ABSTRACT
Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine IFN-{lambda} has been proposed as a possible treatment based on correlative studies in human COVID-19 patients. Here, we show IFN-{lambda} protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron)variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-{lambda}2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-{lambda} was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-{lambda} may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
ABSTRACT
SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Thus, potently neutralizing mAbs require Fc effector functions for maximal therapeutic benefit during therapy to modulate protective immune responses and mitigate lung disease.
ABSTRACT
Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.
ABSTRACT
Objective To assess the efficacy of stone fragmentation and clearance of this new intracorporeal ultrasound lithotripter (CQS-01) compared with currently available ultrasound units (EMS-Ⅲ/Ⅳ).Methods Twenty phantom stones composed of dental gypsum were randomly divided into four groups,and CQS-01 ultrasound lithotripter (70％ power and 70％ duty factor),EMS-Ⅲ ultrasound lithotripter (70％ power and 70％ duty factor),EMS-Ⅳ ultrasound lithotripter (type A,70％ power and 70％ duty factor) and EMS-Ⅳ ultrasound lithotripter (type B,70％ power and 100％ duty factor) were used to fragment and removepbantom stones.The mean stone breakdown time and fragment removal time and stone fragmental sizes for the standard ultrasound devices were compared to determine the completeness and efficiency of stone fragmentation and removal.Results The average time for stone breakdown was 7.4 ± 1.9 s,9.4 ± 1.6 s,82.2 ± 12.6 s and 51.4 ± 18.7 s,respectively.There was no significant difference between CQS-01 and EMS-Ⅲ (P ＞ 0.05),but there was significant difference between CQS-01 and EMS-Ⅳ (A or B) (P ＜ 0.001).The average time for stone clearance using the ultrasound devices was 387.8 ± 68.0 s,41 1.6 ± 57.6 s,568.0 ± 119.1 s and 383.6 ± 75.6 s,respectively.In addition,the average size of the largest fragments removed was the same among the groups (＜ 3 mm).Conclusion The ultrasound capabilities in a newly developed lithotriter (CQS-01) exhibited the same ability to fragment and clear phantom stones compared with standard ultrasound devices.
ABSTRACT
AIM: To investigate the different vasoactive effects of nitric oxide (NO) and endothelin (ET) on splanchnic arterial and venous vessels in cirrhotic rats. METHODS: Cirrhosis was induced in Wistar rats by subcutaneously administration of carbon tetrachloride. Maximal relaxation (Rmax) and contraction (Cmax) to NO and ET were determined in vitro using isolated vascular strips prepared from portal vein (PV) and mesenteric artery (MA) of both cirrhotic and normal rats, and EC50 was calculated for effects of NO and ET, respectively. RESULTS: Rmax of PV and MA to sodium nitroprusside (SNP) (releasing NO) were significantly higher in cirrhotic rats (n=8) than those in normal rats (n=7), and EC50 of NO were dramatically lower in cirrhotic rats than those in control (P
