The COVID-19 disease has spread rapidly across the world within just six months, affecting 169 million people and causing 3.5 million deaths globally (2021). The most affected countries include the USA, Brazil, India, and several European countries such as the UK and Russia. Healthcare professionals face new challenges in finding better ways to manage patients and save lives. In this regard, more comprehensive research is needed, including genomic and proteomic studies, personalized medicines and the design of suitable treatments. However, finding novel molecular entities (NME) using a standard or de novo strategy to drug development is a time-consuming and costly process. Another alternate strategy is discovering new therapeutic uses for old/existing/available medications, known as drug repurposing. There are a variety of computational repurposing methodologies, and some of them have been used to counter the coronavirus disease pandemic of 2019 (COVID-19). This review article compiles recently published data on the origin, transmission, pathogenesis, diagnosis, and management of the coronavirus by drug repurposing and vaccine development approach. We have attempted to screen probable drugs in clinical trials by using literature survey. This systematic review aims to create priorities for future research of drugs repurposed and vaccine development for COVID-19.

Primary immunodeficiencies (PIDs) are a group of diseases that develop as a result of primary or congenital malfunction of the immune system and progress with chronic and/or recurrent bacterial, fungal, protozoal and/or viral infections. In this study, we aimed to examine the effects of the COVID-19 pandemic on depression, anxiety levels and psychological resilience in patients with PID and to compare them with those in controls.

Seventy patients, aged 18-65 years, who were being followed up with a diagnosis of PID and 69 people as healthy control group, participated in our study. The participants were evaluated cross-sectionally once; sociodemographic data form, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Resilience Scale for Adults (RSA), and COVID-19 Evaluation form were administered to the participants.

HAM-A and HAM-D scores were significantly higher in PID patients compared to controls (HAM-D: 5.5 vs. 3.0, p < 0.001; HAM-A: 6.0 vs. 4.0, p = 0.008). RSA was significantly lower in the patient group (RSA total: 122.5 vs. 136.0, p < 0.001), and pandemic-related risk perception was higher (PRPS: 33.9 vs. 28.3, p < 0.001). Sleep, appetite, and attention-related disturbances were also more common in the patient group. Multivariate regression analyses revealed that PID diagnosis was an independent predictor of increased depression severity (HAM-D), lower psychological resilience (RSA), and greater pandemic-related risk perception. Female sex was independently associated with higher anxiety severity (HAM-A). A personal psychiatric history and greater number of comorbidities were also significant predictors of psychological vulnerability, particularly in relation to depression and anxiety.

Given the observed associations between PID and increased levels of depression, anxiety, and reduced psychological resilience during the pandemic, clinicians may consider heightened vigilance for psychological symptoms in this population during times of public health crisis.

Background: SARS-CoV-2 is a positive-sense single-stranded RNA virus that has a propensity for infecting epithelial cells and the respiratory system. The two important proteins, structural and nonstructural proteins, make the architecture of this virus. Aim: This research aimed at studying significant mutations in spike protein of SARS-CoV-2 variants of concern (VoCs) and finding shared mutations among omicron and other four variants (alpha, beta, gamma, and delta). The purpose of this study was to draw structural comparisons between wild type and mutant proteins, followed by identifying potent inhibitors (ligand) that could be used against SARS-CoV-2 spike protein and its latest omicron VoC. Methodology: In this research, we had studied 16 major mutations as well as shared mutations (6) present in spike region of SARS-CoV-2. Subsequently, we determined the structure of the wild-type SARS-CoV-2 protein from the Protein Data Bank (PDB) with the ID 7R4I. Furthermore, the structure of the mutant protein of SARS-CoV-2 omicron variant was modeled in SWISS-MODEL. The ligand dataset for spike protein of SARS-CoV-2 was also collected from literature and different databases. Both wild type and mutant proteins were docked with ligand database in Molecular Operating Environment (MOE). The docking analysis was performed, and two best ligand molecules, AZ_2 and AZ_13, were finalized based on their energy values, interactions, and docking scores to be used against our wild and mutant proteins. Results: AZ_2 demonstrated a docking score of -6.1753 in MOE, with energy values of -4.3889 and -6.1753. It formed key hydrogen bond interactions. AZ_13 showed a docking score of -5.9, with energy values of -9.3 and -5.9, forming hydrogen donor and acceptor interactions with Asp950 (3.06 Å), Ile312 (3.13 Å), and Glu309 (3.27 Å). These interactions suggest strong binding affinity and potential efficacy. Thus, present research work emphasized on identification of significant mutations and finding a potent target-based drug against SARS-CoV-2 and its omicron variant. Outcomes: Based on this computational analysis performed, it is suggested that proposed compound can be used as remedy against SARS-CoV-2 and its omicron variant.

