[Reversal Effect of NVP-BEZ235 on Doxorubicin-Resistance in Burkitt Lymphoma RAJI Cell Line].

OBJECTIVE: To study the reversal effect of NVP-BEZ235 on doxorubicin resistance in Burkitt lymphoma RAJI cell line. METHODS: The doxorubicin-resistant cell line was induced by treating RAJI cells with a concentration gradient of doxorubicin. The levels of Pgp, p-AKT, and p-mTOR in cells were detected by Western blot. Cell viability was detected by MTT assay. IC50 was computed by SPSS. RESULTS: The doxorubicin-resistant Burkitt lymphoma cell line, RAJI/DOX, was established successfully. The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. CONCLUSION: The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Corrigendum: Genomic evolution of BA.5.2 and BF.7.14 derived lineages causing SARS-CoV-2 outbreak at the end of 2022 in China.

[This corrects the article DOI: 10.3389/fpubh.2023.1273745.].

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

[Mechanism about LMP1 of EB Virus Promoting Plasma Blast Differentiation of DLBCL Cell via mTORC1].

OBJECTIVE: To investigate possible mechanism on protien LMP1 expressed by EBV inducing plasmablast differentiation of DLBCL cell via the mTORC1 pathway. METHODS: The expression levels of LMP1 protein, CD38 and the phosphorylation levels of p70S6K in EBV+ and EBV- DLBCL cell lines were detected by Western blot. Cell lines overexpressing LMP1 gene stablely were constructed and LMP1 gene was silenced by RNAi. The expression of LMP1 gene was verified by RT-qPCR. The expression levels of LMP1 and CD38 and the phosphorylation levels of p70S6K in each group were detected by Western blot. RESULTS: Compared with EBV-DLBCL cells, the expression of LMP1 was detected on EBV +DLBCL cells (P =0.0008), EBV +DLBCL cells had higher phosphorylation levels of p70S6K (P =0.0072) and expression levels of CD38(P =0.0091). Compared with vector group, the cells of LMP1OE group had higher expression levels of LMP1 and CD38 (P =0.0353; P <0.0001), meanwhile molecular p70S6K was phosphorylated much more(P =0.0065); expression of LMP1 mRNA was verified(P <0.0001). Compared with si-NC group, expression level of LMP1 protein(P =0.0129) was not detected and phosphorylated p70S6K disappeared of LMP1KO group (P =0.0228); meanwhile, expression of CD38 decreased,although there was no significant difference (P =0.2377). CONCLUSION: LMP1 promotes DLBCL cells plasmablast differentiation via activating mTORC1 signal pathway.

Synthesis of silyl indenes by ruthenium-catalyzed aldehyde- and acylsilane-enabled C-H alkylation/cyclization.

A ruthenium-catalyzed C-H alkylation/cyclization sequence is presented to prepare silyl indenes with atom and step-economy. This domino reaction is triggered by acyl silane-directed C-H activation, and an aldehyde controlled the following enol cyclization/condensation other than ß-H elimination. The protocol tolerates a broad substitution pattern, and the further synthetic elaboration of silyl indenes allows access to a diverse range of interesting indene and indanone derivatives.

Genomic evolution of BA.5.2 and BF.7.14 derived lineages causing SARS-CoV-2 outbreak at the end of 2022 in China.

Since the end of 2022, when China adjusted its COVID-19 response measures, the SARS-CoV-2 epidemic has rapidly grown in the country. It is very necessary to monitor the evolutionary dynamic of epidemic variants. However, detailed reports presenting viral genome characteristics in China during this period are limited. In this study, we examined the epidemiological, genomic, and evolutionary characteristics of the SARS-CoV-2 genomes from China. We analyzed nearly 20,000 genomes belonging to 17 lineages, predominantly including BF.7.14 (22.3%), DY.2 (17.3%), DY.4 (15.5%), and BA.5.2.48 (11.9%). The Rt value increased rapidly after mid-November 2022, reaching its peak at the end of the month. We identified forty-three core mutations in the S gene and forty-seven core mutations in the ORF1ab gene. The positive selection of all circulating lineages was primarily due to non-synonymous substitutions in the S1 region. These findings provide insights into the genomic characteristics of SARS-CoV-2 genomes in China following the relaxation of the 'dynamic zero-COVID' policy and emphasize the importance of ongoing genomic monitoring.

