Overexpression of USP8 inhibits inflammation and ferroptosis in chronic obstructive pulmonary disease by regulating the OTUB1/SLC7A11 signaling pathway.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a familiar disease, and owns high morbidity and mortality, which critically damages the health of patients. Ubiquitin-specific peptidase 8 (USP8) is a pivotal protein to join in the regulation of some diseases. In a previous report, it was determined that USP8 expression is down-regulated in LPS-treated BEAS-2B cells, and USP8 restrains inflammatory response and accelerates cell viability. However, the regulatory roles of USP8 on ferroptosis in COPD are rarely reported, and the associated molecular mechanisms keep vague. OBJECTIVE: To investigate the regulatory functions of USP8 in COPD progression. MATERIAL AND METHODS: The lung functions were measured through the Buxco Fine Pointe Series Whole Body Plethysmography (WBP). The Fe level was tested through the Fe assay kit. The protein expressions were assessed through western blot. The levels of tumor necrosis -factor-α, interleukin 6, and interleukin 8 were evaluated through enzyme-linked immunosorbent serologic assay. Cell viability was tested through CCK-8 assay. RESULTS: In this work, it was discovered that overexpression of USP8 improved lung function in COPD mice. In addition, overexpression of USP8 repressed ferroptosis by regulating glutathione peroxidase 4 and acyl-CoA synthetase long-chain family 4 expressions in COPD mice. Overexpression of USP8 suppressed inflammation in COPD mice. Furthermore, overexpression of USP8 suppressed ferroptosis in COPD cell model. At last, it was verified that overexpression of USP8 accelerated ubiquitin aldehyde-binding protein 1 (OTUB1)/solute carrier family 7 member 11 (SLC7A11) pathway. CONCLUSION: This study manifested that overexpression of USP8 restrained inflammation and ferroptosis in COPD by regulating the OTUB1/SLC7A11 signaling pathway. This discovery hinted that USP8 could be a potential target for COPD treatment.

Activated partial thromboplastin time predicts mortality in patients with severe fever with thrombocytopenia syndrome: A multicenter study in north China.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high lethality. This study aimed to determine whether prolonged activated partial thromboplastin time (APTT) predicted SFTS mortality. Methods: SFTS patients were enrolled from 6 hospitals in the north China. Subjects were divided into training cohort and 5 externally validation cohorts. The least absolute shrinkage and selection operator Cox regression model was performed to screen potential prognostic factors. Risk factors were analyzed using multivariable regression models. Prognostic models were established by Cox regression and random survival forest (RSF) methods, and evaluated regarding discrimination, validity and clinical benefit. Time-dependent receiver operating characteristic (ROC) curve was used to evaluate the predictive effectiveness of variables. Results: 1332 SFTS cases were included, in which 211 patients died. Six potential prognostic factors were screened, and pulse, breath, APTT and aspartic transaminase (AST) were independently associated with mortality in both training cohort (Yantai, N = 791) and external validation cohort (N = 541). APTT was steadily correlated with the fatality (HR: 1.039-1.144; all P < 0.01) in each five sub-validation cohorts (Dandong, Dalian, Tai'an, Qingdao and Beijing). RSF model with variables of APTT, AST, pulse and breath had considerable prognostic effectiveness, which APTT showed the highest prognostic ability with the area under the curve of 0.848 and 0.787 for 7-day and 14-day survival, respectively. Survival differences were found between high and low levels of APTT for mortality using 50s as the optimal cut-off. Conclusions: SFTS patients have prolonged APTT, which is an independent risk factor for fatality. APTT≥50s was recommended as a biomarker to remind physicians to monitor and treat patients more aggressively to improve clinical prognosis.

Increased cTnI Predicts Early Death in Patients with Severe Fever with Thrombocytopenia: A Multicenter Study in North China.