The continuous emergence of SARS-CoV-2 variants underscores the need for novel antiviral candidates. Hypericin (HY), a compound derived from Hypericum perforatum, exhibited potent in vitro activity against SARS-CoV-2 in Vero E6 cells, with low cytotoxicity (CC50 > 200 nM). HY showed no significant activity against Influenza A (H1N1) or dengue virus serotype 2, supporting its selective action. Antiviral effects were most evident when HY was administered post-infection, in a concentration-dependent manner, while cellular pretreatment or viral pre-incubation produced limited effects. Notably, HY also displayed virucidal activity, significantly reducing viral titers at 4 °C, 22 °C, and 37 °C. Combination treatments with remdesivir or nirmatrelvir enhanced antiviral efficacy by 50-70% relative to monotherapy, depending on compound concentration. Molecular simulations revealed stable interactions with conserved residues in RdRp and 3CLpro, suggesting a low risk of resistance. Together, these findings highlight the potential of HY as a selective antiviral and virucidal agent against SARS-CoV-2, particularly in combination regimens.

As age increases, the immune function of elderly individuals gradually decreases, increasing their susceptibility to infectious diseases. Therefore, further research on common viral infections in the elderly population, especially severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, is crucial for scientific progress. This review delves into the genetic structure, infection mechanisms, and impact of coinfections with these two viruses and provides a detailed analysis of the reasons for the increased susceptibility of elderly individuals to dual viral infections. We evaluated the clinical manifestations in elderly individuals following coinfections, including complications in the respiratory, gastrointestinal, nervous, and cardiovascular systems. Ultimately, we have summarized the current strategies for the prevention, diagnosis, and treatment of SARS-CoV-2 and influenza coinfections in older adults. Through these studies, we aim to reduce the risk of dual infections in elderly individuals and provide a scientific basis for the prevention, diagnosis, and treatment of age-related viral diseases, thereby improving their health status.

Several immunosuppressive therapies have been proposed as key treatment options for critically ill patients since the first appearance of severe acute respiratory syndrome coronavirus 2. Mesenchymal stem cells (MSCs) from different sources have been considered for their potential to attenuate the cytokine storm associated to COVID-19 and the consequent multi-organ failure, providing evidence for safe and efficacious treatments. Among them, administration of umbilical cord-derived MSCs (UC-MSCs) has demonstrated a significant increase in survival rates, largely due to their potent immunosuppressive properties.

We applied next-generation sequencing (NGS) analysis to compare the transcriptomic profiles of MSCs isolated from two gestational sources: amniotic fluid (AF) obtained during prenatal diagnosis and their clinically relevant umbilical cord counterparts, for which datasets were publicly available. A full meta-analysis was performed to identify suitable GEO and NGS datasets for comparison between AF- and UC-MSC samples.

Transcriptome analysis revelaed significant differences between groups, despite both cell lines being strongly involved in the tissue development, crucial to achieve the complex task of wound healing. Significantly enriched hallmark genes suggest AF-MSC superior immunomodulatory features against signaling pathways actively involved in the cytokine storm (i.e., IL-2/STAT, TNF-a/NFkB, IL-2/STAT5, PI3K/AKT/mTOR).

The data presented here suggest that AF-MSCs hold significant promise for treating not only COVID-19-associated cytokine storms but also a variety of other inflammatory syndromes (i.e., those induced by bacterial infections, autoimmune disorders, and therapeutic interventions). Realizing the full potential of AF-MSCs as a comprehensive therapeutic approach in inflammatory disease management will require more extensive clinical trials and in-depth mechanistic studies.

Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance by suppressing immune responses against pathogens. The fluctuation of Treg proportions in COVID-19 remains a topic of debate, and the mechanisms triggering Treg activation in COVID-19 are still unclear. Understanding these issues is essential for better managing immune responses in COVID-19 patients.

We collected a cohort of COVID-19 patients with varying disease severity and stage to explore the transcriptomic and functional traits of Tregs in these individuals. Using transcriptomic analysis, we evaluated the proportion and functionality of different Treg subsets, specifically HLA_DR+ Tregs, across different stages of COVID-19 patients.