Kaempferol and ginsenoside Rg1 ameliorate acute hypobaric hypoxia induced lung injury based on network pharmacology analysis.

Acute hypobaric hypoxia at high altitude can cause fatal non-cardiogenic high altitude pulmonary edema. Anti-inflammatory and anti-oxidant treatments appear to be a prospective way to alleviate acute hypoxia lung injury. Kaempferol (KA) and ginsenoside Rg1 (GRg1) can be isolated and purified from ginseng with anti-inflammatory, antioxidant, anti-carcinogenic, neuroprotective, and antiaging effects. However, their effects and pharmacological mechanisms on lung injury remains unclear. Network pharmacology analyses were used to explore potential targets of KA and GRg1 against acute hypobaric hypoxia induced lung injury. Rat lung tissues were further used for animal experiment verification. Among the putative targets of KA and GRg1 for inhibition of acute hypobaric hypoxia induced lung injury, AKT1, PIK3R1, PTK2, STAT3, HSP90AA1 and AKT2 were recognized as higher interrelated targets. And PI3K-AKT signaling pathway is considered to be the most important and relevant pathway. The rat experimental results showed that KA and GRg1 significantly improved histopathological changes and decreased pulmonary edema in rats with lung injury caused by acute hypobaric hypoxia. The concentrations of IL-6, TNF-α, MDA, SOD and CAT in rats treated with KA and GRg1 were significantly ameliorated. Protein and mRNA levels of PI3K and AKTI were significantly inhibited after KA administration. KA and GRg1 can lower lung water content, improve lung tissue damage, reduce the production of pro-inflammatory cytokines and the oxidative stress level.

Single-cell transcriptomic analysis reveals a systemic immune dysregulation in COVID-19-associated pediatric encephalopathy.

Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments. Here, we utilized single-cell transcriptomic analysis and integrated clinical observations and laboratory examination to dissect the host immune responses and reveal pathological mechanisms in COVID-19-associated pediatric encephalopathy. We found that lymphopenia was a prominent characteristic of immune perturbation in COVID-19 patients with encephalopathy, especially those with acute necrotizing encephalopathy (AE). This was characterized a marked reduction of various lymphocytes (e.g., CD8+ T and CD4+ T cells) and significant increases in other inflammatory cells (e.g., monocytes). Further analysis revealed activation of multiple cell apoptosis pathways (e.g., granzyme/perforin-, FAS- and TNF-induced apoptosis) may be responsible for lymphopenia. A systemic S100A12 upregulation, primarily from classical monocytes, may have contributed to cytokine storms in patients with AE. A dysregulated type I interferon (IFN) response was observed which may have further exacerbated the S100A12-driven inflammation in patients with AE. In COVID-19 patients with AE, myeloid cells (e.g., monocytic myeloid-derived suppressor cells) were the likely contributors to immune paralysis. Finally, the immune landscape in COVID-19 patients with encephalopathy, especially for AE, were also characterized by NK and T cells with widespread exhaustion, higher cytotoxic scores and inflammatory response as well as a dysregulated B cell-mediated humoral immune response. Taken together, this comprehensive data provides a detailed resource for elucidating immunopathogenesis and will aid development of effective COVID-19-associated pediatric encephalopathy treatments, especially for those with AE.

Case report: A toxoplasmic encephalitis in an immunocompromised child detected through metagenomic next-generation sequencing.

