Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection

Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. This study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan -- T cell subsets decrease less than 2-fold -- and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was higher in females than in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.

The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

SARS-CoV-2 Spike protein variant D614G increases infectivity and retains sensitivity to antibodies that target the receptor binding domain

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.

Investigation of clinicopathological features and indication of endoscopic resection in young patients with intramucosal early gastric cancer / 中国肿瘤临床

Objective: To investigate clinicopathological features, risk of lymph node metastasis, and indications of endoscopic submu-cosal dissection (ESD) in young patients with intramucosal early gastric cancer (EGC). Methods: In total, 325 EGC patients who under-went radical gastrectomy and had complete clinicopathological data in Anhui Provincial Hospital from March 2009 to December 2016 were retrospectively evaluated. All patients were confirmed to have intramucosal cancer based on their postoperative pathology re-sults. The patients were assigned into two groups according to their age: young group (≤40 years) and old group (>40 years). The clini-copathological features and safety of ESD in the youth group were analyzed. Results: Among all patients with intramucosal EGC, 30 (9.2%) were in the youth group. Intramucosal cancer in the youth group occurred predominantly in women, and the pathological types were mainly undifferentiated and mixed, which were more likely to metastasize to the lymph nodes. In the youth group, EGC patients with intramucosal differentiated type, who had ESD indications, had no risk of lymph node metastasis. However, the rate of lymph node metastasis was up to 25% in intramucosal undifferentiated-type EGC patients who had expanded ESD indications. Conclusions:Young patients with intramucosal EGC have poor pathological differentiation and strong invasiveness, and ESD may be considered for the treatment of differentiated intramucosal cancer.

Endoscopic submucosal excavation for the treatment of gastric submucosal tumor originated from the muscularis propria layer / 中国医师进修杂志

Objective To evaluate surgical approach,safety and efficacy of endoscopic submucosal excavation (ESE) for the treatment of gastric submucosal tumors originated from the muscularis propria layer.Methods Fifty-three patients with submucosal tumors of the stomach diagnosed by gastroscope,were examined using endoscopic ultrasonography (EUS) from February 2012 to April 2013.The patients were completed ESE at general anesthesia.Results The diameter of the tumor was from 5 to 35 mm (median 13.2 mm).The tumors of 48 patients were complete resection,the complete resection rate was 90.6％(48/53).The operation time was from 30 to 150 min (median 45 min).Three patients (5.7％,3/53) had impulsivity hemorrhage during ESE,no patients had unmanageable hemorrhea under the gastroscope.Perforation occurred in 6 patients during ESE,perforation rate was 11.3％ (6/53),the perforation was closed by endoclip in 5 patients.Five patients with inability resection and 1 patient with perforation inability closed were treated with surgical operation.None was developed perforation postoperative and hemorrhea.Conclusion ESE is a safety and efficacy method for treating gastric submucosal tumors originating from the muscularis propria layer.

Analysis of 108 cases of submucosal tumor treated by endoscopic submucosal excavation / 中华消化杂志

Objective To evaluate the efficacy and safety of endoscopic submucosal excavation in the treatment of suhmucosal tumor.Methods From 2010 to 2013,a total of 108 cases of suhmucosal tumor detected by endoscopic,endoscopic ultrasonography and computed tomography (CT) scan,most of which grew toward the lumen,were treated by endoscopic suhmucosal excavation.After the lesions were completely excavated,pathological examination were performed.All the cases were followed up with endoscopic examination at one,three,six,12 and 24 months after operation.Results Among 108 cases of lesions,27 cases were located in esophagus,eight in cardia,59 in stomach,two in duodenum and 12 cases in rectum.The diameters of the lesions ranged from 0.5 to 5.5 cm (median 2.1 cm).Operation time was between 18 and 240 minutes (median 105 minutes).The endoscopic treatment was converted to laparoscopic operation in three cases because the submucosal tumors of gastric body growing towards outside the lumen,or adhesive to muscular layer tightly and or perforation too big to be sutured.Three cases of submucosal tumor of fundus were failed to excavate,the other 102 cases (94.44％) of lesions were completely removed.Perforation occurred in 19 cases (17.59％).The procedure was converted to laparoscopic operation in one case.Effective endoscopic suture was complered in 18 cases.The volume of haemorrhage during operation was about 0 to 50 mL and no post-operational bleeding was found.Eight cases had cervical subcutaneous emphysema.Nine cases had pneumoperitoneum.Left parotid gland swollen was found in one case.Nine cases were lost to follow up.The left 99 cases were followed up for one to 24 months and no recurrence.Conclusion ndoscopic submucosal excavation safety and effectively achieve once complete removed of the big submucosal tumor which grows towards inside the lumen,and provide complete pathologic data.