Background: Myocardial injury is common in severe fever with thrombocytopenia syndrome (SFTS) patients. Currently, research on the prognostic value of cardiac troponin I (cTnI) for predicting the mortality of SFTS patients, especially death within 7 days is limited. Methods: Between May 2011 and October 2022, clinical and laboratory data on admission of consecutive SFTS cases were collected from six medical centres in China. The clinical endpoint was in-hospital all-cause death within seven days. Risk factors of myocardial injury and death were analysed using multivariable regression models. Prognostic models were established using Cox regression and performance of indicators was evaluated in terms of calibration, discrimination. Results: A total of 1379 laboratory-confirmed patients were enrolled, in which 686 subjects were included for analysis. The median age was 66 years, with 48.1% of male. Eighty-seven patients died within seven days and 396 patients diagnosed with myocardial injury during hospitalization. Non-survivors had significant higher levels of cardiac indices than survivors, including cTnI, aspartic transaminase (AST) and lactate dehydrogenase (LDH). Elevated levels of cTnI (HR = 1.058, 95% CI:1.032-1.085), AST (HR = 1.191, 95% CI:1.150-1.234) and LDH (HR = 1.019, 95% CI:1.009-1.029) predicted risk of early in-hospital mortality. cTnI model performed best, with area under curve of 0.850 (0.774-0.926) and concordance index of 0.842, respectively. Statistical differences were found between high and low levels of cTnI for mortality (P<0.001) using 0.35 ng/mL as the optimal cut-off. Conclusion: The risk of early in-hospital death can be predicted by cTnI. Clinical doctors should remind vigilant concerning the elevation of cardiac enzyme as soon as possible.

The differences in cytokine signatures between severe fever with thrombocytopenia syndrome (SFTS) and hemorrhagic fever with renal syndrome (HFRS).

Severe fever with thrombocytopenia syndrome (SFTS) virus and hantavirus are categorized under the Bunyavirales order. The severe disease progression in both SFTS and hemorrhagic fever with renal syndrome (HFRS) is associated with cytokine storms. This study aimed to explore the differences in cytokine profiles and immune responses between the two diseases. A cross-sectional, single-center study involved 100 participants, comprising 46 SFTS patients, 48 HFRS patients, and 6 healthy controls. The study employed the Luminex cytokine detection platform to measure 48 cytokines. The differences in cytokine profiles and immune characteristics between the two diseases were further analyzed using multiple linear regression, principal component analysis, and random forest method. Among the 48 cytokines tested, 30 showed elevated levels in SFTS and/or HFRS compared to the healthy control group. Furthermore, there were 19 cytokines that exhibited significant differences between SFTS and HFRS. Random forest analysis suggested that TRAIL and CTACK were predictive of SFTS, while IL2Ralpha, MIG, IL-8, IFNalpha2, HGF, SCF, MCP-3, and PDGFBB were more common with HFRS. It was further verified by the receiver operating characteristic with area under the curve >0.8 and P-values <0.05, except for TRAIL. Significant differences were observed in the cytokine profiles of SFTS and HFRS, with TRAIL, IL2Ralpha, MIG, and IL-8 being the top 4 cytokines that most clearly distinguished the two diseases. IMPORTANCE: SFTS and HFRS differ in terms of cytokine immune characteristics. TRAIL, IL-2Ralpha, MIG, and IL-8 were the top 4 that differed markedly between SFTS and HFRS.

Development and validation of the PLNA score to predict cytokine storm in acute-phase SFTS patients: A single-center cohort study.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease known for its high mortality rate and its correlation with Cytokine Storms (CS). Timely detection of CS is crucial for improving the prognosis of the disease. The objective of this investigation was to develop a model for identifying cytokine storms in the acute phase of SFTS. METHODS: A total of 245 patients diagnosed with SFTS were included in this study between January 2020 and July 2022. Among them, 184 patients were part of the training set, while 61 patients were part of the validation set. Variables identified by LASSO were subsequently included in a multivariate logistic regression analysis to determine independent predictors. Subsequently, a nomogram was then developed to predict the likelihood of CS in SFTS patients. The predictive efficacy and clinical applicability of the nomogram model were further assessed through ROC analysis and the DCA curve. RESULTS: Following LASSO analysis, a total of 11 indicators were included in multivariate logistic regression analysis. The findings indicated that PLT (OR 0.865, P < 0.001), LDH (OR 1.002, P < 0.001), Na+ (OR 1.155, P = 0.005), and ALT (OR 1.019, P < 0.001) serve as independently predictors of CS in the acute phase of SFTS. Furthermore, a nomogram named the PLNA was constructed by integrating these four factors. The PLNA model exhibited favorable predictive accuracy with an AUC of 0.958. Moreover, the PLNA model exhibited excellent clinical applicability in both the training and validation sets, as evidenced by the DCA curve. CONCLUSIONS: The PLNA model, constructed using clinical indicators, can predict the probability of cytokine storm in the acute phase of SFTS patients.