Our analysis revealed that the proportion of CCR7 + Tregs decreased as the disease advanced, while the cell proportion of HLA_DR+ regs escalated with the severity of the disease. Moreover, the transcription actor CARHSP1 exhibited apositive correlation with the proportion of HLA_DR+ Tregs. Notably, the heightened suppressive function of HLA_DR+ Tregs in severe COVID-19 patients, with interactions between PF4 and CXCR3, contributed to the homeostasis of HLA_DR+ Tregs in severe COVID-19 patients. Furthermore, we observed that Tregs in COVID-19 patients exhibited weakened TCR clonotype expansion, and the suppression of HLA_DR+ Tregs with expanded TCR clonotypes in severe COVID-19 cases did not show a significant increase compared to asymptomatic and mild COVID-19 groups. The findings indicate that Tregs may be activated through the bystander effect, as evidenced by the analysis of TCR clonotype characteristics.

Our research delineates the diversity of dynamic alterations in Tregs and sheds light on potential mechanisms underlying Treg activation, providing a theoretical foundation and offering treatment strategies for managing COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affects the respiratory system but may induce hematological alterations such as anemia, lymphopenia and thrombocytopenia. Previous studies have reported that SARS-CoV-2 efficiently infects hematopoietic stem and progenitor cells (HSPCs); however, the subsequent effects on hematopoiesis and immune reconstitution have not yet been described. Here we evaluated the pathological effects of infection of umbilical-cord-blood-derived HSPCs with the SARS-CoV-2 Omicron variant pseudovirus (PsV). Transcriptomic analysis of Omicron PsV-infected HSPCs revealed the upregulation of genes involved in inflammation, aging and the NLRP3 inflammasome, suggesting a potential trigger of inflammaging. Omicron PsV-infected HSPCs presented decreased numbers of multipotential progenitors (granulocyte‒erythrocyte‒macrophage‒megakaryocyte colony-forming units) ex vivo and repopulated primitive hematopoietic stem cells (Ki-67-hCD34+ cells) in an HSPC transplantation NOD-scid IL2rγnull mouse model (Omicron mouse). Furthermore, Omicron PsV infection induced myeloid-biased differentiation of HSPCs. Treatment with nanographene oxide, an antiviral agent, partially mitigated the myeloid bias and inflammaging phenotype both in vitro and in vivo. These findings provide insights into the abnormal hematopoietic and immune effects of SARS-CoV-2 infection and highlight potential therapeutic interventions.

This study aimed to identify possible early biomarkers of mortality among clinical and biochemical parameters, iron metabolism parameters, and cytokines detected within 24 h from admission in hospitalized COVID-19 patients. We enrolled 80 hospitalized patients (40 survivors and 40 non-survivors) with COVID-19 pneumonia and acute respiratory failure. The median time from the onset of COVID-19 symptoms to hospital admission was lower in non-survivors than survivors (p < 0.05). Respiratory failure, expressed as the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen (P/F), was more severe in non-survivors than survivors (p < 0.0001). Comorbidities were similar in both groups. Among biochemical parameters and cytokines, eGFR and interleukin (IL)-1β were found to be significantly lower (p < 0.05), while LDH, IL-10, and IL-8 were significantly higher in non-survivors than in survivors (p < 0.0005, p < 0.05 and p < 0.005, respectively). Among other parameters, LDH values distribution showed the most significant difference between study groups (p < 0.0001). LASSO feature selection combined with Cox proportional hazards and logistic regression models was applied to identify features distinguishing between survivors and non-survivors. Both approaches highlighted LDH as the strongest predictor, with IL-22 and creatinine emerging in the Cox model, while IL-10, eGFR, and creatinine were influential in the logistic model (AUC = 0.744 for Cox, 0.723 for logistic regression). In a similar manner, we applied linear regression for predicting LDH levels, identifying the P/F ratio as the top predictor, followed by IL-10 and eGFR (NRMSE = 0.128). Collectively, these findings underscore LDH's critical role in mortality prediction, with P/F and IL-10 as key determinants of LDH increases in this Italian COVID-19 cohort.

Patients infected with SARS-CoV-2 may experience acute and long-term immune disorders. Immunological factors are thought to play an important role in Kawasaki disease. To analyze the impact of COVID-19 infection on Kawasaki disease, this study retrospectively analyzed 161 children with Kawasaki disease onset during the COVID-19 pandemic. The proportion of IVIG-Resistant individuals and the rate of corticosteroid use in the 1-7 weeks from COVID-19 infection to Kawasaki disease onset were higher than that of the noninfected group, even after excluding suspected cases of multiple system inflammatory syndrome. Compared to the noninfected group, the level of CD4 was lower, and the levels of CD3-CD16+CD56+, complement C4, TNF-α, and IFN-γ were higher in the 1-7 weeks after COVID-19 infection. In conclusion, the risk of IVIG resistance was significantly increased in children with Kawasaki disease onset 1-7 weeks after COVID-19 infection, which may be related to the long-term impact of COVID-19 on immunity.

