Literature DB >> 35711451

Autophagy Hijacking in PBMC From COVID-19 Patients Results in Lymphopenia.

Cristiana Barbati1, Alessandra Ida Celia1, Tania Colasanti1, Marta Vomero2, Mariangela Speziali1, Erisa Putro1, Giorgia Buoncuore1, Flavia Savino1, Serena Colafrancesco1, Federica Maria Ucci1, Claudia Ciancarella1, Eugenia Balbinot1, Susanna Scarpa3, Francesco Natalucci1, Greta Pellegrino1, Fulvia Ceccarelli1, Francesca Romana Spinelli1, Claudio Maria Mastroianni4, Fabrizio Conti1, Cristiano Alessandri1.   

Abstract

Autophagy is a homeostatic process responsible for the self-digestion of intracellular components and antimicrobial defense by inducing the degradation of pathogens into autophagolysosomes. Recent findings suggest an involvement of this process in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the role of autophagy in the immunological mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis remains largely unexplored. This study reveals the presence of autophagy defects in peripheral immune cells from COVID-19 patients. The impairment of the autophagy process resulted in a higher percentage of lymphocytes undergoing apoptosis in COVID-19 patients. Moreover, the inverse correlation between autophagy markers levels and peripheral lymphocyte counts in COVID-19 patients confirms how a defect in autophagy might contribute to lymphopenia, causing a reduction in the activation of viral defense. These results provided intriguing data that could help in understanding the cellular underlying mechanisms in COVID-19 infection, especially in severe forms.
Copyright © 2022 Barbati, Celia, Colasanti, Vomero, Speziali, Putro, Buoncuore, Savino, Colafrancesco, Ucci, Ciancarella, Balbinot, Scarpa, Natalucci, Pellegrino, Ceccarelli, Spinelli, Mastroianni, Conti and Alessandri.

Entities:  

Keywords:  COVID-19; SARS-CoV-2; apoptosis; autophagy; inflammation; lymphocytes

Mesh：

Year:  2022        PMID： 35711451      PMCID： PMC9196331          DOI： 10.3389/fimmu.2022.903498

Source DB:  PubMed          Journal:  Front Immunol        ISSN： 1664-3224            Impact factor:   8.786


Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus that emerged in late 2019 and caused a pandemic of acute respiratory disease, named “coronavirus disease 2019” (COVID-19), which still now threatens human health and public safety (1). In severe COVID-19 patients, both adaptive and innate immune responses that are critical for antiviral reactions were described as impaired (2). In particular, lymphopenia (lymphocyte count <1.0 × 109/L)3 and inflammatory cytokine storm are typical abnormalities found in COVID-19 patients, probably associated with disease severity, highlighting the strong SARS-CoV-2 ability in suppressing the adaptive immune responses (3). Recent studies have shown that COVID-19 patients, compared to healthy controls, had significantly lower absolute numbers of total lymphocytes and subsets of CD3+, CD4+, and CD8+ T cells, CD19+ B cells, and CD56+ NK cells (4). Concerning this, lymphocytes’ survival is known to be closely regulated by autophagy (5). Autophagy is a metabolic process involved in the degradation of intracellular components via lysosomal machinery, by engulfment of damaged proteins and organelles in double-membrane vesicles called autophagosomes (6). Furthermore, the crosstalk between autophagy and apoptosis, crucial for cell survival, has been previously shown (7), and several studies correlated the disruption of autophagy with the contemporary increase of apoptotic cell death in several diseases (8). In COVID-19 patients, the accumulation of autophagosomes promoted by SARS-CoV-2 infection may exacerbate the processes of apoptotic cell death (9), and higher levels of apoptosis in lymphocytes could be related to lymphopenia detected in severe COVID-19 conditions (10). To date, the mechanism underlying the kinetics of peripheral lymphocyte changes due to COVID-19 is unclear. This study sought to investigate the relationship between COVID-19 and the autophagy of circulating peripheral blood mononuclear cells (PBMCs) to better characterize lymphopenia during SARS-CoV-2 infection.

Material and Methods

Patients

Eighteen COVID-19 patients attending the University Hospital Policlinico Umberto I, Sapienza University of Rome, were enrolled. The study was approved by the local ethics committee (protocol number 0586/20), and informed consent was obtained from each patient. As a control group, twelve age- and sex-matched healthy donors (HDs) were studied. From every participant in the study, a blood sample was collected to purify PBMCs by Ficoll-Hypaque. Sera were obtained by centrifugation at 3,500 rpm for 15 min and then stored at −20°C until use for in vitro treatments.

Cell Cultures and Treatments

After counting, isolated PBMCs were cultured on 6-well dishes at a concentration of 2 × 106 PBMCs/ml/well in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 2 mM of glutamine, and 50 μg/ml of gentamycin and treated with the following: i) lysosomal inhibitors E64d and pepstatin A (both at 10 μg/ml) for 2 h before the end of culture; ii) 10% COVID-19 or HD sera (as a replacement of FBS) for 24 h, selected by preliminary time-course experiments (11).

