may explain this finding, although very speculatively. CONCLUSIONS: Even if further studies taking into account genetic background, population density, temporal dynamics of individual epidemics, access to healthcare, social disparities and immunological response to SARS-CoV2 are needed, our preliminary observation urges to open a discussion on gene-environment interactions in COVID-19.

SARS-CoV-2 infection in alpha1-antitrypsin deficiency.

Alpha1-antitrypsin deficiency arises due to mutations in alpha1-antitrypsin (AAT) gene and represents the most prominent genetic predisposition to chronic obstructive pulmonary disease and emphysema. Since AAT plays important immunomodulatory and tissue-protective roles and since it was suggested to protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed this association in United Kingdom Biobank, a community-based cohort with >500,000 participants. The most common, mild AATD genotypes were associated neither with increased SARS-CoV-2 infection rates nor with increased SARS-CoV-2 fatalities, while the numbers of severe AATD cases were too low to allow definitive conclusions.

Does Genetic Predisposition Contribute to the Exacerbation of COVID-19 Symptoms in Individuals with Comorbidities and Explain the Huge Mortality Disparity between the East and the West?

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin-angiotensin-aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.

SARS-CoV-2 and the safety margins of cell-based biological medicinal products.

With the pandemic emergence of SARS-CoV-2, the exposure of cell substrates used for manufacturing of medicines has become a possibility. Cell lines used in biomanufacturing were thus evaluated for their SARS-CoV-2 susceptibility, and the detection of SARS-CoV-2 in culture supernatants by routine adventitious virus testing of fermenter harvest tested.