There exist numerous pathogens that are capable of causing infections within the central nervous system (CNS); however, conventional detection and analysis methods prove to be challenging. Clinical diagnosis of CNS infections often depends on clinical characteristics, cerebrospinal fluid (CSF) analysis, imaging, and molecular detection assays. Unfortunately, these methods can be both insensitive and time consuming, which can lead to missed diagnoses and catastrophic outcomes, especially in the case of infrequent diseases. Despite the application of appropriate prophylactic regimens and evidence-based antimicrobial agents, CNS infections continue to result in significant morbidity and mortality in hospital settings. Metagenomic next-generation sequencing (mNGS) is a novel tool that enables the identification of thousands of pathogens in a target-independent manner in a single run. The role of this innovative detection method in clinical pathogen diagnostics has matured over time. In this particular research, clinicians employed mNGS to investigate a suspected CNS infection in a child with leukemia, and unexpectedly detected Toxoplasma gondii. Case: A 3-year-old child diagnosed with T-cell lymphoblastic lymphoma was admitted to our hospital due to a 2-day history of fever and headache, along with 1 day of altered consciousness. Upon admission, the patient's Glasgow Coma Scale score was 14. Brain magnetic resonance imaging revealed multiple abnormal signals. Due to the patient's atypical clinical symptoms and laboratory test results, determining the etiology and treatment plan was difficulty.Subsequently, the patient underwent next-generation sequencing examination of cerebrospinal fluid. The following day, the results indicated the presence of Toxoplasma gondii. The patient received treatment with a combination of sulfamethoxazole (SMZ) and azithromycin. After approximately 7 days, the patient's symptoms significantly improved, and they were discharged from the hospital with oral medication to continue at home. A follow-up polymerase chain reaction (PCR) testing after about 6 weeks revealed the absence of Toxoplasma. Conclusion: This case highlights the potential of mNGS as an effective method for detecting toxoplasmic encephalitis (TE). Since mNGS can identify thousands of pathogens in a single run, it may be a promising detection method for investigating the causative pathogens of central nervous system infections with atypical features.

Fecal calprotectin as an intestinal inflammation marker is elevated in glaucoma.

Objective: The aim of this study was to investigate the potential association between glaucoma and fecal calprotectin. Methods: A total of 144 glaucomatous patients and 66 healthy controls were enlisted for this study. The fecal calprotectin was assessed using enzyme-linked immunosorbent assay. Results: The median fecal calprotectin levels were significantly elevated in glaucoma (73.67 vs 41.97 µg/g; p < 0.001), primary angle-closure glaucoma (76.85 µg/g; p < 0.001) and primary open-angle glaucoma (69.29 µg/g; p = 0.016) groups compared with controls. A notable proportion of the glaucoma (24%; p < 0.001), primary angle-closure glaucoma (21%; p < 0.001) and primary open-angle glaucoma (24%; p < 0.001) subgroups exhibited highly abnormal fecal calprotectin levels (≥250 µg/g). Conclusion: Elevated fecal calprotectin might indicate potential intestinal inflammation in glaucoma.

Electrolyte-Impregnated Mesoporous Hollow Microreactor to Supplement an Inner Reaction Pathway for Boosting the Cyclability of Li-CO2 Batteries.

Li-CO2 batteries that integrate energy storage with greenhouse gas fixation have received a great deal of attention in the pursuit of carbon neutrality. However, cyclic accumulation of the insulative and insoluble Li2CO3 on the cathode surface severely restrains the battery cyclability, especially under a high depth of discharge/charge. Herein, we design and fabricate a microreactor-type catalyst by embedding Ru nanoparticles into the shells of mesoporous hollow carbon spheres. We show that both the hollow cavity and mesoporous shell are indispensable for concertedly furnishing a high activity to catalyze reversible Li2CO3 formation/decomposition. This unique structure ensures that the Ru sites masked by exterior Li2CO3 deposits during charging can resume the redox process of discharge by working with the prestored electrolyte to establish an inner reaction path. The thus fabricated Li-CO2 batteries demonstrate remarkable cyclability of 1085 cycles under 0.5 Ah g-1 and 326 cycles under 2 Ah g-1 at 1 A g-1, outshining most of the literature reports. This study highlights a smart catalyst design to boost the reversibility and cyclability of Li-CO2 batteries through an "in & out" strategy.