Bispecific antibodies targeting two glycoproteins on SFTSV exhibit synergistic neutralization and protection in a mouse model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.

Two noncompeting human neutralizing antibodies targeting MPXV B6 show protective effects against orthopoxvirus infections.

The recent outbreak of mpox epidemic, caused by monkeypox virus (MPXV), poses a new threat to global public health. Here, we initially assessed the preexisting antibody level to the MPXV B6 protein in vaccinia vaccinees born before the end of the immunization program and then identified two monoclonal antibodies (MAbs), hMB621 and hMB668, targeting distinct epitopes on B6, from one vaccinee. Binding assays demonstrate that both MAbs exhibit broad binding abilities to B6 and its orthologs in vaccinia (VACV), variola (VARV) and cowpox viruses (CPXV). Neutralizing assays reveal that the two MAbs showed potent neutralization against VACV. Animal experiments using a BALB/c female mouse model indicate that the two MAbs showed effective protection against VACV via intraperitoneal injection. Additionally, we determined the complex structure of B6 and hMB668, revealing the structural feature of B6 and the epitope of hMB668. Collectively, our study provides two promising antibody candidates for the treatment of orthopoxvirus infections, including mpox.

MCP-3 as a prognostic biomarker for severe fever with thrombocytopenia syndrome: a longitudinal cytokine profile study.

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is characterized by a high mortality rate and is associated with immune dysregulation. Cytokine storms may play an important role in adverse disease regression, this study aimed to assess the validity of MCP-3 in predicting adverse outcomes in SFTS patients and to investigate the longitudinal cytokine profile in SFTS patients. Methods: The prospective study was conducted at Yantai Qishan Hospital from May to November 2022. We collected clinical data and serial blood samples during hospitalization, patients with SFTS were divided into survival and non-survival groups based on the clinical prognosis. Results: The levels of serum 48 cytokines were measured using Luminex assays. Compared to healthy controls, SFTS patients exhibited higher levels of most cytokines. The non-survival group had significantly higher levels of 32 cytokines compared to the survival group. Among these cytokines, MCP-3 was ranked as the most significant variable by the random forest (RF) model in predicting the poor prognosis of SFTS patients. Additionally, we validated the predictive effects of MCP-3 through receiver operating characteristic (ROC) curve analysis with an AUC of 0.882 (95% CI, 0.787-0.978, P <0.001), and the clinical applicability of MCP-3 was assessed favorably based on decision curve analysis (DCA). The Spearman correlation analysis indicated that the level of MCP-3 was positively correlated with ALT, AST, LDH, α-HBDH, APTT, D-dimer, and viral load (P<0.01). Discussion: For the first time, our study identified and validated that MCP-3 could serve as a meaningful biomarker for predicting the fatal outcome of SFTS patients. The longitudinal cytokine profile analyzed that abnormally increased cytokines were associated with the poor prognosis of SFTS patients. Our study provides new insights into exploring the pathogenesis of cytokines with organ damage and leading to adverse effects.

The first reported cases of severe fever with thrombocytopenia syndrome virus from domestic sick camel to humans in China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with an increasing annual incidence rate. In this case report, we presented two patients infected with the SFTS virus, suggesting a potential direct transmission route from camels to humans through blood contact. Both patients developed symptoms after engaging in the slaughtering of one sick camel, while their family members living in the same environment or co-diners remained unaffected. Subsequent detection revealed a high viral load of SFTS virus, reaching 1010 viral RNA copies/ml, in the sample obtained from the sick camel. Metagenomic sequencing did not identify any other pathogens. The SFTS virus was successfully isolated from both patient and camel samples. The complete nucleotide sequences obtained from the infected patients demonstrated a remarkable 100% similarity to those found in the camel, and genetic evolution analysis classified the virus as genotype A. Additionally, partial sequences of the SFTS virus were identified in ticks captured from the camel rearing environment, however, these sequences showed only 95.9% similarity to those found in camel and humans. Furthermore, immunoglobulin M and immunoglobulin G antibodies were detected in serum samples collected from the patient. Our findings provide evidence that camel may serve as a competent reservoir for transmitting the SFTS virus to humans. Further in vitro investigations into SFTS virus infections in large animals are warranted to understand their role in viral maintenance and transmission.