A subset of COVID-19 disease patients suffers a severe form of the illness; however, underlying early pathophysiological mechanisms associated with the severe form of COVID-19 disease remain to be fully understood. Several studies showed the association of COVID-19 disease severity with the changes in the expression profile of various matrix metalloproteinases (MMPs) and defensins (DA). However, the link between the changes in the expression of MMPs and DA in the nasopharyngeal milieu during early phases of infection and disease severity remains poorly understood. Therefore, we performed differential gene expression analysis of MMPs and DA in the nasopharyngeal swab samples collected from normal (COVID-19 negative), mild, and severe COVID-19 cases and examined the association between MMP and DA expression and disease severity.

A total of 118 previously collected nasopharyngeal samples from mild and severe COVID-19 patients (as per the WHO criteria) and 10 healthy individuals (COVID-19 negative, controls) were used in this study. A real-time qPCR assay was used to determine the viral loads and assess the mRNA expression of MMPs and DA. One-way ANOVA was applied to perform multiple comparisons (estimate differences) in MMPs and defensin gene expression in the normal vs mild vs severe groups. In addition, a multivariable logistic regression analysis was carried out with all the variables from the data set using 'severity' as the outcome variable.

Our results showed that as compared to controls, DA1, DA3, and DA4 expression was significantly (p < 0.05) upregulated in the mild group, whereas the expression of DA6 was significantly downregulated in both mild and severe groups (p-value < 0.05). Similarly, compared to controls, the expression of MMP1 and MMP7 was significantly downregulated in both mild and severe groups, whereas MMP2 expression was upregulated in the mild group (p-value < 0.05). Additionally, the regression analysis showed that the expression of MMP1, MMP2, and MMP9 was significantly associated with the severity of the disease.

The early detection of changes in the expression of MMPs and defensins may act as a useful biomarker/predictor for possible severe COVID-19 disease, which may be useful in the clinical management of patients to reduce COVID-19-associated morbidity and mortality.

Asthma has long been associated with increased susceptibility to viral respiratory infections, leading to significant exacerbations and poorer clinical outcomes. Contrarily and interestingly, emerging data and research surrounding the COVID-19 pandemic have shown that patients with asthma infected with SARS-CoV-2 experienced decreased severity of disease, lower hospitalization rates, as well as decreased morbidity and mortality. Research has shown that eosinophils could enhance immune defense against viral infections, while inhaled corticosteroids can assist in controlling systematic inflammation. Moreover, reduced ACE-2 expression in individuals with asthma may restrict viral entry, and the Th2 immune response may offset the Th1 response typically observed in severe COVID-19 patients. These factors may help explain the favorable outcomes seen in asthmatic patients during the COVID-19 pandemic. This review highlights potential protective mechanisms seen in asthmatic patients, including eosinophilia, the use of inhaled corticosteroids, reduced ACE-2 expression, and a dominate Th2 immune response. Such a study will be helpful to better manage patients with asthma who have contracted COVID-19.

Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1β-driven NF-κB transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.

Research on long-term follow-up in individuals who have recovered from coronavirus disease-19 (COVID-19) would yield insights regarding their immunity status and identify those who need booster vaccinations. This study evaluated the longevity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular and humoral memory responses, as well as T cell effector functionalities, at 1-2 months (n = 40), 8-9 months (n = 40), and 12 months/1 year (n = 27) following recovery from SARS-CoV-2 infection. CTL response by enzyme-linked immunospot (ELISPOT); levels of cytokine by Bio-Plex, natural killer (NK), CD4+ helper, and CD8+ cytotoxic T cell functionalities using flow cytometry; anti-SARS-CoV-2 IgG by ELISA; and levels of neutralizing antibodies (NAbs) by surrogate virus NAb assay were assessed. The levels of SARS-CoV-2-specific IgG and NAb at 1-2 and 8-9 months postrecovery were hand in hand and appeared declining. SARS-CoV-2-specific B, memory B and plasma cells, and T cells sustained up to 8-9 months. Increased expression of CD107a/IFN-γ by NK cells and cytotoxic T cells at 8-9 months could be indicative of SARS-CoV-2-specific effector functions. Recovered individuals with positive and negative IgG antibody status displayed T cell response up to 1 year and 8-9 months, respectively, emphasizing the durabilty of effector immunity up to 8-9 months regardless of IgG antibody status. Overall, the recovered individuals exhibited robust immunological memory, sustained T cell response with effector functionality against SARS-CoV-2 that persists for at least 8-9 months.