Autophagy Marker Detection by Western Blotting

On the same day of the blood sample collection and after in vitro treatment with sera, PBMCs were lysed in radioimmunoprecipitation assay (RIPA) buffer (100 mM of Tris-HCl pH 8, 150 mM of NaCl, 1% Triton X-100, 1 mM of MgCl, 25 mM of NaVO4, and protease-inhibitor mixture). Lysates were loaded onto a 15% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) in denaturing conditions. Subsequently, Western blotting was performed, and the membranes were incubated with a rabbit anti-human LC3IIB and a rabbit anti-p62 Abs (1:1,000 diluted in Tris-buffered saline containing milk at 5%) (Cell Signaling, Danvers, MA, USA) (12). Peroxidase-conjugated goat anti-rabbit IgG was used as a secondary Abs, and the reaction was developed using the SuperSignal West Pico Chemiluminescent Substrate (Millipore, Billerica, MA, USA). A rabbit anti-human β-actin Ab was used to ensure the presence of equal amounts of protein. Quantification of protein expression was performed by densitometry analysis.

Flow Cytometry for Apoptosis and Autophagy Analysis

As before, PBMC apoptosis was analyzed using a fluorescein isothiocyanate (FITC)-conjugated annexin V (AV) and phycoerythrin (PE)-conjugated propidium iodide (PI) apoptosis detection kit, according to the manufacturer’s protocol (MBL, Woburn, MA, USA). In particular, 1 × 106 PBMCs were stained in AV buffer with AV-FITC and PI-PE (1:100 diluted) for 10 min in the dark. After washing, cells were transferred into fluorescence-activated cell sorting (FACS) tubes and analyzed. The acquisition was performed on a FACSCalibur cytometer (BD, San Jose, CA, USA), and 10,000 events/sample were run. Data were analyzed using the Cell Quest Pro software (11). Autophagy levels in CD4+, CD8+, CD19+ lymphocytes, and CD14+ cells from COVID-19 were also detected using the Cyto-ID autophagy detection kit (Enzo Life Sciences, Farmingdale, NY, USA). The probe used in this kit consists of cationic amphiphilic tracer dye that stains autophagolysosomes (13). For the immunophenotyping analysis, see the .

Immunofluorescence of Autophagy Markers

An indirect immunofluorescence assay was developed on freshly isolated PBMCs from both COVID-19 patients and HDs, prepared by the cytospin technique. In detail, after slide preparation, a cell suspension of 0.5 × 106 cells/ml was gently pipetted into the cytofunnel and centrifuged at 1,000 × g for 5 min. The removed slides, after drying at least 2 h at room temperature (RT), were fixed with paraformaldehyde (PFA) at 4% in phosphate-buffered saline (PBS) for 15 min at RT, then treated with PBS-Triton X-100 0.1% for 10 min, and blocked with 3% bovine serum albumin (BSA) in PBS for 30 min at RT. Successively, slides were incubated overnight at 4°C with the following primary antibodies: rabbit anti-human LC3IIB (Cell Signaling; 1:100 diluted) and a mouse anti-human lysosomal-associated membrane protein 1 (LAMP1) (Invitrogen, Carlsbad, CA, USA; 1:100 diluted). The day after, slides were washed three times in PBS, and Tetramethylrhodamine-isothiocyanate (TRITC)–anti-rabbit and FITC–anti-mouse IgG (Sigma Aldrich) were added and incubated for 45 min at RT. After incubation, slides were washed three times in PBS, and the second wash was performed with the addition of Hoechst (Molecular Probes, Eugene, OR, USA) for nuclear staining. Fluorescence was analyzed by a fluorescence microscope (Olympus, Tokyo, Japan; BX52). Image acquisition and processing were conducted by IAS 2000 software. Morphometric analysis of cellular expression was carried out by counting at least 200 cells in different microscopic fields at magnifications of 50× and 100×.

Statistical Analysis

Data are expressed as means ± SD. Results were analyzed with GraphPad Prism 6. The Mann–Whitney test or Student’s t-test was used to compare quantitative variables in different groups, and the chi-square test was used to test a correlation between categorical variables. Spearman’s rank correlation coefficient was applied for the calculation of the correlation between parallel variables in single samples. Values of p < 0.05 were considered statistically significant.

Results

Serological Characteristics of COVID-19 Patients

The serological characteristics of COVID-19 patients are summarized in .
Table 1

Summarizes serological features of the enrolled patients.

