The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity. The severe groups showed trends to enhanced superoxide production in parallel to lower OPA1-S levels. Unbalance of pivotal mitochondrial fusion (MFN2, OPA1) and fission (DRP1, FIS1) proteins was detected, suggesting a disruption in mitochondrial dynamics, as well as a lack of structural integrity in the electron transport chain. In serum, altered cytokine levels of IL-1β, IFN-α2, and IL-27 persisted long after clinical recovery, and growing amounts of the latter after severe infection correlated with lower basal and maximal respiration, ATP production, and glycolytic capacity. Finally, a trend for higher circulating levels of 3-hydroxybutyrate was found in individuals recovered after severe compared to mild course. In summary, long after acute infection, mitochondrial and metabolic changes seem to differ in a situation of full recovery after mild infection versus the one evolving from severe infection.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) preserve cardiac and renal function by mechanisms that are not completely elucidated. Among other things, SGLT2i promote nutrient-deprivation signalling, which might affect the immune function. As the fate of immune cells is controlled by their metabolism, we aimed to study the mitochondrial integrity of lymphocytes isolated from renal transplant recipients with type 2 diabetes (T2D) upon SGLT2i therapy instauration and six-month follow up. In this real-world pilot study, the mitochondrial respiration of isolated peripheral blood mononuclear cells was monitored in a Seahorse XFp extracellular-flux analyzer and cells were photographed with a confocal microscope. Mitochondrial mass, membrane potential, and superoxide content of lymphocyte subpopulations were measured by flow cytometry (MitoTracker^TM Green, TMRM, and MitoSOX^TM Red probes). Leveraging in vivo conditions of immune cells, we evaluated their metabolic profiles associated with immune activation. Herein, we identified changes in redox homeostasis with sustained membrane polarization, and an increased mitochondrial biogenesis upon PHA stimulation that significantly correlated with changes in body weight and LDL-cholesterol levels, and a resultant compensatory mitochondrial function of lymphocytes. Our data suggest novel mechanisms induced by SGLT2i to modulate immune cells, which probably underlie the observed beneficial effects in kidney transplant recipients. Nonetheless, further mechanistic studies are required to extend these exploratory findings and encourage the use of this therapeutic strategy.

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.

Corrigendum: High complement factor H-related (FHR)-3 levels are associated with the atypical hemolytic uremic syndrome-risk allele CFHR3*BName of all authors as they appear in the published original article (If correcting author names please put the correct spelling. If adding authors, please include additional authors.)Richard B. Pouw1,2; Irene Gómez Delgado3; Alberto López Lera4; Santiago Rodríguez de Córdoba5; Diana Wouters1; Taco W. Kuijpers2; and Pilar Sánchez-Corral3,*Affiliations of all authors as they appear in the published original version of the article (If correcting affiliations please put the correct version. If adding affiliations, please include additional affiliations).1Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.2Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, Amsterdam, Netherlands.3Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, and Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain. 4Immunology Unit, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, and Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.5Biological Research Center (CIB)-CSIC, and Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.* Correspondence: pilar.sanchez-corral@idipaz.esKeywords: Complement, Factor H-related protein 3, CFHR3 gene, Atypical hemolytic uremic syndrome.Corrigendum on: Front Immunol. 2018 Apr 24;9:848. doi: 10.3389/fimmu.2018.00848. eCollection2018.High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B. Pouw RB(1)(2), Gómez Delgado I(3), López Lera A(4), Rodríguez de Córdoba S(5),Wouters D(1), Kuijpers TW(2)(6), Sánchez-Corral P(3).Incorrect Funder NameThere is an error in the Funding statement. The correct Name for the Funder “Spanish Ministerio de Economía y Competitividad” is “Spanish Instituto de Salud Carlos III”. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of unknown etiology, resulting in unmet therapeutic needs. Symptoms heterogeneity and incomplete mechanistic understanding hinder effective patient stratification. We aimed to evaluate the integrated peripheral immune response in established MS clinical subtypes, focusing on differences in mitochondrial function that might validate this stratification and further clarify MS etiology. Mitochondrial activity of peripheral blood mononuclear cells (PBMCs) upon PHA-stimulation was analysed in MS patients (58 relapsing-remitting (RRMS), 21 secondary progressive (SPMS), and 35 primary progressive (PPMS)) and 35 healthy controls (HC). In unstimulated conditions, MS patients presented higher mitochondrial ROS (reactive oxygen species) and decreased coupling than HC. Compared with other progressive MS (PMS) subtypes, PBMCs from RRMS presented significantly higher early/late activation and proliferation after PHA stimulation (P = 0.013/P = 0.002, and P = 0.04, respectively), with increased mitochondrial depolarization (P = 0.017). Compared to HC, PHA-stimulated PBMCs from PMS exhibited marked decreases in basal (P = 0.017), maximal, and ATP-linked respiration, increased coupling (P = 0.009), and lower spare respiratory and glycolytic capacities (basal: P = 0.015, maximal: P = 0.064), with parallel decreased GLUT1 expression (P = 0.025). These changes appeared independent of some treatments. Upon PHA-stimulation, PMS patients displayed decreased basal, maximal, ATP-linked respiration, and reduced spare respiratory and glycolytic capacities, compared to RRMS and HC, mirroring opposed trends in unstimulated conditions. These findings suggest a severity gradient across MS clinical forms, supporting a disease continuum rather than strictly defined subtypes. The central role of unresolved mitochondrial dysfunction in MS warrants further investigation and may guide novel therapeutic strategies.