https://doi.org/10.1016/j.virol.2022.01.003

SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway

The SARS-CoV-2 Omicron variant is more immune evasive and less virulent than other major viral variants that have so far been recognized1-12. The Omicron spike (S) protein, which has an unusually large number of mutations, is considered to be the main driver of these phenotypes. Here we generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron (BA.1 lineage) in the backbone of an ancestral SARS-CoV-2 isolate, and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escaped vaccine-induced humoral immunity, mainly owing to mutations in the receptor-binding motif; however, unlike naturally occurring Omicron, it efficiently replicated in cell lines and primary-like distal lung cells. Similarly, in K18-hACE2 mice, although virus bearing Omicron S caused less severe disease than the ancestral virus, its virulence was not attenuated to the level of Omicron. Further investigation showed that mutating non-structural protein 6 (nsp6) in addition to the S protein was sufficient to recapitulate the attenuated phenotype of Omicron. This indicates that although the vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of the S protein. 

https://www.nature.com/articles/s41586-023-05697-2.pdf

Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation

Abstract Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double‐membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy‐related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome–lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS‐Cov‐2 and COVID‐19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

Autophagy in health and disease: From molecular mechanisms to therapeutic target

https://doi.org/10.1016/j.micpath.2022.105699

Unique mutations in SARS-CoV-2 Omicron subvariants' non-spike proteins: Potential impacts on viral pathogenesis and host immune evasion

Soluble arabinoxylans extracted from soft and hard wheat show a differential prebiotic effect in vitro and in vivo

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited. 

/pdf/sars-cov-2-non-structural-protein-6-triggers-nlrp3-dependent-1xvcnha0.pdf

SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1

Non-toxigenic Bacteroides fragilis is regarded as a potential candidate for probiotic owing to its various advantages We previously isolated a new strain of B fragilis (ZY-312) and verified its biosafety and capability of inhibiting the growth of pathogens in vivo However, the colonization of ZY-312 in gastrointestinal (GI) tract remains to be determined To track the colonization of ZY-312, mice were gavaged with ZY-312 labeled by means of metabolic oligosaccharide engineering and bioorthogonal click chemistry or given AF647-dibenzocyclooctyne (DIBO) directly Then the fluorescence was detected in GI tract, spleen and kidneys Results showed that ZY-312 could be labeled by metabolic oligosaccharide engineering, and the optimal incubation time with AF647-DIBO was 5 h in vitro Following oral gavage with AF647-DIBO labeled ZY-312 or AF647-DIBO alone, mice were subjected to in vivo imaging and the fluorescence intensity was similar in both groups 3 h, 6 h, and 12 h post the gavage The fluorescence of AF647-DIBO group disappeared 24 h post gavage which was probably due to the excretion via GI tract While the fluorescence of AF647-DIBO labeled ZY-312 retained in the cecum for as long as 48 h Immunofluorescence assay further confirmed that labeled ZY-312 transiently colonized not only in cecum but also in stomach, ileum and colon of mice 48 h post-gavage and that no massive accumulation of ZY-312 was detected in other organs such as kidneys and spleen In conclusion, ZY-312 could transiently colonize in GI tract, mainly in cecum, for at least 48 h, and it hardly disseminate to other organs, which shed new light on the future development of B fragilis as a probiotic product

/pdf/in-vivo-imaging-of-a-novel-strain-of-bacteroides-fragilis-4yb8g2ddgi.pdf

In vivo Imaging of a Novel Strain of Bacteroides fragilis via Metabolic Labeling.

Zinc ion as an enzyme cofactor exhibits antiviral and anti-inflammatory activity during infection, but circulating zinc ion level during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is unclear. This study aimed to evaluate serum zinc ion level in Coronavirus Disease 2019 (COVID-19) patients and healthy subjects, as well as its correlation with antibodies against SARS-CoV-2. 114 COVID-19 patients and 48 healthy subjects (38 healthy volunteers and 10 close contacts of patients with COVID-19) were included. Zinc ion concentration and levels of antibodies against SARS-CoV-2 Spike 1 + Spike 2 proteins, nucleocapsid protein, and receptor-binding domain in serum were measured. Results showed that the concentration of zinc ion in serum from COVID-19 patients [median: 6.4 nmol/mL (IQR 1.5 – 12.0 nmol/mL)] were significantly lower than that from the healthy subjects [median: 15.0 nmol/mL (IQR 11.9 – 18.8 nmol/mL)] (p < 0.001) and the difference remained significant after age stratification (p < 0.001) or when the patients were at the recovery stage (p < 0.001). Furthermore, COVID-19 patients with more severe hypozincemia showed higher levels of IgG against the receptor-binding domain of SARS-CoV-2 spike protein. Further studies to confirm the effect of zinc supplementation on improving the outcomes of COVID-19, including antibody response against SARS-CoV-2, are warranted.

/pdf/hypozincemia-in-covid-19-patients-correlates-with-stronger-3geoe5dc.pdf

Wenye Xu

Papers

SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1

In vivo Imaging of a Novel Strain of Bacteroides fragilis via Metabolic Labeling.

Hypozincemia in COVID-19 Patients Correlates With Stronger Antibody Response

322: longitudinal multi-omics reveals mechanisms underlying beneficial effects of a novel microbiome immunity formula (sim01) in covid-19 patients

874 the impact of covid-19 on early life gut microbiome: implications from two independent mother-baby dyad cohorts in the greater bay area of china