This study aimed to evaluate the long-term impact of mild COVID-19 infection and COVID-19 vaccination on ovarian function in patients undergoing assisted reproductive technology (ART). Specifically, we assessed ovarian outcomes between 9 and 18 months post-infection and investigated the effects of COVID-19 vaccines (inactivated virus and adenovirus) on reproductive parameters.

The study included two objectives: (a) examining ovarian function in post-COVID-19 patients (9-18 months post-infection) compared to a control group and (b) comparing reproductive outcomes in vaccinated versus unvaccinated patients. According to the study objectives, ART patients were divided into the following groups: a control group (n = 30), a post-COVID-19 group (n = 55), an unvaccinated group (n = 70), and a vaccinated group (n = 55). Findings revealed a reduction in the number of retrieved and mature oocytes in patients over 36 years in the post-COVID-19 group. Lower IL-1β levels were found in follicular fluid (FF) of post-COVID-19 patients, while VEGF levels were reestablished between 9 and 18 months post-infection. Although cell migration was reduced in endothelial cells incubated with post-COVID-19 FF, angiogenic factor levels and DNA integrity remained stable. No significant differences in retrieved or mature oocytes were observed between vaccinated and unvaccinated patients.

VEGF levels and DNA integrity in FF from post-COVID-19 patients were normalized between 9 and 18 months post-infection. Additionally, COVID-19 vaccination did not negatively impact ovarian response in ART patients, supporting vaccine safety in reproductive contexts.

The 2019 coronavirus illness (COVID 2019) first manifests as a newly identified pneumonia and may quickly escalate to acute respiratory distress syndrome, which has caused a global pandemic. Except for individualized supportive care, no curative therapy has been steadfastly advised for COVID-19 up until this point. T cells and virus-specific T lymphocytes are required to guard against viral infection, particularly COVID-19. Delayed immunological reconstitution (IR) and cytokine storm (CS) continue to be significant barriers to COVID-19 cure. While severe COVID-19 patients who survived the disease had considerable lymphopenia and increased neutrophils, especially in the elderly, their T cell numbers gradually recovered. Exhausted T lymphocytes and elevated levels of pro-inflammatory cytokines, including IL6, IL10, IL2, and IL17, are observed in peripheral blood and the lungs. It implies that while convalescent plasma, IL-6 blocking, mesenchymal stem cells, and corticosteroids might decrease CS, Thymosin α1 and adaptive COVID-19-specific T cells could enhance IR. There is an urgent need for more clinical research in this area throughout the world to open the door to COVID-19 treatment in the future.

The Immunoglobulin Heavy Chain (IGH) genomic region is responsible for the production of circulating antibodies and warrants careful investigation for its association with COVID-19 characteristics. Multiple allelic variants within and across different IGH gene segments form a limited set of haplotypes. Previous studies have shown associations between some of these haplotypes and clinical outcomes of COVID-19. We typed 445 individuals of European ancestry, stratified for gender, age, and clinical status for 4 SNPs, two of which result in amino acid substitutions in IGHA2 and IGHG4, respectively. We analyzed associations at the single-locus level and for 4-loci haplotypes, inferred by phasing, after stratifying the overall cohort by gender, age, and disease severity.

Only weak evidence of significant differences between subgroups was obtained at the level of a single SNP. However, when the haplotypic data were analyzed for the young and old subgroups separately, uneven partitioning was observed regarding the occurrence of severe cases and Resistors. We then examined the cross-tabulation of disease severity in males and females, based on the presence of each haplotype in the genotype. Two haplotypes were underrepresented in young severe cases compared to old severe ones. The same two haplotypes were overrepresented among young Resistors. These findings provide stronger support for, the weak associations observed at the single locus level.

Two haplotypes seem to act as protective factors specifically in young individuals, counteracting the general increase in vulnerability with age. This observation aligns with stronger genetic effects seen in young patients for other susceptibility genes. Our findings complement previous research identifying specific genetic variants that influence COVID-19 susceptibility and severity, emphasizing the complex interplay between host genetics and viral infection outcomes. Our results are consistent with a potential causative role of IGH regulatory regions (e.g. HS1.2), which are flanked by the SNP set here analyzed.