Identification of CCL20 as a prognostic predictor for severe fever with thrombocytopenia syndrome based on plasma proteomics.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), a lethal tick-borne hemorrhagic fever, prompted our investigation into prognostic predictors and potential drug targets using plasma Olink Proteomics. METHODS: Employing the Olink assay, we analyzed 184 plasma proteins in 30 survivors and 8 non-survivors of SFTS. Validation was performed in a cohort of 154 SFTS patients using enzyme-linked immunosorbent assay. We utilized the Drug Gene Interaction database to identify protein-drug interactions. RESULTS: Non-survivors exhibited 110 differentially expressed proteins (DEPs) compared to survivors, with functional enrichment in the cell chemotaxis-related pathway. Thirteen DEPs, including C-C motif chemokine 20 (CCL20), calcitonin gene-related peptide alpha and Pleiotrophin, were associated with multiple organ dysfunction syndrome. CCL20 emerged as the top predictor of death, demonstrating an area under the curve of 1 (P = .0004) and 0.9033 (P < .0001) in the discovery and validation cohort, respectively. Patients with CCL20 levels exceeding 45.74 pg/mL exhibited a fatality rate of 45.65%, while no deaths occurred in those with lower CCL20 levels. Furthermore, we identified 202 FDA-approved drugs targeting 37 death-related plasma proteins. CONCLUSIONS: Distinct plasma proteomic profiles characterize SFTS patients with different outcomes, with CCL20 emerging as a novel, sensitive, accurate, and specific biomarker for predicting SFTS prognosis.

Evaluation of reverse transcription loop-mediated isothermal amplification assay for the detection of severe fever with thrombocytopenia syndrome in clinical laboratories: A single-center study.

Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease prevalent in East Asia with a high mortality rate (5%-30%). Reverse transcription loop-mediated isothermal amplification (RT-LAMP), a rapid nucleic acid-based diagnostic technique, is a useful alternative for the clinical diagnosis of SFTS, particularly in resource-limited hospitals or rural clinics in SFTS virus-endemic regions. However, the actual clinical sensitivity and specificity of RT-LAMP remain unclear. This study evaluated the field application of RT-LAMP. This prospective field study included 130 patients with laboratory-confirmed SFTS from Yantai, Shandong Province, China. Two sets of RT-LAMP primers were validated, and one set of RT-LAMP assays was optimized for field detection. Nucleic acids of serially collected serum/plasma samples were identified using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and RT-LAMP. In laboratory tests, we optimized the detection time of primer set 2 for the RT-LAMP to 60 min. Notably, the onsite testing of 279 plasma samples from patients with SFTS revealed that the sensitivity and specificity of the test were 81.9% and 96.3%, respectively. We also analyzed samples with different durations of the disease, and our study showed that the sensitivity of RT-LAMP detection at the beginning of admission was 89.92%. Univariate analysis showed that the detection rate of RT-LAMP was similar to that of RT-qPCR in the first 5 days of the disease course and was lower than that of RT-qPCR on Days 6 and 14-15 of the disease course. The positive detection rate in patients aged ≥ 65 years was significantly higher than that in younger age groups. RT-LAMP is a simple, suitable, and rapid clinical detection method of SFTS onsite screening. It is more suitable for screening patients in the early stages of the disease and analyzing samples obtained from patients aged ≥ 65 years before the 6th day of the disease course.

Cross-species recognition of bat coronavirus RsYN04 and cross-reaction of SARS-CoV-2 antibodies against the virus.