PATIENTGENDERHAEMOGLOBIN (g/dL)PLATELET (103X µL) LEUKOCYTE (103X µL)NEUTROPHILS (103X µL) LYMPHOCYTES (103X µL) EOSINOPHILS (103X µL)ESR (mm/h)CPR (µg/L)Ferritin (ng/mL)D-dimersIL-6 (pg/mL)
(ng/mL)
HIGH INFLAMMATORY PROFILE (HIP)
3 F14.62285860426099040NA3700965257.75
5 M13.331610590907075010616140066734449.62
8 F9.91124580355066010266007217014.06
9 M8.4237231019302201056139800614730NA
12 M109858104860370200NANANANANA
16 M12.14831289011580790120NA1390NA1079NA
LOW INFLAMMATORY PROFILE (LIP)
6 M12.4222741049901830302210300150177521.43
7 M14.323746402610161020381060023065814.83
11 M16.1130142409270180010NA97800NANANA
15 M11.6387101605930335060NA12900NA455NA
10 F14.62641180096801113400NA3640NA1194NA
14 M13.736580306300115020NA5080NA1574NA
1 M15282838058661187243929001471704.65
2 M12.5244770049701960160NA35022467NA
4 M15.1173704038402270150NA13002471703.08
13 F12.931457203830116020NA4520NANANA
17 M8.924074160393064300100NA3100NANANA
18 FNANANANANANANANANANANA

Laboratory abnormalities findings are reported in red. Patients were divided into two groups. The first group, High Inflammatory Profile (HIP), includes patients who reported lymphopenia (Lymphocyte <1000 cells/μL), and almost one of the following serological features: Platelets <100.000/μL, IL-6 >5.9 pg/mL, CRP >5000 µg/L, D-dimers >1000 μg/L , Ferritin >250 ng/mL, ESR > 30 mmh. The second group didn’t meet the above mentioned criteria and was defined Low Inflammatory Profile (LIP). Green lines displayed patients who showed high PBMC LC3IIB level (>2.5) based on the Western blot analysis. Not Available (NA).

Summarizes serological features of the enrolled patients. Laboratory abnormalities findings are reported in red. Patients were divided into two groups. The first group, High Inflammatory Profile (HIP), includes patients who reported lymphopenia (Lymphocyte <1000 cells/μL), and almost one of the following serological features: Platelets <100.000/μL, IL-6 >5.9 pg/mL, CRP >5000 µg/L, D-dimers >1000 μg/L , Ferritin >250 ng/mL, ESR > 30 mmh. The second group didn’t meet the above mentioned criteria and was defined Low Inflammatory Profile (LIP). Green lines displayed patients who showed high PBMC LC3IIB level (>2.5) based on the Western blot analysis. Not Available (NA). Patients were divided into two groups, high inflammatory profile (HIP) and low inflammatory profile (LIP), according to serological and laboratory features. Specifically, HIP patients displayed lymphocyte < 1,000 × 109/L with the addition of one of the following serological features: platelets < 100,000 × 109/L, IL-6 > 5.9 pg/ml, C-reactive protein (CRP) > 5,000 mg/ml, D-dimers > 1,000 ng/ml, ferritin > 250 ng/ml, and erythrocyte sedimentation rate (ESR) > 30 mm/h. LIP patients did not meet the abovementioned criteria.

Spontaneous Autophagy and Apoptosis in COVID-19 Patients and Healthy Donors

Basal autophagy and apoptosis in PBMCs from COVID-19 patients and HDs were evaluated, and our results showed significantly higher LC3IIB levels in COVID-19 patients compared to HDs (p < 0.0001) ( ), presuming an upregulation of autophagy. In addition, p62 levels were significantly higher in COVID-19 patients than in HDs (p < 0.0001) ( ), underlining an accumulation of p62 due to an autophagy impairment in these patients. Furthermore, freshly isolated PBMC apoptosis was higher in COVID-19 patients in comparison to HDs (p = 0.0186) ( ).
Figure 1

Spontaneous autophagy and apoptosis in COVID-19 patients and HDs. (A) LC3IIB and p62 Western blotting analysis of PBMC lysates (30 μg/lane) from 4 COVID-19 patients and 4 HDs. Blots shown are representative of independent experiments performed on COVID-19 patients (n = 18) and HDs (n = 12). Quantification of LC3IIB (B) and p62 (C) levels relative to β-actin is also shown (mean with range is presented) (Mann–Whitney test). (D) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as independent experiments performed in PBMC from COVID-19 patients (n = 18) and HDs (n = 12) (Mann–Whitney test). (E) Contingency: prospective data (chi-square test) between LC3IIB level and HIP/LIP patients. Values are expressed as means ± SD. *p < 0.05. COVID-19, coronavirus disease 2019; HDs, healthy donors; PBMC, peripheral blood mononuclear cell; AV, annexin V; HIP, high inflammatory profile; LIP, low inflammatory profile.

