Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Trained immunity contributes to the prevention of Mycobacterium tuberculosis infection, a novel role of autophagy.

Mycobacterium tuberculosis (M. tuberculosis) is the pathogen which causes tuberculosis (TB), a significant human public health threat. Co-infection of M. tuberculosis and the human immunodeficiency virus (HIV), emergence of drug resistant M. tuberculosis, and failure to develop highly effective TB vaccines have limited control of the TB epidemic. Trained immunity is an enhanced innate immune response which functions independently of the adaptive/acquired immune system and responds non-specifically to reinfection with invading agents. Recently, several studies have found trained immunity has the capability to control and eliminate M. tuberculosis infection. Over the past decades, however, the consensus was adaptive immunity is the only protective mechanism by which hosts inhibit M. tuberculosis growth. Furthermore, autophagy plays an essential role in the development of trained immunity. Further investigation of trained immunity, M. tuberculosis infection, and the role of autophagy in this process provide new possibilities for vaccine development. In this review, we present the general characteristics of trained immunity and autophagy. We additionally summarize several examples where initiation of trained immunity contributes to the prevention of M. tuberculosis infection and propose future directions for research in this area.

The therapeutic promises of Lianhuaqingke in the mice model of coronavirus pneumonia (HCoV-229E and SARS-CoV-2).

BACKGROUND: Lianhuaqingke (LHQK) has been approved for the treatment of acute tracheobronchitis and exerts a broad-spectrum antiviral effect in our previous study. METHODS: Acute pneumonia caused by HCoV-229E was modeled in BALB/c mice. The anti-viral effect of LHQK was assessed by measuring the lung index and virus titer of lung tissues. The expression levels of pro-inflammatory cytokines in lung tissues and peripheral blood were measured by ELISA. The morphological changes of lung tissues were observed by H&E staining. The subsets of Th cells were assayed by the flow cytometry, including Th0, Th1, Th2, Treg, and Th17. The expression level of MUC5AC in 16HBE cells treated with TNFα was measured by ELISA. Immunofluorescence staining for ß-IV tubulin was used to identify the airway epithelial ciliary in the condition-cultured RTE cells treated with TNFα. The direct antiviral effect of LHQK was assessed in vitro in Vero E6 infected by SARS-CoV-2, validated in vivo in the COVID-19 model of hACE2 transgenic mouse by detecting the lung index, the SARS-CoV-2 virus load, and the morphological changes of lung tissues. RESULTS: LHQK reduced the weight loss and the lung index by inhibiting the HCoV-229E replication and reducing the expression of pro-inflammatory cytokines in lung tissues. An assay for the Th cell subsets in peripheral blood revealed that LHQK could reduce the ratio of Th1/Th2 and increase the Treg/Th17 ratio in a dose-dependent way, which indicated that LHQK could coordinate the Th-mediated immune responses against the virus. In in vitro injury by TNFα, LHQK inhibited MUC5AC expression in 16HBE cells and increased the number of ß-IV tubulin positive staining cells in the condition-cultured RTE cells. In the SARS-CoV-2-infected mice, LHQK could reduce weight loss, inhibit viral replication, and alleviate lung tissue damage. CONCLUSIONS: Our results demonstrate that LHQK exerts therapeutic effects on pneumonia caused by HCoVs (HCoV-229E and SARS-CoV-2) in mice, and that the anti-HCoV effects might depend on its immunomodulatory capacities. All these results suggest that LHQK serves as a potential adjuvant for anti-HCoV therapies.

Challenges Caused by Imported Cases Abroad for the Prevention and Control of COVID-19 in China.

