B and T cell responses to the 3rd and 4th dose of the BNT162b2 vaccine in dialysis patients.

Patients on dialysis (PoD) are at high risk of severe morbidity and mortality from COVID-19. Characterizing long-term vaccine immune responses in these patients will help optimize vaccine schedule for PoD. This study aimed to determine whether long-term humoral and B and T cell-responses post 3rd and 4th dose of the BNT162b2 vaccine differed between PoD and controls. Non-infected PoD and controls vaccinated with BNT162b2 were recruited in Ziv Medical Center, Israel, between 2021 and 2022. Specimens were collected 1-2 months pre 3rd dose; 1-3 months post 3rd dose; 4-5 months post 3rd dose and 3-5 months post the 4th dose. Anti-SARS-CoV-2 spike (spike) specific antibodies, spike specific memory B cells, and spike specific CD154+ T cells as well as cytokines producing CD4+/CD8+ T cells were measured using standardized assays and compared between PoD and controls at each time point using Mann Whitney and Fisher's exact tests. We recruited 22 PoD and 20 controls. Antibody levels in PoD were lower compared to controls pre 3rd dose but not post 3rd and 4th doses. Frequencies of spike specific memory B cell populations were similar between PoD and controls overall. Frequencies of spike specific T cells, including those producing IFNγ and TNFα, were not lower in PoD. B and T cell mediated immune response in PoD following a 3rd and a 4th dose of the BNT162b2 vaccine was not inferior to controls up to 5 months post vaccination. Our results suggest that standard BNT162b2 vaccination is suitable for this group.

Protective Effects of BNT162b2 Vaccination on Aerobic Capacity Following Mild to Moderate SARS-CoV-2 Infection: A Cross-Sectional Study Israel.

Patients previously infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may experience post-acute adverse health outcomes, known as long COVID. The most reported symptoms are fatigue, headache and attention/concentration issues, dyspnea and myalgia. In addition, reduced aerobic capacity has been demonstrated in both mild and moderate COVID-19 patients. It is unknown whether COVID-19 vaccination mitigates against reduced aerobic capacity. Our aim was to compare the aerobic capacity of vaccinated and unvaccinated individuals previously infected with SARS-CoV-2. Methods: Individuals aged 18 to 65 years with laboratory-confirmed mild to moderate COVID-19 disease were invited to Ziv Medical Centre, Israel, three months after SARS-CoV-2 infection. We compared individuals unvaccinated at the time of infection to those vaccinated in terms of aerobic capacity, measured using symptom-limited cardiopulmonary exercise test (CPET). Results: We recruited 28 unvaccinated and 22 vaccinated patients. There were no differences in baseline demographic and pulmonary function testing (PFT) parameters. Compared with unvaccinated individuals, those vaccinated had higher V'O2/kg at peak exercise and at the anaerobic threshold. The V'O2/kg peak in the unvaccinated group was 83% of predicted vs. 100% in the vaccinated (p < 0.002). At the anaerobic threshold (AT), vaccinated individuals had a higher V'O2/kg than those unvaccinated. Conclusions: Vaccinated individuals had significantly better exercise performance. Compared with vaccinated individuals, a higher proportion of those unvaccinated performed substantially worse than expected on CPET. These results suggest that vaccination at the time of infection is associated with better aerobic capacity following SARS-CoV-2 infection.

Insulin Directly Regulates the Circadian Clock in Adipose Tissue.

Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a "zeitgeber" aligning the clock in AT with the external time, but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes PER2, PER3, and NR1D1 in SAT were differentially changed upon insulin and saline infusion, suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells, and AT explants from mPer2Luc knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression, leading to the phase shift of circadian oscillations, with similar effects for Per1 Insulin effects were dependent on the region between -64 and -43 in the Per2 promoter but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes, thus representing a primary mechanism of feeding-induced AT clock entrainment.

Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor α activity.

Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo- and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RARα activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RARα signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RARα. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RARα activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RARα activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinol-dependent metabolic function of RBP4 that may have important implications for the treatment of obesity.