Spontaneous autophagy and apoptosis in COVID-19 patients and HDs. (A) LC3IIB and p62 Western blotting analysis of PBMC lysates (30 μg/lane) from 4 COVID-19 patients and 4 HDs. Blots shown are representative of independent experiments performed on COVID-19 patients (n = 18) and HDs (n = 12). Quantification of LC3IIB (B) and p62 (C) levels relative to β-actin is also shown (mean with range is presented) (Mann–Whitney test). (D) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as independent experiments performed in PBMC from COVID-19 patients (n = 18) and HDs (n = 12) (Mann–Whitney test). (E) Contingency: prospective data (chi-square test) between LC3IIB level and HIP/LIP patients. Values are expressed as means ± SD. *p < 0.05. COVID-19, coronavirus disease 2019; HDs, healthy donors; PBMC, peripheral blood mononuclear cell; AV, annexin V; HIP, high inflammatory profile; LIP, low inflammatory profile. Interestingly, we observed that patients showing high levels of LC3IIB (>2.5) were classified as HIP ( ). Moreover, COVID-19 immunophenotyping studies revealed higher levels of autophagolysosome formation in CD4+ and CD8+ cells compared to CD14+ cells (p = 0.04 and p = 0.0007, respectively); however, the autophagy level in CD19+ cells was not higher as compared to CD14+ cells ( — ).

Autophagy Block in Peripheral Blood Mononuclear Cells From COVID-19 Patients and Its Correlation With Apoptosis

According to these results, we hypothesized an autophagy dysfunction and/or blockade in PBMCs from COVID-19 patients. Thus, we assessed in vitro experiments with lysosomal inhibitors E64d and pepstatin A. In PBMCs from patients affected by COVID-19, LC3IIB levels did not change in the presence of lysosomal inhibitors, compared to untreated cells (p > 0.05) ( ). As previously demonstrated (11), we observed an increase in LC3IIB levels in HD PBMCs treated with lysosomal inhibitors versus untreated (p = 0.0286) ( ). Concurrently, p62 levels did not change in COVID-19 PBMCs treated with lysosomal inhibitors but increased in treated PBMCs from HDs, compared to untreated in both conditions (p > 0.05 and p = 0.0286, respectively) ( ). This result explains how a blocked mechanism does not undergo modifications under further inhibitory conditions. So PBMCs from COVID-19 patients, in which the mechanism is blocked, contrary to HD PBMCs, do not respond to inhibitors, and neither LC3IIB nor p62 nor apoptosis changed under E64d/pepstatin A treatment.
Figure 2

Effects of lysosomal inhibitors E64d and pepstatin A on PBMC autophagy. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 2 representative COVID-19 patients and 2 HDs (10 independent experiments). Where indicated, cells were treated with the lysosomal inhibitors E64d and pepstatin A indicated as “ini.” Densitometry analysis of LC3IIB (B) and p62 (C) levels relative to β-actin is also shown (Mann–Whitney test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019.

Effects of lysosomal inhibitors E64d and pepstatin A on PBMC autophagy. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 2 representative COVID-19 patients and 2 HDs (10 independent experiments). Where indicated, cells were treated with the lysosomal inhibitors E64d and pepstatin A indicated as “ini.” Densitometry analysis of LC3IIB (B) and p62 (C) levels relative to β-actin is also shown (Mann–Whitney test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019. However, we observed variability in p62 expression levels among patients in the COVID-19 cohort ( ). In detail, LIP patients were susceptible to E64d/pepstatin A treatment (p < 0.0001 for autophagy, p = 0.002 for apoptosis, versus untreated) (i.e., pz 2 in Western blotting of ), while HIP patients did not respond to autophagy inhibitors (p > 0.05) [i.e., pz 1 in ( )].
Figure 3

Expression level of autophagy and apoptosis markers in HIP and LIP COVID-19 patients treated with lysosomal inhibitors. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 2 representative COVID-19 patients (1 HIP indicated as pz1 and 1 LIP indicated as pz2 of the 18 analyzed). Densitometry analysis of LC3IIB (B) and p62 (D) levels relative to β-actin is also shown (Mann–Whitney test). (C) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as independent experiments performed in PBMCs from COVID-19 patients (n = 18) (Student’s t-test). Where indicated, cells were treated with the lysosomal inhibitors E64d and pepstatin A indicated as “ini.” Values are expressed as means ± SD. *p < 0.05. (E, F) Correlation and linear regression analysis of apoptosis and LC3IIB and p62 levels in PBMCs from COVID-19 patients. HIP, high inflammatory profile; LIP, low inflammatory profile; PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019; AV, annexin V.