Gut-licensed ß7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma.

Glaucoma is the leading cause of irreversible blindness. Currently, most therapeutic strategies aim to reduce elevated intraocular pressure (EIOP), but this does not always halt disease progression. Evidence suggests a role for T cells in glaucoma pathogenesis, but the underlying mechanisms remain largely unknown. Here, we found that the percentage of circulating CD4+ T cells expressing a gut-homing integrin ß7 was increased in patients with glaucoma and was associated with disease stage. In an EIOP-triggered glaucoma mouse model, ß7+ CD4+ T cells infiltrated the retina in the progressive phase of glaucoma via eliciting retinal endothelial cell expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 was minimally detected in retinas of healthy mice, and neutralization with an MAdCAM-1 antibody ameliorated retinal ganglion cell (RGC) loss and glial activity in mice with glaucoma. We furthermore found that EIOP-induced ß7+ CD4+ T cells homed to the gut during the acute phase of glaucoma, which was essential for progressive RGC damage in diseased mice. Gut-homing ß7+ CD4+ T cells underwent transcriptional reprogramming, showing up-regulated pathways enriched in autoimmune diseases, bacteria responses, mucosal immunity, and glial activity. Gut-homing ß7+ CD4+ T cells gained the competence to induce retinal MAdCAM-1 expression and to cross the blood-retina barrier. Together, our study reveals a role of gut-licensed ß7+ CD4+ T cells and MAdCAM-1 in RGC degeneration and emphasizes the importance of the "gut-retina" axis in glaucoma.

Tracking the first SARS-CoV-2 Omicron BA.5.1.3 outbreak in China.

The SARS-CoV-2 is still undergoing rapid evolution, resulting in the emergence of several variants of concern, especially the Omicron variants (B.1.1.529), which are surging worldwide. In this study, we tracked Omicron subvariant BA.5.1.3 as the causative agent in the Hainan Province wave in China, which started on 1 August 2022. This was China's first case of Omicron subvariant BA.5.1.3 and led to an indefinite total lockdown in Hainan with more than 8,500 confirmed cases. We obtained 391 whole genomes from positive nasopharyngeal swab samples in the city of Sanya in Hainan Province, which was the center of this outbreak. More than half of the infected cases were female (58%, 227/391) with a median age of 37.0 years (IQR 23.0-53.0). Median Ct values were 24.9 (IQR 22.6-27.3) and 25.2 (IQR 22.9-27.6) for ORF1ab and N genes, respectively. The total single-nucleotide polymorphism (SNP) numbers of Omicron BA.5.1.3 sampled in Sanya (median 69.0, IQR = 69.0-70.0) compared to those worldwide (median 63.0, IQR = 61.0-64.0) showed a significant difference (p < 0.05). Unique core mutations, including three non-synonymous mutations in ORF1ab (Y1064N, S2844G, and R3574K) and one synonymous mutation in ORF3a (S74S), were found. Phylogenetic analysis showed that virus from Sanya formed an independent sub-clade within the BA.5.1.3 subvariant, and could be divided into 15 haplotypes based on the S gene. The most recent common ancestor for the virus from Sanya was estimated as appearing on 5 July 2022, with 95% HPD ranging from 15 May to 20 September 2022. Thanks to our results, we were also able to delineate the mutational profile of this outbreak and highlight the importance of global genomic surveillance and data sharing.

Design, Synthesis and Biological Evaluation of 7-Substituted-1,3-diaminopyrrol[3,2-f]quinazolines as Potential Antibacterial Agents.

