Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT04288102). METHODS: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). FINDINGS: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. INTERPRETATION: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. FUNDING: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).

Machine Learning-Based Scoring System for Early Prognosis Evaluation of Patients with Coronavirus Disease 2019

Background The global spread of coronavirus disease 2019 (COVID-19) continues to threaten human health security, exerting considerable pressure on healthcare systems worldwide. While prognostic models for COVID-19 hospitalized or intensive care patients are currently available, prognostic models developed for large cohorts of thousands of individuals are still lacking. Methods Between February 4 and April 16, 2020, we enrolled 3,974 patients admitted with COVID-19 disease in the Wuhan Huo-Shen-Shan Hospital and the Maternal and Child Hospital, Hubei Province, China. (1) Screening of key prognostic factors: A univariate Cox regression analysis was performed on 2,649 patients in the training set, and factors affecting prognosis were initially screened. Subsequently, a random survival forest model was established through machine analysis to further screen for factors that are important for prognosis. Finally, multivariate Cox regression analysis was used to determine the synergy among various factors related to prognosis. (2) Establishment of a scoring system: The nomogram algorithm established a COVID-19 patient death risk assessment scoring system for the nine selected key prognostic factors, calculated the C index, drew calibration curves and drew training set patient survival curves. (3) Verification of the scoring system: The scoring system assessed 1,325 patients in the test set, splitting them into high- and low-risk groups, calculated the C-index, and drew calibration and survival curves. Results The cross-sectional study found that age, clinical classification, sex, pulmonary insufficiency, hypoproteinemia, and four other factors (underlying diseases: blood diseases, malignant tumor;complications: digestive tract bleeding, heart dysfunction) have important significance for the prognosis of the enrolled patients with COVID-19. Herein, we report the discovery of the effects of hypoproteinemia and hematological diseases on the prognosis of COVID-19. Meanwhile, the scoring system established here can effectively evaluate objective scores for the early prognoses of patients with COVID-19 and can divide them into high- and low-risk groups (using a scoring threshold of 117.77, a score below which is considered low risk). The efficacy of the system was better than that of clinical classification using the current COVID-19 guidelines (C indexes, 0.95 vs. 0.89). Conclusions Age, clinical typing, sex, pulmonary insufficiency, hypoproteinemia, and four other factors were important for COVID-19 survival. Compared with general statistical methods, this method can quickly and accurately screen out the relevant factors affecting prognosis, provide an order of importance, and establish a scoring system based on the nomogram model, which is of great clinical significance.

Immunogenicity of COVID-19 Vaccination in People Living with HIV: Progress and Challenges

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in numerous confirmed cases and deaths worldwide. Recent studies have shown that people living with HIV (PLWH) are prone to develop severe illness and poor outcomes if they experience coronavirus disease 2019 (COVID-19), especially those with uncontrolled viremia and low CD4 T-cell count. Therefore, many countries prioritized PLWH for COVID-19 vaccination. However, lower magnitude or faster waning humoral immune responses elicited by other vaccines have been documented in PLWH, raising concerns regarding the efficacy of the COVID-19 vaccine in these specific populations. Here, we summarize the current progress in the immunogenicity and efficacy of different types of SARS-CoV-2 vaccinations in PLWH and highlight several challenges faced by PLWH in the current COVID-19 pandemics.

Effect of Different Factors on the Quality of Life and Sequelae of COVID-19 Patients After Discharge