Expression level of autophagy and apoptosis markers in HIP and LIP COVID-19 patients treated with lysosomal inhibitors. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 2 representative COVID-19 patients (1 HIP indicated as pz1 and 1 LIP indicated as pz2 of the 18 analyzed). Densitometry analysis of LC3IIB (B) and p62 (D) levels relative to β-actin is also shown (Mann–Whitney test). (C) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as independent experiments performed in PBMCs from COVID-19 patients (n = 18) (Student’s t-test). Where indicated, cells were treated with the lysosomal inhibitors E64d and pepstatin A indicated as “ini.” Values are expressed as means ± SD. *p < 0.05. (E, F) Correlation and linear regression analysis of apoptosis and LC3IIB and p62 levels in PBMCs from COVID-19 patients. HIP, high inflammatory profile; LIP, low inflammatory profile; PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019; AV, annexin V. As expected, in HIP patients displaying a basal block of autophagy and higher levels of apoptosis, the amount of p62 in the presence of lysosomal inhibitors versus untreated did not change (p > 0.05) ( ); on the contrary, LIP patients presenting basal levels of autophagy and apoptosis, similar to HDs, showed an accumulation of p62 under lysosomal inhibitors treatment (p = 0.0008) ( ). In addition, a positive correlation between autophagy markers and apoptosis was observed in PBMCs from COVID-19 patients ( ), leading us to speculate that autophagy hijacking in PBMCs from COVID-19 patients is directly involved in cell death. To confirm the alteration in the autophagy process, immunofluorescence analysis was also used to verify the expression levels of the autophagosome marker LC3IIB and the lysosome marker LAMP1. Specifically, the presence of intracellular autophagolysosomes indicating the ongoing PBMC autophagy was assessed by the detection of colocalization between LC3IIB and LAMP1, revealed by the yellow color in immunofluorescence analysis ( ).
Figure 4

Immunofluorescence analysis of autophagy in PBMCs from COVID-19 patients and HDs. LC3IIB (red fluorescence) and LAMP1 (green fluorescence) expression in PBMCs from COVID-19 patients (A, B, G, H) and HDs (D, E, L, M). Intracellular autophagolysosome formation detection by colocalization between LC3IIB and LAMP1 (yellow fluorescence) in PBMCs from COVID-19 patients (C, I) and HDs (F, N). (A–F) Magnification, 50×. (G-I, L-N) Magnification, 100×. (J, K) Magnification, x200. (O) Table of total cells and autophagic cells percentage and analysis of the percentage of autophagic cells in COVID-19 and HD PBMCs (Student’s t-test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019; HDs, healthy donors.

Immunofluorescence analysis of autophagy in PBMCs from COVID-19 patients and HDs. LC3IIB (red fluorescence) and LAMP1 (green fluorescence) expression in PBMCs from COVID-19 patients (A, B, G, H) and HDs (D, E, L, M). Intracellular autophagolysosome formation detection by colocalization between LC3IIB and LAMP1 (yellow fluorescence) in PBMCs from COVID-19 patients (C, I) and HDs (F, N). (A–F) Magnification, 50×. (G-I, L-N) Magnification, 100×. (J, K) Magnification, x200. (O) Table of total cells and autophagic cells percentage and analysis of the percentage of autophagic cells in COVID-19 and HD PBMCs (Student’s t-test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019; HDs, healthy donors. In PBMCs from COVID-19 and HDs, the expression of LC3IIB and LAMP1 was diffusely detectable ( ). However, the expression of both LC3IIB puncta and LAMP1 was more regularly distributed in PBMCs from HDs ( ) as compared to PBMCs from COVID-19 ( ). Additionally, the aberrant autophagolysosome formation was commonly observed in PBMCs from COVID-19 patients ( ), showing a diffuse pattern, while autophagolysosomes of PBMCs from HDs had the typical dotted pattern ( ). This result confirmed an alteration of the degradation cellular mechanism. The autophagic cells and the total stained cells were then counted in 10 different selected fields per specimen, and autophagic cells resulted from 28.1% in COVID-19 PBMCs and 15.2% in HD PBMCs (p = 0.0001) ( ).

Sera From COVID-19 Patients Differentially Modulate Autophagy and Apoptosis In Vitro

Our findings suggest the presence of soluble factors able to hijack PBMCs autophagy and apoptosis in COVID-19 patients’ sera. To confirm this, we conducted in vitro studies treating PBMCs from HDs with COVID-19 patients’ sera for 24 h. For this set of experiments, we chose sera from a pool of COVID-19 patients classified as HIP or LIP. Interestingly, sera from COVID-19 patients were able to modulate autophagy and apoptosis based on their inflammatory profile ( ). PBMCs from HDs in vitro cultured with sera from COVID-19 patients classified as HIP, displayed high levels of apoptosis and a block of autophagy, as confirmed by LC3IIB and p62 accumulation (p = 0.02, p = 0.002, and p = 0.0007 versus untreated, for apoptosis, LC3IIB, and p62 levels, respectively). In contrast, sera from patients classified as LIP were not able to modulate apoptosis and autophagy in PBMCs from HDs in vitro (p > 0.05 for all parameters) ( ).
Figure 5

Effects of sera from patients with COVID-19 on HD PBMC autophagy and apoptosis. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 1 representative HDs in vitro treated with autologous sera (S.A), with sera from 1 HIP COVID-19 patients (S.C.HIP) and from 1 COVID-19 classified as LIP (S.C.LIP) (B) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as 10 independent experiments performed on HDs in vitro treated with sera from HIP COVID-19 patients and COVID-19 classified as LIP (Student’s t-test). Densitometry analysis of LC3IIB (C) and p62 (D) levels relative to β-actin is also shown (10 independent experiments) (Mann–Whitney test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; HD, healthy donor; COVID-19, coronavirus disease 2019; HIP, high inflammatory profile; LIP, low inflammatory profile.