The evolution of drug-resistant bacteria poses a serious threat to public health; hence, it is imperative to develop new and efficient antibiotics. Irresistin-16 (IRS-16) is a dual-target antibacterial candidate that affects folate biosynthesis and membrane integrity and exhibits potent lethality against various bacteria. In this study, a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (DAPQ) derivatives based on IRS-16 was designed and synthesized to identify outstanding antibacterial candidates. The most promising compound, 7-(4-(4-methylpiperazin-1-yl) benzyl)-7H-pyrrol[3,2-f] quinazoline-1,3-diamine (18 e), displayed excellent antibacterial activity against both gram-positive and gram-negative bacteria (minimum inhibitory concentrations=1-4 µg/mL), improved water solubility, poor hemolytic activity and low cytotoxicity. Compound 18 e exhibited rapid bactericidal properties and prevented bacterial resistance in laboratory simulations. These results provide a basis for the development of new DAPQ-based compounds to combat emerging bacterial resistance.

IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B-cell lymphoma.

PURPOSE: Large B-cell lymphoma with IRF4 rearrangement (LBCL, IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due to IRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates of IRF4+. METHODS: The histopathology, immunophenotype, IRF4 status of the tumors, and clinical data were reviewed. RESULTS: Twenty-one tumors were diagnosed as LBCL, IRF4+, which were more frequently associated with a follicular growth pattern, medium-sized blastoid cytology, germinal center B-cell-like, and CD5+ phenotype, compared with IRF4- ones. While most of the patients received chemotherapy with or without radiation, eight IRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome. IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared with IRF4- ones. Multivariate analysis confirmed IRF4+ correlates with a better survival. CONCLUSION: Our work confirmed the unique clinicopathologic features of LBCL, IRF4+, and disclosed for the first time the independent favorable prognostic impact of IRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.

Cholesterol homeostasis regulated by ABCA1 is critical for retinal ganglion cell survival.

Genome-wide association studies have suggested a link between primary open-angle glaucoma and the function of ABCA1. ABCA1 is a key regulator of cholesterol efflux and the biogenesis of high-density lipoprotein (HDL) particles. Here, we showed that the POAG risk allele near ABCA1 attenuated ABCA1 expression in cultured cells. Consistently, POAG patients exhibited lower ABCA1 expression, reduced HDL, and higher cholesterol in white blood cells. Ablation of Abca1 in mice failed to form HDL, leading to elevated cholesterol levels in the retina. Counting retinal ganglion cells (RGCs) by using an artificial intelligence (AI) program revealed that Abca1-deficient mice progressively lost RGCs with age. Single-cell RNA sequencing (scRNA-seq) revealed aberrant oxidative phosphorylation in the Abca1-/- retina, as well as activation of the mTORC1 signaling pathway and suppression of autophagy. Treatment of Abca1-/- mice using atorvastatin reduced the cholesterol level in the retina, thereby improving metabolism and protecting RGCs from death. Collectively, we show that lower ABCA1 expression and lower HDL are risk factors for POAG. Accumulated cholesterol in the Abca1-/- retina causes profound aberrant metabolism, leading to a POAG-like phenotype that can be prevented by atorvastatin. Our findings establish statin use as a preventive treatment for POAG associated with lower ABCA1 expression.

Influenza vaccination features revealed by a single-cell transcriptome atlas.

Emerging and re-emerging viruses like influenza virus pose a continuous global public health threat. Vaccines are one of the most effective public health strategies for controlling infectious diseases. However, little is known about the immunological features of vaccination at the single-cell resolution, including for influenza vaccination. Here, we report the single-cell transcriptome atlas of longitudinally collected peripheral blood mononuclear cells (PBMCs) in individuals immunized with an inactivated influenza vaccine. Overall, vaccination with the influenza vaccine only had a small impact on the composition of peripheral immune cells, but elicited global transcriptional changes in multiple immune cell subsets. In plasma and B cell subsets, transcriptomic changes, which were mostly involved in antibody production as well as B cell activation and differentiation, were observed after influenza vaccinations. In influenza-vaccinated individuals, we found a reduction in multiple biological processes (e.g., interferon response, inflammatory response, HLA-I/II molecules, cellular apoptosis, migration, and cytotoxicity, etc.,) 7 days postvaccination in multiple immune cell subsets. However, 14 days postvaccination, these levels returned to similar levels observed in prevaccination samples. Additionally, we did not observe significant upregulation of pro-inflammatory response genes and key thrombosis-related genes in influenza-vaccinated individuals. Taken together, we report a cell atlas of the peripheral immune response to influenza vaccination and provide a resource for understanding the immunological response mechanisms of influenza vaccination.