Background The continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an international public health emergency, resulting in a significant global disease burden. The long-term effects of SARS-CoV-2 infection in humans and the long-term prognosis of patients with coronavirus disease 2019 (COVID-19) after discharge remain unclear. We aimed to assess the quality of life (QoL) and sequelae in patients with COVID-19 after discharge from the hospital by conducting multiple follow-up visits to understand the long-term effects of SARS-CoV-2 on patients' health and its possible influencing factors. Methods COVID-19 patients discharged from Huoshenshan Hospital (Wuhan, China) between February 15 and April 5, 2020, were followed up at 6, 9, and 12 months after discharge. They completed questionnaires on postdischarge QoL and sequelae under the guidance of medical staff with professional training. The demographic and clinical characteristics of the COVID-19 patients were analyzed using descriptive statistics. A generalized estimating equation model was used to analyze the QoL-related factors. The χ2 test (or Fisher exact test) and multivariate logistic regression analysis were used to analyze the sequelae and influencing factors. Results A total of 175 patients participated in at least 1 follow-up visit, and 120 completed all 3 follow-up visits. Patients diagnosed with severe and critically ill COVID-19 had worse mental conditions (χ2 = 7.653, P = 0.022) than those with the nonsevere type (not severe or critical) and were more likely to feel fatigued (χ2 = 4.836, P = 0.028). Female patients had a higher risk of sleep disturbance (χ2 = 10.026, P = 0.002) and dyspnea (χ2 = 5.672, P = 0.017) and had more difficulty returning to their original work and life (χ2 = 8.922, P = 0.003) than male patients. Patients with diabetes had a worse appetite (χ2 = 4.669, P = 0.031) and were more prone to sleep disturbance (χ2 = 4.417, P = 0.036) after discharge. The proportion of patients with at least 1 sequela increased from 29.76% (50/168) at 6 months to 51.11% (69/135) at 9 months (χ2 = 14.305, P < 0.001). Compared with the nonsevere type, patients diagnosed with severe and critically ill COVID-19 had an odds ratio (OR) of 4.325 (95% confidence interval [CI], 1.215–15.401) for memory decline. Female patients had an OR of 4.632 (95% CI, 1.716–12.501) for joint or muscle pain. Patients with hypertension had an OR of 3.014 (95% CI, 1.193–7.615) for joint or muscle pain. Conclusion One year after discharge, there were still some patients with varying degrees of decline in QoL and sequelae, which occurred in all follow-up visits. Moreover, QoL and sequelae after discharge were related to sex, clinical classification of COVID-19, and underlying diseases.

Dynamics of SARS-CoV-2 Antibody Responses up to 9 Months Post-Vaccination in Individuals with Previous SARS-CoV-2 Infection Receiving Inactivated Vaccines.

Humoral immunity confers protection against COVID-19. The longevity of antibody responses after receiving an inactivated vaccine in individuals with previous SARS-CoV-2 infection is unclear. Plasma samples were collected from 58 individuals with previous SARS-CoV-2 infection and 25 healthy donors (HDs) who had been vaccinated with an inactivated vaccine. The neutralizing antibodies (NAbs) and S1 domain-specific antibodies against the SARS-CoV-2 wild-type and Omicron strains and nucleoside protein (NP)-specific antibodies were measured using a chemiluminescent immunoassay. Statistical analysis was performed using clinical variables and antibodies at different timepoints after SARS-CoV-2 vaccination. NAbs targeting the wild-type or Omicron strain were detected in individuals with previous SARS-CoV-2 infection at 12 months after infection (wild-type: 81%, geometric mean (GM): 20.3 AU/mL; Omicron: 44%, GM: 9.4 AU/mL), and vaccination provided further enhancement of these antibody levels (wild-type: 98%, GM: 53.3 AU/mL; Omicron: 75%, GM: 27.8 AU/mL, at 3 months after vaccination), which were significantly higher than those in HDs receiving a third dose of inactivated vaccine (wild-type: 85%, GM: 33.6 AU/mL; Omicron: 45%, GM: 11.5 AU/mL). The level of NAbs in individuals with previous infection plateaued 6 months after vaccination, but the NAb levels in HDs declined continuously. NAb levels in individuals with previous infection at 3 months post-vaccination were strongly correlated with those at 6 months post-vaccination, and weakly correlated with those before vaccination. NAb levels declined substantially in most individuals, and the rate of antibody decay was negatively correlated with the neutrophil-to-lymphocyte ratio in the blood at discharge. These results suggest that the inactivated vaccine induced robust and durable NAb responses in individuals with previous infection up to 9 months after vaccination.

Host-directed therapies for COVID-19.

PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus-2-induced hyperinflammation is a major cause of death or end-organ dysfunction in COVID-19 patients. We review adjunct host-directed therapies (HDTs) for COVID-19 management. RECENT FINDINGS: The use of umbilical cord-derived mesenchymal stem cells as HDT for COVID-19 has been shown to be safe in phase 1 and 2 trials. Trials of anti-interleukin-6 receptor antibodies show promising mortality benefit in hospitalized COVID-19 patients. Repurposed drugs and monoclonal antibodies targeting specific cytokines acting on different aspects of the pro- and anti-inflammatory cascades are under evaluation. SUMMARY: A range of HDTs shows promise for reducing mortality and improving long term disability in patients with severe COVID-19, and require evaluation in randomized, controlled trials.

Safety and immunogenicity of COVID-19 vaccination in immunocompromised patients.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic poses a great threat to public health. Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes. Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations; however, these clinical trials have excluded immunocompromised populations. Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines, raising concerns regarding the efficacy of COVID-19 vaccination in these populations. Thus, there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations. Here, we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations, including HIV-infected patients and those receiving immunosuppressive treatment, especially solid organ transplant recipients and those undergoing anti-CD20 treatment. We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.