Effects of sera from patients with COVID-19 on HD PBMC autophagy and apoptosis. (A) LC3IIB and p62 Western blotting analysis of PBMC lysate (30 μg/lane) from 1 representative HDs in vitro treated with autologous sera (S.A), with sera from 1 HIP COVID-19 patients (S.C.HIP) and from 1 COVID-19 classified as LIP (S.C.LIP) (B) Flow cytometry analysis of PBMC apoptosis. Data are referred to as AV-positive cells and are presented as 10 independent experiments performed on HDs in vitro treated with sera from HIP COVID-19 patients and COVID-19 classified as LIP (Student’s t-test). Densitometry analysis of LC3IIB (C) and p62 (D) levels relative to β-actin is also shown (10 independent experiments) (Mann–Whitney test). Values are expressed as means ± SD. *p < 0.05. PBMC, peripheral blood mononuclear cell; HD, healthy donor; COVID-19, coronavirus disease 2019; HIP, high inflammatory profile; LIP, low inflammatory profile.

Correlation Between Autophagy Block and Lymphopenia

Finally, we observed a significant correlation between lymphopenia and autophagic/apoptotic markers in COVID-19 PBMCs. In particular, peripheral lymphocyte count negatively correlated with LC3IIB and p62 levels and with cell apoptosis rate ( ).
Figure 6

Correlation between lymphopenia and autophagy/apoptotic markers. (A–C) Correlation and linear regression analysis of lymphocyte count and LC3IIB and p62 levels, and apoptosis in PBMCs from COVID-19 patients (n = 18) (Spearman’s rank correlation). PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019.

Correlation between lymphopenia and autophagy/apoptotic markers. (A–C) Correlation and linear regression analysis of lymphocyte count and LC3IIB and p62 levels, and apoptosis in PBMCs from COVID-19 patients (n = 18) (Spearman’s rank correlation). PBMC, peripheral blood mononuclear cell; COVID-19, coronavirus disease 2019. These results suggest that in these patients the inflammatory condition could interfere with the major mechanism of cellular survival, which is autophagy, leading to lymphocyte death by apoptosis.

Discussion

In our study, we firstly showed a block of autophagy in PBMCs from COVID-19 patients who displayed high expression of LC3IIB and p62 levels. These results were strengthened by experiments under lysosomal inhibition conditions, in which lysosomal proteases did not affect autophagy levels in HIP COVID-19 PBMCs but affected autophagy only in those patients showing a LIP. It is well known that autophagy is a mechanism involved in the most important steps of the immune response, such as intracellular pathogen sensing, lymphocyte development, homeostasis, and survival (14). Although autophagy is a cell survival mechanism, it is also linked to cell death, through the interaction with apoptosis-related proteins (15). In the present study, patients with a HIP showed a block of autophagy and a concomitant high percentage of PBMCs undergoing apoptosis. This could mean that cellular death is the direct consequence of the aberration of the survival mechanism. This hypothesis is supported by the increased apoptosis and the block of autophagy in PBMCs from HDs in vitro treated with COVID-19 sera showing HIP. In PBMCs from COVID-19 patients, at a molecular level, the interplay between lymphocyte autophagy and apoptosis has never been investigated, but our results indicate cytokines or circulating proinflammatory molecules as a possible main culprit. In literature, it is known that many circulating cytokines, such as IL-6, TNF-alpha, and BlyS, as in autoimmune/inflammatory diseases, could be involved in the regulation of this process (16, 17), causing a cytokine storm that could contribute to a more severe COVID-19 disease also by exhaustion of lymphocytes (18). Data from the present study suppose a possible effect of the virus on lymphocyte autophagy dysregulation, likely as a result of a cytokine storm (19). To strengthen our hypothesis on the autophagy blockade in circulating lymphocytes from COVID-19 patients, the analysis of the autophagolysosome formation level in the PBMC subpopulations, which is significantly higher in lymphocytes than in monocytes, contributes to lymphocyte death. In this regard, we observed also a strong positive correlation between autophagy markers and apoptosis. In addition, the indirect correlation between autophagy/apoptotic markers and lymphocyte count demonstrates the interaction between autophagy block and the concomitant apoptosis increase with the decrease in circulating lymphocytes. Moreover, lymphocytes are crucial in the maintenance of immune homeostasis and inflammatory response; thus, the understanding of the mechanism of reduced blood lymphocyte levels could provide an additional strategy for the treatment of COVID-19 (20). In our previous study, we speculated the direct infection of the virus on lymphocytes, resulting in death due to lymphocyte expression of the coronavirus receptor ACE2 (19). In accordance with our hypothesis, Tan et al. added the direct destruction of lymphatic organs by the virus as a possible cause of lymphocyte decline, with the inflammatory cytokine storm that leads to lymphocyte apoptosis (20). The authors concluded that lymphopenia is an indicator of the severity of COVID-19 hospitalized patients and suggested including the evaluation of blood lymphocyte percentage in the guidelines for the diagnosis of COVID-19 (21). Our results reinforce this suggestion and add new knowledge on the mechanisms underlying lymphopenia in COVID-19 patients. Considering these results, drugs targeting autophagy could represent an important issue, worthy to be considered as a new therapeutic strategy in the context of COVID-19. Although additional studies are needed to confirm our hypotheses, since autophagy and apoptosis are usually involved in many disease conditions, this study provides intriguing data to better understand the mechanisms underlying COVID-19 and causing the disease progression. The strength of this study is the use of different experimental approaches to confirm a block of autophagy in PBMCs from COVID-19 patients. Despite the promising information obtained from the analysis of COVID-19 PBMC homeostasis, limitations are present. The number of patients is small due to the difficult enrollment during the pandemic period. In addition, we do not know the patients’ therapy that could interfere with the investigated mechanisms.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The study was approved by the ethics committee of Sapienza University of Rome (protocol number 0586/20). The patients/participants provided their written informed consent to participate in this study.