Nocardia sputi sp. nov. isolated from the sputum of patients with pulmonary infection.

Two Gram-stain-positive, aerobic and rod-shaped actinomycetes (strains CY18T and CY8) were isolated from the sputum of two patients with pulmonary infections, and their taxonomic status was investigated. The 16S rRNA gene sequences and the results of phylogenetic analyses indicated that CY18T and CY8 were identical (100 %) and were most closely related to Nocardia beijingensis CGMCC 4.1521T (99.9 %) and Nocardia araoensis NBRC 100135T (99.5 %). The predominant cellular fatty acids of CY18T and CY8 were C16 : 0, C18 : 0, C18 : 1ω9c and summed feature 3 (comprising C16 : 1É·7c and/or C16 : 1É·6c), and the major menaquinone was MK-8(H4ω-cycl).The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The whole-cell hydrolytic sugar pattern consisted of arabinose and glucose. The polar lipid profile contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside, two unidentified phospholipids, three unidentified glycolipids and two unidentified lipids.The DNA G+C contents of CY18T and CY8 were 67.9 and 68.0 % respectively. The digital DNA-DNA hybridization and average nucleotide identity values between the two novel strains and closely related species were well under the 70 % and 95-96 % thresholds, respectively, but these values between the two novel strains were 95.5 % and 99.5 %, respectively. On the basis of morphological and chemotaxonomic characteristics and the results of phylogenetic analyses, strains CY18T and CY8 represent a novel species of the genus Nocardia, for which the name Nocardia sputi sp. nov. is proposed. The type strain is CY18T (=GDMCC 1.3318T = JCM 33932T).

Single-cell transcriptomic atlas reveals distinct immunological responses between COVID-19 vaccine and natural SARS-CoV-2 infection.

To control the ongoing coronavirus disease-2019 (COVID-19) pandemic, CoronaVac (Sinovac), an inactivated vaccine, has been granted emergency use authorization by many countries. However, the underlying mechanisms of the inactivated COVID-19 vaccine-induced immune response remain unclear, and little is known about its features compared to (Severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection. Here, we implemented single-cell RNA sequencing (scRNA-seq) to profile longitudinally collected PBMCs (peripheral blood mononuclear cells) in six individuals immunized with CoronaVac and compared these to the profiles of COVID-19 infected patients from a Single Cell Consortium. Both inactivated vaccines and SARS-CoV-2 infection altered the proportion of different immune cell types, caused B cell activation and differentiation, and induced the expression of genes associated with antibody production in the plasma. The inactivated vaccine and SARS-COV-2 infection also caused alterations in peripheral immune activity such as interferon response, inflammatory cytokine expression, innate immune cell apoptosis and migration, effector T cell exhaustion and cytotoxicity, however, the magnitude of change was greater in COVID-19 patients, especially those with severe disease, than in immunized individuals. Further analyses revealed a distinct peripheral immune cell phenotype associated with CoronaVac immunization (HLA class II upregulation and IL21R upregulation in naïve B cells) versus SARS-CoV-2 infection (HLA class II downregulation and IL21R downregulation in naïve B cells from severe disease individuals). There were also differences in the expression of important genes associated with proinflammatory cytokines and thrombosis. In conclusion, this study provides a single-cell atlas of the systemic immune response to CoronaVac immunization and revealed distinct immune responses between inactivated vaccines and SARS-CoV-2 infection.

Proteomic and Metabolomic Signatures Associated With the Immune Response in Healthy Individuals Immunized With an Inactivated SARS-CoV-2 Vaccine.

CoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results help us to understand the host response to vaccination of CoronaVac and highlight the utility of a systems biology approach in defining molecular correlates of protection to vaccination.