The immune status of Coronavirus disease 2019 (COVID-19) patients in different stages of infection remains difficult to determine. In this study, we performed high-throughput single-cell mass cytometry on peripheral blood samples from 10 COVID-19 patients and four healthy donors to analyze their immune status at acute and convalescence phases. During the acute stage, the proportion of neutrophils increased significantly while natural killer (NK) cells decreased. In contrast, during the convalescence phase, the proportion of plasma cells decreased from the acute stage of disease onset and was lower than normal. The proportions of B, mast and plasma cell subsets decreased significantly with the process of disease recovery. Further analysis of the subsets of major immune cell types in COVID-19 patients with different clinical presentations in different stages showed that in the acute stages of disease progression, the T helper cell 1 (Th1), IgD+ B and neutrophil subsets increased in COVID-19 patients, especially in symptomatic patients, while the central memory CD4+T cells (CD4 TCM), mucosa-associated invariant T (MAIT) and NK cell subsets decreased significantly, especially in symptomatic patients. Then CD4 TCM and MAIT returned to normal levels at the recovery phase. Dynamic assessment displayed that the immune imbalance at the onset of COVID-19 could be corrected during recovery. Our study provides additional information on the immune status of COVID-19 patients with different clinical manifestations in different stages. These findings may provide new insights into COVID-19 immunotherapy and immune intervention.

Acute upper respiratory tract infections are a major public health issue, with uncontrolled inflammation triggered by upper respiratory viruses being a significant cause of patient deterioration or death. This study focuses on the Janus kinase-signal transducer and activator of transcription Rho-associated coiled-coil containing protein kinase (JAK-STAT-ROCK) signaling pathway, providing an in-depth analysis of the interplay between uncontrolled inflammation after upper respiratory tract infections and the development of neurodegenerative diseases. It offers a conceptual framework for understanding the lung-brain-related immune responses and potential interactions. The relationship between the ROCK-JAK-STAT signaling pathway and inflammatory immunity is a complex and multi-layered research area and exploring potential common targets could open new avenues for the prevention and treatment of related inflammation.

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers, thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade could be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low-density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.

Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells.

Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]).

The approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major concern due to its astonishing prevalence and high fatality rate, especially among elderly people. Patients suffering from COVID-19 may exhibit immunosuppression in the initial stage of infection, while a cytokine storm can occur when the disease progresses to a severe stage. This inopportune immune rhythm not only makes patients more susceptible to the virus but also leads to numerous complications resulting from the excessive production of inflammatory factors. A20, which is widely accepted as a pivotal regulator of inflammation, has been shown to be implicated in the processes of antiviral responses and immunosuppression. Thus, A20 may participate in regulating the pathological processes of COVID-19.

This narrative literature review summarizes recent evidence on the mechanisms of A20 in regulating the pathological processes of COVID-19. We also downloaded single-cell RNA-seq data sets from healthy individuals and patients with varying severities of COVID-19 from the NCBI GEO database to further dissect A20's regulatory mechanisms of these intricate cytokine pathways that are closely associated with SARS-CoV-2 infection.

A20 might be one of the most critical anti-infectious and anti-inflammatory factors involved in the pathogenesis of COVID-19. It effectively suppresses the immune damage and inflammatory storm caused by viral infection.

Understanding the relationship between A20-regulated signaling pathways and pathological processes of COVID-19 can provide insight into potential targets for intervention. Precise regulation of A20 to induce antiviral activity and an anti-inflammatory response could mediate the pathogenesis of COVID-19 and could become an effective treatment.

Pulmonary hypertension (PH) is a severe condition characterized by elevated pressure in the pulmonary artery, where metabolic and mitochondrial dysfunction may contribute to its progression. Within the PH spectrum, pulmonary arterial hypertension (PAH) stands out with its primary pulmonary vasculopathy. PAH's prevalence varies from 0.4 to 1.4 per 100,000 individuals and is associated with diverse conditions, including viral infections such as HIV. Notably, recent observations highlight an increased occurrence of PAH among COVID-19 patients, even in the absence of pre-existing cardiopulmonary disorders. While current treatments offer partial relief, there's a pressing need for innovative therapeutic strategies, among which mesenchymal stromal cells (MSCs) and their derivatives hold promise. This review critically evaluates recent investigations into viral-induced PAH, encompassing pathogens like human immunodeficiency virus, herpesvirus, Cytomegalovirus, Hepatitis B and C viruses, SARS-CoV-2, and Human endogenous retrovirus K (HERKV), with a specific emphasis on mitochondrial dysfunction. Furthermore, we explore the underlying rationale driving novel therapeutic modalities, including MSCs, extracellular vesicles, and mitochondrial interventions, within the framework of PAH management.