Following the outbreak of coronavirus disease 2019 (COVID-19), several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related coronaviruses have been discovered. Previous research has identified a novel lineage of SARS-CoV-2-related CoVs in bats, including RsYN04, which recognizes human angiotensin-converting enzyme 2 (ACE2) and thus poses a potential threat to humans. Here, we screened the binding of the RsYN04 receptor-binding domain (RBD) to ACE2 orthologs from 52 animal species and found that the virus showed a narrower ACE2-binding spectrum than SARS-CoV-2. However, the presence of the T484W mutation in the RsYN04 RBD broadened its range. We also evaluated 44 SARS-CoV-2 antibodies targeting seven epitope communities in the SARS-CoV-2 RBD, together with serum obtained from COVID-19 convalescents and vaccinees, to determine their cross-reaction against RsYN04. Results showed that no antibodies, except for the RBD-6 and RBD-7 classes, bound to the RsYN04 RBD, indicating substantial immune differences from SARS-CoV-2. Furthermore, the structure of the RsYN04 RBD in complex with cross-reactive antibody S43 in RBD-7 revealed a potently broad epitope for the development of therapeutics and vaccines. Our findings suggest RsYN04 and other viruses belonging to the same clade have the potential to infect several species, including humans, highlighting the necessity for viral surveillance and development of broad anti-coronavirus countermeasures.

Serological Responses after a Fourth Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis.

The humoral immune response and safety of the fourth dose of the coronavirus disease 2019 (COVID-19) vaccine in solid organ transplant (SOT) recipients need to be fully elucidated. We conducted a systematic review and meta-analysis to assess the efficacy and safety associated with this additional dose of the COVID-19 vaccine in the SOT recipients. A comprehensive search was conducted to identify studies on SOT patients without prior natural SARS-CoV-2 infection who received the fourth dose of the COVID-19 vaccine. Serological antibody responses following vaccination were synthesized by a meta-analysis of proportions. The proportions for each outcome were integrated by using a random-effects model. Approximately 56-92% of the SOT patients developed a humoral immune response, and the pooled seroprevalence rate was 75% (95% confidence interval [CI], 62-82%) after administering the third vaccine dose. Following the fourth dose of vaccination, approximately 76-95% of the patients developed a humoral immune response. The pooled seroprevalence rate after the fourth dose was 85% (95% CI, 79-91%). Of the patients who initially tested seronegative after the second dose, approximately 22-76% of patients subsequently became seropositive after the third dose. The pooled seroconversion rate for the third dose was 47% (95% CI, 31-64%). Among the patients who were seronegative after the third dose, approximately 25-76% turned seropositive after the fourth dose. The pooled seroconversion rate after the fourth dose was 51% (95% CI, 40-63%). Safety data were reported in three studies, demonstrating that adverse effects following the fourth dose were generally mild, and patients with these adverse effects did not require hospitalization. No transplant rejection or serious adverse events were observed. A fourth dose of the COVID-19 vaccine in SOT recipients was associated with an improved humoral immune response, and the vaccine was considered relatively safe.

High C-reactive protein to lymphocyte ratio predicts mortality outcomes of patients with severe fever with thrombocytopenia syndrome: A multicenter study in China.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease caused by the SFTS virus (SFTSV). This study aimed to evaluate the predictive power of C-reactive protein to lymphocyte ratio (CLR) and establish an early-warning model for SFTS mortality. We retrospectively analyzed hospitalized SFTS patients in six clinical centers from May 2011 to 2022. The efficacy of CLR prediction was evaluated by the receiver operating characteristic (ROC) analysis. A nomogram was established and validated. Eight hundred and eighty-two SFTS patients (median age 64 years, 48.5% male) were enrolled in this study, with a mortality rate of 17.8%. The area under the ROC curve (AUC) of CLR was 0.878 (95% confidence interval [CI]: 0.850-0.903, p < 0.001), which demonstrates high predictive strength. The least absolute shrinkage and selection operator regression selected seven potential predictors. Multivariate logistic regression analysis determined three independent risk factors, including CLR, to construct the nomogram. The performance of the nomogram displayed excellent discrimination and calibration, with significant net benefits in clinical uses. CLR is a brand-new predictor for SFTS mortality. The nomogram based on CLR can serve as a convenient tool for physicians to identify critical SFTS cases in clinical practice.