Background: Overseas imported cases of COVID-19 continue to increase in China, so we conducted this study to review the epidemiological characteristics of these patients. Methods: From February 26 to April 4, 2020, the imported cases from abroad were enrolled in this study. The effect of prevention countermeasures in curbing the spread of COVID-19 was assessed in this study. Moreover, we defined incubation period and confirmed time as from the date of leaving the epicenter to date of symptom onset and date of final diagnosed, respectively, and the interval of symptom onset to final diagnosed time was defined as diagnostic time. Categorical variables were summarized as numbers and percentages, and the difference among the variables were analyzed. Results: For 670 cases imported from abroad, 555 were Chinese and 115 were foreigners. Apparently, confirmed cases had significantly decreased after China was compelled to temporarily suspend the entry of foreign passport holders with valid visas or residence permits; 6 days after implement of controlled measures, the daily new confirmed cases were reduced to 13 cases. Moreover, about 84.3% of patients (166/197) presented symptoms 1 week after leaving the epicenter, and notably seven patients (3.6%) had symptoms 2 weeks after leaving the epicenter. The median incubation period was 3.0 days (inter quartile range, 1.0 to 6.0), the 95th percentile was 11.6 days. Additionally, most of cases (92.9%) were detected positively of nucleic acid after symptom onset with 4 days, the median diagnostic time was 2.0 days (interquartile range, 1.0 to 3.0), and the 95th percentile of the distribution was 5.0 days. Finally, about 5.8% of patients were healthy carriers, and the median confirmed time of asymptomatic patients was 4.0 days (interquartile range, 2.0 to 9.0). The following variables might be associated with confirmed time: symptom type (P = 0.005), exported regions (P < 0.001), and symptom onset time (P < 0.001). Conclusions: The prevention countermeasures for imported cases implemented by the Chinese government played an indispensable role in curbing the spread of COVID-19; the time of departure from epicenter could provide an estimate of the incubation period; and a confirmed time, 2-week quarantine period might need to be prolonged, while asymptomatic patients should be closely monitored.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Epidemiological Characteristics and Clinical Outcomes of Coronavirus Disease Patients in Northwest China: High-Volume Research From Low Population Density Regions.

Background: Few studies have reported the transmission characteristics of coronavirus disease (COVID-19) in low-density populations. This study has therefore analyzed the epidemiological characteristics and clinical outcomes of COVID-19 patients in Northwestern China, an area with low population density. Methods: From January 21 to March 11, 2020, data from patients diagnosed with novel coronavirus pneumonia (NCP) in areas of Northwestern China with lower population densities were retrospectively analyzed. Certain variables were categorized as numbers and percentages, with the ratio between resident patients (no history of going out during the epidemic) and imported patients representing the contagiousness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19. Hospitalization time was also calculated. Results: A total of 617 COVID-19 patients were reported in Northwestern China, and the morbidity and mortality rates of 0.000005 and 0.011, respectively. Further analysis showed that the morbidity was inversely proportional to population density and distance from Wuhan City. This study enrolled 473 confirmed cases; among these patients, there were 248 residents and 225 imported cases with a ratio of 1:1. The youngest and oldest patients were 1 and 94 years of age, respectively, with a median age of 42 years. Fifteen (3.2%) patients were children or infants. Two patients were pregnant, and one patient gave birth to a healthy baby with negative results during her disease course. About 17.3% of patients (82 cases) were healthy carriers without any symptoms during their disease course. One male patient (0.2%) had recurrence of a positive test result 4 days after discharge. The median hospitalization time was 16.0 days, ranging from 2.0 to 43.0 days. Further analysis showed that age (P = 0.03) and severity status (P < 0.001) were significantly correlated with hospitalization time. Conclusions: The morbidity and mortality rates of COVID-19 patients in the regions with a low population density were lower than those of the national average in China. All populations were susceptible to infection by SARS-CoV-2. Asymptomatic patients with positive results should be taken seriously, and the hospitalization time of patients is associated with their age and severity status.

Comparative life cycle assessment of emergency disposal scenarios for medical waste during the COVID-19 pandemic in China.

The COVID-19 pandemic attracts concerns globally and leads to an exponential increase in medical waste generation, and disposal of medical waste is an urgent need for preventing the epidemic spread. Emergency disposal scenarios of medical waste generated during the COVID-19 pandemic require a systematic assessment to quantify their potential environmental impacts. The environmental impacts and key factors of three movable disposal scenarios (i.e. incineration disposal vehicle, movable steam and microwave sterilization equipment both followed by co-incineration with municipal solid waste) were quantified via life cycle assessment approach. Furthermore, the environmental impacts of three movable disposal and two co-incineration scenarios were compared via life cycle assessment by expanding system boundaries. The results show that co-incineration with municipal solid waste has the lowest environmental impacts due to environmental benefits produced by power generation, while co-incineration with hazardous waste is the highest due to the high energy consumption. Energy consumption (i.e. kerosene, electricity and diesel) are the key factors for three movable disposal scenarios. For movable steam and microwave sterilization equipment followed by co-incineration with municipal solid waste, power generation from incinerating disinfected medical waste has significant beneficial environmental impacts due to avoided impacts of electricity consumption. The recommendations for improvement of the emergency disposal and management of medical waste during the COVID-19 pandemic globally and other serious epidemic in the future are provided.