The literature review presents an analysis of the pathogenesis and pathological anatomy of liver damage in COVID-19. Liver damage with the steatosis, vascular disorders, mild portal and lobular inflammatory infiltration, cholestasis and clinically - liver failure is observed in majority of the patients with COVID-19. Chronic liver diseases with infection SARS-CoV-2 tend to decompensate, which significantly worsens the prognosis of the disease. Pathogenesis of liver damage in COVID19 is unclear. There was no convincing evidence for the hypothesis of cytotoxicity for hepatocytes or cholangiocytes by SARS-CoV-2. Similar liver morphological changes described by different authors suggest their nonspecific nature and multifactorial pathogenesis related to hypoxia, cytokin storm, systemic inflammatory response syndrome, sepsis and shock, Covid-associated angio- and coagulopathy, as well as drug-induced hepatotoxicity. Further research is needed to clarify the pathogenesis and pathological anatomy of the liver pathology in COVID-19.

Demyelinating diseases including multiple sclerosis are associated with prior infectious exposures, so we assessed whether SARS-CoV-2 infection is associated with subsequent diagnoses of non-multiple sclerosis demyelinating diseases and multiple sclerosis. All residents of Sweden aged 3-100 years were followed between 1 January 2020 and 30 November 2022, excluding those with demyelinating disease prior to 2020, comprising 9 959 818 individuals divided into uninfected and those who were infected were categorized into those with and without hospital admission for the infection as a marker of infection severity. Cox regression assessed the risk of two separate outcomes: hospital diagnosed non-multiple sclerosis demyelinating diseases of the CNS and multiple sclerosis. The exposures were modelled as time-varying covariates (uninfected, infection without hospital admission and infected with hospital admission). Hospital admission for COVID-19 was associated with raised risk of subsequent non-multiple sclerosis demyelinating disease, but only 12 individuals had this outcome among the exposed, and of those, 7 has an unspecified demyelinating disease diagnosis. Rates per 100 000 person-years (and 95% confidence intervals) were 3.8 (3.6-4.1) among those without a COVID-19 diagnosis and 9.0 (5.1-15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio and (and 95% confidence interval) of 2.35 (1.32-4.18, P = 0.004). Equivalent associations with multiple sclerosis (28 individuals had this outcome among the exposed) were rates of 9.5 (9.1-9.9) and 21.0 (14.5-30.5) and an adjusted hazard ratio of 2.48 (1.70-3.61, P < 0.001). Only a small number of non-multiple sclerosis demyelinating disease diagnoses were associated with hospital admission for COVID-19, and while the number with multiple sclerosis was somewhat higher, longer duration of follow-up will assist in identifying whether the associations are causal or due to shared susceptibility or surveillance bias, as these diseases can have long asymptomatic and prodromal phases.

Little is known about immunophenotyping characteristics and clinical outcomes of COVID-19 patients treated with azvudine during the Omicron variant surge.

This study enrolled patients diagnosed with COVID-19 from December 2022 to February 2023. The primary outcome was defined as all-cause mortality, along with a composite outcome reflecting disease progression. The enrolled patients were followed for a period of 60 days from their admission.

A total of 268 COVID-19 patients treated with azvudine were enrolled in this retrospective study. The study found that the counts of lymphocyte subsets were significantly reduced in the composite outcome and all-cause mortality groups compared to the non-composite outcome and discharge groups (all p < 0.001). Correlation analysis revealed a negative association between lymphocyte subsets cell counts and inflammatory markers levels. The receiver operating characteristic (ROC) curve analysis identified low CD4+ T cell count as the most significant predictor of disease progression and all-cause mortality among the various lymphocyte subsets. Additionally, both the Kaplan-Meier curve and multivariate regression analysis demonstrated that low CD4+ T cell count level (< 156.00 cells/μl) was closely associated with all-cause mortality in COVID-19 patients treated with azvudine.

A low CD4+ T cell count may serve as a significant predictive indicator for identifying COVID-19 patients receiving azvudine treatment who are at an elevated risk of experiencing adverse outcomes. These findings may offer valuable insights for physicians in optimizing the administration of azvudine.