Author Contributions

All authors have made a substantial, direct, and intellectual contribution to the work and approved the final manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Review 1.  Autophagy and cell death.

Authors:  Tohru Yonekawa; Andrew Thorburn
Journal:  Essays Biochem       Date:  2013       Impact factor: 8.000

Review 2.  Autophagosome formation in mammalian cells.

Authors:  Noboru Mizushima; Yoshinori Ohsumi; Tamotsu Yoshimori
Journal:  Cell Struct Funct       Date:  2002-12       Impact factor: 2.212

3.  Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

Authors:  Daniel J Klionsky; Amal Kamal Abdel-Aziz; Sara Abdelfatah; Mahmoud Abdellatif; Asghar Abdoli; Steffen Abel; Hagai Abeliovich; Marie H Abildgaard; Yakubu Princely Abudu; Abraham Acevedo-Arozena; Iannis E Adamopoulos; Khosrow Adeli; Timon E Adolph; Annagrazia Adornetto; Elma Aflaki; Galila Agam; Anupam Agarwal; Bharat B Aggarwal; Maria Agnello; Patrizia Agostinis; Javed N Agrewala; Alexander Agrotis; Patricia V Aguilar; S Tariq Ahmad; Zubair M Ahmed; Ulises Ahumada-Castro; Sonja Aits; Shu Aizawa; Yunus Akkoc; Tonia Akoumianaki; Hafize Aysin Akpinar; Ahmed M Al-Abd; Lina Al-Akra; Abeer Al-Gharaibeh; Moulay A Alaoui-Jamali; Simon Alberti; Elísabet Alcocer-Gómez; Cristiano Alessandri; Muhammad Ali; M Abdul Alim Al-Bari; Saeb Aliwaini; Javad Alizadeh; Eugènia Almacellas; Alexandru Almasan; Alicia Alonso; Guillermo D Alonso; Nihal Altan-Bonnet; Dario C Altieri; Élida M C Álvarez; Sara Alves; Cristine Alves da Costa; Mazen M Alzaharna; Marialaura Amadio; Consuelo Amantini; Cristina Amaral; Susanna Ambrosio; Amal O Amer; Veena Ammanathan; Zhenyi An; Stig U Andersen; Shaida A Andrabi; Magaiver Andrade-Silva; Allen M Andres; Sabrina Angelini; David Ann; Uche C Anozie; Mohammad Y Ansari; Pedro Antas; Adam Antebi; Zuriñe Antón; Tahira Anwar; Lionel Apetoh; Nadezda Apostolova; Toshiyuki Araki; Yasuhiro Araki; Kohei Arasaki; Wagner L Araújo; Jun Araya; Catherine Arden; Maria-Angeles Arévalo; Sandro Arguelles; Esperanza Arias; Jyothi Arikkath; Hirokazu Arimoto; Aileen R Ariosa; Darius Armstrong-James; Laetitia Arnauné-Pelloquin; Angeles Aroca; Daniela S Arroyo; Ivica Arsov; Rubén Artero; Dalia Maria Lucia Asaro; Michael Aschner; Milad Ashrafizadeh; Osnat Ashur-Fabian; Atanas G Atanasov; Alicia K Au; Patrick Auberger; Holger W Auner; Laure Aurelian; Riccardo Autelli; Laura Avagliano; Yenniffer Ávalos; Sanja Aveic; Célia Alexandra Aveleira; Tamar Avin-Wittenberg; Yucel Aydin; Scott Ayton; Srinivas Ayyadevara; Maria Azzopardi; Misuzu Baba; Jonathan M Backer; Steven K Backues; Dong-Hun Bae; Ok-Nam Bae; Soo Han Bae; Eric H Baehrecke; Ahruem Baek; Seung-Hoon Baek; Sung Hee Baek; Giacinto Bagetta; Agnieszka Bagniewska-Zadworna; Hua Bai; Jie Bai; Xiyuan Bai; Yidong Bai; Nandadulal Bairagi; Shounak Baksi; Teresa Balbi; Cosima T Baldari; Walter Balduini; Andrea Ballabio; Maria Ballester; Salma Balazadeh; Rena Balzan; Rina Bandopadhyay; Sreeparna Banerjee; Sulagna Banerjee; Ágnes Bánréti; Yan