Immunogenicity of inactivated coronavirus disease 2019 vaccines in patients with chronic hepatitis B undergoing antiviral therapy.

Objectives: To investigate the effect and its mechanisms of different antiviral agents on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic hepatitis B (CHB). Methods: A total of 125 patients with CHB receiving nucleos(t)ide analogs (NAs) monotherapy or combined with Peg-interferon-alpha (Peg-IFNα) therapy and 29 healthy controls (HCs) were enrolled. Adverse reactions (ADRs) and levels of neutralizing antibody (NAb), immunoglobulin G (IgG), immunoglobulin M (IgM), and peripheral cytokines post-vaccination were analyzed. Results: All ADRs were tolerable in CHB patients. Overall, no significant difference was observed in the antibody levels between patients and HCs after two doses of vaccination. An inverse correlation between NAb, IgG titers and the days after two doses was found in non-IFN group but not in IFN group. Correspondingly, peripheral interferon-γ levels were significantly higher in IFN group than in non-IFN group. After a booster dose, NAb and IgG antibodies were maintained at high levels in NA-treated patients. Conclusion: Peg-interferon-alpha-based therapy may be beneficial for maintaining the immunogenicity of SARS-CoV-2 vaccines in CHB patients, which may be related to the high levels of IFN-γ induced by Peg-IFNα therapy. A booster dose can effectively recall the robust and long-lasting immunogenicity of SARS-CoV-2 vaccines.

Prolonged Viral Shedding in Three Young Adult Cases of COVID-19

Severe acute respiratory syndrome coronavirus-2 infection is usually self-limited, with a short duration for viral shedding within several weeks. However, prolonged viral shedding has been observed in severe or immune-compromised coronavirus disease 2019 (COVID-19) cases. Here, we reported that three young adult cases of COVID-19 patients, who were either immunosuppressed nor severe, showed prolonged viral RNA shedding from the upper respiratory tract for 58, 81, and 137 days since initial diagnosis. To our knowledge, this is the longest duration of viral shedding reported to date in young adult patients. Further studies on factors relevant to prolonged viral positivity, as well as the correlation between viral positivity and transmission risk are needed for the optimal management of COVID-19 patients with prolonged nucleic acid positive.

Effect of methylprednisolone therapy on hospital stay and viral clearance in patients with moderate COVID-19

Background The benefits and harms of methylprednisolone treatment in patients with moderate coronavirus disease 2019 (COVID-19) remain controversial. In this study, we investigated the effect of methylprednisolone on mortality rate, viral clearance, and hospitalization stay in patients with moderate COVID-19. Methods This retrospective study included 4827 patients admitted to Wuhan Huoshenshan and Wuhan Guanggu hospitals from February to March 2020 diagnosed with COVID-19 pneumonia. The participants’ epidemiological and demographic data, comorbidities, laboratory test results, treatments, outcomes, and vital clinical time points were extracted from electronic medical records. The primary outcome was in-hospital death;secondary outcomes were time from admission to viral clearance and hospital stay. Univariate and multivariate logistic or linear regression analysis were used to assess the roles of methylprednisolone in different outcomes. The propensity score matching (PSM) method was used to control for confounding factors. Results A total of 1320 patients were included in this study, of whom 100 received methylprednisolone. Overall in-hospital mortality was 0.91% (12/1320);the 12 patients who died were all in the methylprednisolone group, though multivariate logistic regression analysis showed methylprednisolone treatment was not a risk factor for in-hospital death in moderate patients before or after adjustment for confounders by PSM. Methylprednisolone treatment was correlated with longer length from admission to viral clearance time and hospital stay before and after adjustment for confounders. Conclusions Methylprednisolone therapy was not associated with increased in-hospital mortality but with delayed viral clearance and extended hospital stay in moderate COVID-19 patients.

Mesenchymal stem cell treatment for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a global pandemic since late 2019 that resulted in more than 360 million population infection. Among them, less than 7% of infected individuals develop severe or critical illness. Mass vaccination has been carried out, but reinfection and vaccine breakthrough cases still occur. Besides supportive and antiviral medications, much attention has been paid in immunotherapies that aim at reducing pathological changes in the lungs. Mesenchymal stem cells (MSCs) is used as an option because of their immunomodulatory, anti-inflammatory, and regenerative properties. As of January 16, 2022, when ClinicalTrials.gov was searched for "Mesenchymal stem cells and COVID-19," over 80 clinical trials were registered. MSC therapy was found to be safe and some effective in preclinical and clinical studies. Here, we summarize the major pathological characteristics of COVID-19 and provide scientific and rational evidence for the safety and possible effectiveness of MSCs in COVID-19 treatment.

Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

Dynamic changes in liver function parameters in patients with coronavirus disease 2019: a multicentre, retrospective study.

BACKGROUND: Liver injuries have been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate the clinical role played by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: In this multicentre, retrospective study, the parameters of liver function tests in COVID-19 inpatients were compared between various time-points in reference to SARS-CoV-2 shedding, and 3 to 7 days before the first detection of viral shedding was regarded as the reference baseline. RESULTS: In total, 70 COVID-19 inpatients were enrolled. Twenty-two (31.4%) patients had a self-medication history after illness. At baseline, 10 (14.3%), 7 (10%), 9 (12.9%), 2 (2.9%), 15 (21.4%), and 4 (5.7%) patients already had abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), albumin, and total bilirubin (TBIL) values, respectively. ALT and AST abnormal rates and levels did not show any significant dynamic changes during the full period of viral shedding (all p > 0.05). The GGT abnormal rate (p = 0.008) and level (p = 0.033) significantly increased on day 10 of viral shedding. Meanwhile, no simultaneous significant increases in abnormal ALP rates and levels were observed. TBIL abnormal rates and levels significantly increased on days 1 and 5 of viral shedding (all p < 0.05). Albumin abnormal decrease rates increased, and levels decreased consistently from baseline to SARS-CoV-2 clearance day (all p < 0.05). Thirteen (18.6%) patients had chronic liver disease, two of whom died. The ALT and AST abnormal rates and levels did not increase in patients with chronic liver disease during SARS-CoV-2 shedding. CONCLUSIONS: SARS-CoV-2 does not directly lead to elevations in ALT and AST but may result in elevations in GGT and TBIL; albumin decreased extraordinarily even when SARS-CoV-2 shedding ended.

Mesenchymal stem cell therapy for severe COVID-19.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.

Single-Cell Transcriptomic Profiling of MAIT Cells in Patients With COVID-19.

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.

Acute Kidney Injury and Early Predictive Factors in COVID-19 Patients.

Objectives: Our objective was to explore the incidence and early predictive factors of acute kidney injury in coronavirus disease 2019 (COVID-19) patients. Method: We established a retrospective cohort of 408 patients who were admitted to Shenzhen Third People's Hospital in Shenzhen, China, between January 1 and March 31, 2020. Clinical outcomes and renal function were monitored until April 12, 2020, with a median follow-up duration of 21 days [interquartile range (IQR) = 14-33]. Results: When first admitted to hospital (baseline), 19.36% (79/408) presented renal dysfunction [estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2]. During follow-up, 3.9% (16/408) developed acute kidney injury (AKI). Age ≥60 years [hazard ratio (HR) = 4.78, 95% CI = 1.10-20.69], PaO2/FiO2 ratio <300 (HR = 3.48, 95% CI = 1.04-11.62), and higher creatinine (HR = 1.04, 95% CI = 1.01-1.07) at baseline independently predicted the risk of AKI. Respectively, 25.0% (102/408), 3.9% (16/408), 0.5% (2/408), 1.0% (4/408), and 0.2% (1/408) experienced G2, G3a, G3b, G4, and G5 as their most severe category during hospitalization, while 69.4% (283/408) had normal eGFRs throughout the follow-up period. When finally discharged from hospital, there were 12.5% (51/408) of patients with abnormal eGFRs. Conclusions: COVID-19 patients can be at risk of AKI and continuous eGFR decline during hospitalization, which can be early predicted by baseline factors. Some individuals still had renal dysfunction when finally discharged from hospital.

A multi-omics investigation of the composition and function of extracellular vesicles along the temporal trajectory of COVID-19.

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane1. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes2,3, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.

Immunometabolism: new insights and lessons from antigen-directed cellular immune responses.

Modulation of immune responses by nutrients is an important area of study in cellular biology and clinical sciences in the context of cancer therapies and anti-pathogen-directed immune responses in health and disease. We review metabolic pathways that influence immune cell function and cellular persistence in chronic infections. We also highlight the role of nutrients in altering the tissue microenvironment with lessons from the tumor microenvironment that shapes the quality and quantity of cellular immune responses. Multiple layers of biological networks, including the nature of nutritional supplements, the genetic background, previous exposures, and gut microbiota status have impact on cellular performance and immune competence against molecularly defined targets. We discuss how immune metabolism determines the differentiation pathway of antigen-specific immune cells and how these insights can be explored to devise better strategies to strengthen anti-pathogen-directed immune responses, while curbing unwanted, non-productive inflammation.