Host range and structural analysis of bat-origin RshSTT182/200 coronavirus binding to human ACE2 and its animal orthologs.

Bat-origin RshSTT182 and RshSTT200 coronaviruses (CoV) from Rhinolophus shameli in Southeast Asia (Cambodia) share 92.6% whole-genome identity with SARS-CoV-2 and show identical receptor-binding domains (RBDs). In this study, we determined the structure of the RshSTT182/200 receptor binding domain (RBD) in complex with human angiotensin-converting enzyme 2 (hACE2) and identified the key residues that influence receptor binding. The binding of the RshSTT182/200 RBD to ACE2 orthologs from 39 animal species, including 18 bat species, was used to evaluate its host range. The RshSTT182/200 RBD broadly recognized 21 of 39 ACE2 orthologs, although its binding affinities for the orthologs were weaker than those of the RBD of SARS-CoV-2. Furthermore, RshSTT182 pseudovirus could utilize human, fox, and Rhinolophus affinis ACE2 receptors for cell entry. Moreover, we found that SARS-CoV-2 induces cross-neutralizing antibodies against RshSTT182 pseudovirus. Taken together, these findings indicate that RshSTT182/200 can potentially infect susceptible animals, but requires further evolution to obtain strong interspecies transmission abilities like SARS-CoV-2.

A model based on meta-analysis to evaluate poor prognosis of patients with severe fever with thrombocytopenia syndrome.

Background: Early identification of risk factors associated with poor prognosis in Severe fever with thrombocytopenia syndrome (SFTS) patients is crucial to improving patient survival. Method: Retrieve literature related to fatal risk factors in SFTS patients in the database, extract the risk factors and corresponding RRs and 95% CIs, and merge them. Statistically significant factors were included in the model, and stratified and assigned a corresponding score. Finally, a validation cohort from Yantai Qishan Hospital in 2021 was used to verify its predictive ability. Result: A total of 24 articles were included in the meta-analysis. The model includes six risk factors: age, hemorrhagic manifestations, encephalopathy, Scr and BUN. The analysis of lasso regression and multivariate logistic regression shows that model score is an independent risk factor (OR = 1.032, 95% CI 1.002-1.063, p = 0.034). The model had an area under the curve (AUC) of 0.779 (95% CI 0.669-0.889, P<0.001). The validation cohort was divided into four risk groups with cut-off values. Compared with the low-medium risk group, the mortality rate of high-risk and very high-risk patients was more significant (RR =5.677, 95% CI 4.961-6.496, P<0.001). Conclusion: The prediction model for the fatal outcome of SFTS patients has shown positive outcomes.Systematic review registration:https://www.crd.york.ac.uk/prospero/ (CRD42023453157).

Cross-reaction of current available SARS-CoV-2 MAbs against the pangolin-origin coronavirus GX/P2V/2017.

Since the identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, multiple SARS-CoV-2-related viruses have been characterized, including pangolin-origin GD/1/2019 and GX/P2V/2017. Our previous study indicated that both viruses have the potential to infect humans. Here, we find that CB6 (commercial name etesevimab), a COVID-19 therapeutic monoclonal antibody (MAb) developed by our group, efficiently inhibits GD/1/2019 but not GX/P2V/2017. A total of 50 SARS-CoV-2 MAbs divided into seven groups based on their receptor-binding domain (RBD) epitopes, together with the COVID-19 convalescent sera, are systematically screened for their cross-binding and cross-neutralizing properties against GX/P2V/2017. We find that GX/P2V/2017 displays substantial immune difference from SARS-CoV-2. Furthermore, we solve two complex structures of the GX/P2V/2017 RBD with MAbs belonging to RBD-1 and RBD-5, providing a structural basis for their different antigenicity. These results highlight the necessity for broad anti-coronavirus countermeasures and shed light on potential therapeutic targets.