The severity of COVID-19's outcomes has been positively correlated with an increased risk of respiratory failure and death, especially in patients with chronic illnesses. This case-control design study aims to examine the correlation in the Palestinian population in light of its impact on diabetic patients. The study was conducted from March 2020 to June 2021 on 417 patients admitted to the Palestinian National Center for Rehabilitation. Of them, 198 cases were tested positive for COVID-19 and had diabetes, whereas the remaining 219 were those who tested positive for COVID-19 but were not diagnosed with diabetes and acted as controls. Data from patient files were collected to address the study questions. Patients' ages ranged from 17 to 98 years, with a mean age of 58. Male participants represented 53.5% of the total. The results of the current study indicated that the case fatality rate (CFR) was 14.2% for all participants and 19.7% for patients with diabetes. In regard to patients' health conditions, 5.7% had cardiovascular diseases (CVD), 33.6% had hypertension, 6.5% had kidney diseases, and 47.4% had diabetes. According to the multivariate analysis, diabetic patients had a 1.63 times higher risk for COVID-19 infection compared to nondiabetic patients (adjustment of odds ratio of 1.63 and confidence interval [CI] = 0.354-1.856). This is the first study to investigate the relationship between the severity of COVID-19 outcomes in Palestine and the diabetes status, and the majority of its findings are consistent with other research studies that assessed the impact of COVID-19 on diabetic patients (with minor variations in the number and percentage). The study confirms that along with diabetes, age, hypertension, kidney diseases, shortness of breath, requirement of oxygen, D-dimer, C-reactive protein (CRP), kidney function test (KFT), and days of hospitalization were also associated with severe COVID-19 outcomes, whereas gender, CVDs, and liver function test (LFT) were not associated with severe COVID-19 outcomes.

Emerging infectious diseases like coronavirus pneumonia (COVID-19) present significant challenges to global health, extensively affecting both human society and the economy. Extracellular vesicles (EVs) have demonstrated remarkable potential as crucial biomedical tools for COVID-19 diagnosis and treatment. However, due to limitations in the performance and titer of natural vesicles, their clinical use remains limited. Nonetheless, EV-inspired strategies are gaining increasing attention. Notably, biomimetic vesicles, inspired by EVs, possess specific receptors that can act as "Trojan horses," preventing the virus from infecting host cells. Genetic engineering can enhance these vesicles by enabling them to carry more receptors, significantly increasing their specificity for absorbing the novel coronavirus. Additionally, biomimetic vesicles inherit numerous cytokine receptors from parent cells, allowing them to effectively mitigate the "cytokine storm" by adsorbing pro-inflammatory cytokines. Overall, this EV-inspired strategy offers new avenues for the treatment of emerging infectious diseases. Herein, this review systematically summarizes the current applications of EV-inspired strategies in the diagnosis and treatment of COVID-19. The current status and challenges associated with the clinical implementation of EV-inspired strategies are also discussed. The goal of this review is to provide new insights into the design of EV-inspired strategies and expand their application in combating emerging infectious diseases.

Despite medical interventions, COVID-19 continues to persist at pandemic proportions. A hypercoagulation state was rapidly observed in the severely ill, and the incidence of thromboembolic events remains elevated. Interleukin inhibitors have demonstrated positive effects on the hyperactivation of the immune system in COVID-19, with the interleukin-6 inhibitor tocilizumab showing promising results in reducing mortality. Nevertheless, the impact of interleukin inhibitors on the coagulation system remains incompletely understood.

In this clinical trial conducted in Stockholm, Sweden, interleukin inhibitors, namely anakinra (ANA) or tocilizumab (TOCI), were randomly administered in addition to standard care (SC) to hospitalized patients with COVID-19. A control group received only SC. The primary outcome sought to measure effects on global hemostasis, as indicated by changes in functional coagulation tests, specifically Rotational Thromboelastometry (ROTEM) or Overall Hemostatic Potential (OHP), visualized through scanning electron microscopy images. Secondary outcomes included effects on conventional coagulation laboratory tests.

The study enrolled 74 patients who were randomized to receive either ANA or TOCI in addition to SC, or SC alone. In the TOCI group, ROTEM variables exhibited less hypercoagulation after 29 days compared with ANA or SC treatment groups, characterized by prolonged clot formation time and decreased clot firmness. OHP decreased, but there were no significant differences among the three treatment groups. Plasma fibrinogen levels, initially elevated, decreased significantly in TOCI recipients over time.

Tocilizumab treatment demonstrated a significant reduction of hypercoagulation in hospitalized COVID-19 patients, by improvements in both global coagulation tests and conventional laboratory tests, in comparison with anakinra or SC alone. This finding underscores the significance of tocilizumab as a viable treatment option in severe COVID-19 cases, with the potential to decrease thrombosis incidence.

How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9+ macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9+ macrophages contain SARS-CoV-2, recruit and interact with Isg12+Cst7+ neutrophils to clear the viruses. After viral clearance, Slamf9+ macrophages differentiate into Trem2+ and Fbp1+ macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9+ macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.