Eosinophils and basophils in severe fever with thrombocytopenia syndrome patients: Risk factors for predicting the prognosis on admission.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne phlebovirus with a high fatality rate. Previous studies have demonstrated the poor prognostic role of eosinophils (EOS) and basophils (BAS) in predicting multiple viral infections. This study aimed to explore the role of EOS and BAS in predicting prognosis of patients with SFTS. METHODOLOGY: A total of 194 patients with SFTS who were admitted to Yantai City Hospital from November 2019 to November 2021 were included. Patients' demographic and clinical data were collected. According to the clinical prognosis, they were divided into survival and non-survival groups. Independent risk factors were determined by univariate and multivariate logistic regression analyses. FINDINGS: There were 171 (88.14%) patients in the survived group and 23 (11.86%) patients in the non-survived group. Patients' mean age was 62.39 ± 11.85 years old, and the proportion of males was 52.1%. Older age, neurological manifestations, hemorrhage, chemosis, and increased levels of laboratory variables, such as EOS% and BAS% on admission, were found in the non-survival group compared with the survival group. EOS%, BAS%, aspartate aminotransferase (AST), direct bilirubin (DBIL), and older age on admission were noted as independent risk factors for poor prognosis of SFTS patients. The combination of the EOS% and BAS% had an area under the curve (AUC) of (0.82; 95% CI: 0.725, 0.932, P = 0.000), which showed an excellent performance in predicting prognosis of patients with SFTS compared with neutrophil-to-lymphocyte ratio (NLR), and both exhibited a satisfactory performance in predicting poor prognosis compared with De-Ritis ratio (AST/alanine aminotransferase (ALT) ratio). EOS% and BAS% were positively correlated with various biomarkers of tissue damage and the incidence of neurological complications in SFTS patients. CONCLUSION: EOS% and BAS% are effective predictors of poor prognosis of patients with early-stage SFTS. The combination of EOS% and BAS% was found as the most effective approach.

Epidemiological and clinical characteristics of vaccinated COVID-19 patients: A meta-analysis and systematic review.

OBJECTIVE: With the global epidemic of coronavirus disease 2019 (COVID-19), vaccination rates are increasing globally. This study evaluated the relevant clinical manifestations of vaccinated COVID-19 patients. METHODS: We searched carefully in 11 databases such as PubMed, Embase, Scopus, Cochrane Library, Web of Science, Ovid, China National Knowledge Infrastructure Database, Wan Fang Data, Sinomed, VIP Database, and Reading Showing Database up to 26 March 2022. To search for articles that have described the characteristics of vaccinated patients including epidemiological and clinical symptoms. Statistical analysis of the extracted data using STATA 14.0. RESULTS: A total of 58 articles and 263,708 laboratory-confirmed COVID-19 patients were included. Most of the patients in the vaccinated group had more asymptomatic infection and fewer severe illnesses. There were significant differences in ethnicity, and strain infected with COVID-19, and comorbidities (hyperlipidemia, diabetes, obesity, kidney disease, immunocompromised, cardiovascular disease, and tumor) and symptoms (fever, cough, gastrointestinal symptoms, neurological symptoms, and dysgeusia/anosmia) between vaccinated group and unvaccinated group. Oxygen support, use of steroid, days in hospital, hospital treatment, ICU treatment, death, and poor prognosis were also significantly different. CONCLUSION: Compared with the vaccinated group, patients in the unvaccinated group had a more severe clinical manifestations. Vaccines are also protective for infected people.

A neutralizing-protective supersite of human monoclonal antibodies for yellow fever virus.

The yellow fever virus (YFV) is a life-threatening human pathogen. Owing to the lack of available therapeutics, non-vaccinated individuals are at risk. Here, we isolated eight human monoclonal antibodies that neutralize YFV infection. Five recognized overlapping epitopes and exhibited potent neutralizing activity. Two (YD6 and YD73) were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model. Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre- and post-fusion states, suggesting viral inhibition by a "double-lock" mechanism. The recognition determinants for YD6 and YD73 are clustered at the premembrane (prM)-binding site. Notably, antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization, suggesting a vulnerable supersite of YFV. We provide two promising candidates for immunotherapy against YFV, and the supersite represents an ideal target for epitope-based vaccine design.