Bao; Mauricio S Baptista; Alessandra Baracca; Cristiana Barbati; Ariadna Bargiela; Daniela Barilà; Peter G Barlow; Sami J Barmada; Esther Barreiro; George E Barreto; Jiri Bartek; Bonnie Bartel; Alberto Bartolome; Gaurav R Barve; Suresh H Basagoudanavar; Diane C Bassham; Robert C Bast; Alakananda Basu; Henri Batoko; Isabella Batten; Etienne E Baulieu; Bradley L Baumgarner; Jagadeesh Bayry; Rupert Beale; Isabelle Beau; Florian Beaumatin; Luiz R G Bechara; George R Beck; Michael F Beers; Jakob Begun; Christian Behrends; Georg M N Behrens; Roberto Bei; Eloy Bejarano; Shai Bel; Christian Behl; Amine Belaid; Naïma Belgareh-Touzé; Cristina Bellarosa; Francesca Belleudi; Melissa Belló Pérez; Raquel Bello-Morales; Jackeline Soares de Oliveira Beltran; Sebastián Beltran; Doris Mangiaracina Benbrook; Mykolas Bendorius; Bruno A Benitez; Irene Benito-Cuesta; Julien Bensalem; Martin W Berchtold; Sabina Berezowska; Daniele Bergamaschi; Matteo Bergami; Andreas Bergmann; Laura Berliocchi; Clarisse Berlioz-Torrent; Amélie Bernard; Lionel Berthoux; Cagri G Besirli; Sebastien Besteiro; Virginie M Betin; Rudi Beyaert; Jelena S Bezbradica; Kiran Bhaskar; Ingrid Bhatia-Kissova; Resham Bhattacharya; Sujoy Bhattacharya; Shalmoli Bhattacharyya; Md Shenuarin Bhuiyan; Sujit Kumar Bhutia; Lanrong Bi; Xiaolin Bi; Trevor J Biden; Krikor Bijian; Viktor A Billes; Nadine Binart; Claudia Bincoletto; Asa B Birgisdottir; Geir Bjorkoy; Gonzalo Blanco; Ana Blas-Garcia; Janusz Blasiak; Robert Blomgran; Klas Blomgren; Janice S Blum; Emilio Boada-Romero; Mirta Boban; Kathleen Boesze-Battaglia; Philippe Boeuf; Barry Boland; Pascale Bomont; Paolo Bonaldo; Srinivasa Reddy Bonam; Laura Bonfili; Juan S Bonifacino; Brian A Boone; Martin D Bootman; Matteo Bordi; Christoph Borner; Beat C Bornhauser; Gautam Borthakur; Jürgen Bosch; Santanu Bose; Luis M Botana; Juan Botas; Chantal M Boulanger; Michael E Boulton; Mathieu Bourdenx; Benjamin Bourgeois; Nollaig M Bourke; Guilhem Bousquet; Patricia Boya; Peter V Bozhkov; Luiz H M Bozi; Tolga O Bozkurt; Doug E Brackney; Christian H Brandts; Ralf J Braun; Gerhard H Braus; Roberto Bravo-Sagua; José M Bravo-San Pedro; Patrick Brest; Marie-Agnès Bringer; Alfredo Briones-Herrera; V Courtney Broaddus; Peter Brodersen; Jeffrey L Brodsky; Steven L Brody; Paola G Bronson; Jeff M Bronstein; Carolyn N Brown; Rhoderick E Brown; Patricia C Brum; John H Brumell; Nicola Brunetti-Pierri; Daniele Bruno; Robert J Bryson-Richardson; Cecilia Bucci; Carmen Buchrieser; Marta Bueno; Laura Elisa Buitrago-Molina; Simone Buraschi; Shilpa Buch; J Ross Buchan; Erin M Buckingham; Hikmet Budak; Mauricio Budini; Geert Bultynck; Florin Burada; Joseph R Burgoyne; M Isabel Burón; Victor Bustos; Sabrina Büttner; Elena Butturini; Aaron Byrd; Isabel Cabas; Sandra Cabrera-Benitez; Ken Cadwell; Jingjing Cai; Lu Cai; Qian Cai; Montserrat Cairó; Jose A Calbet; Guy A Caldwell; Kim A Caldwell; Jarrod A Call; Riccardo Calvani; Ana C Calvo; Miguel Calvo-Rubio Barrera; Niels Os Camara; Jacques H Camonis; Nadine Camougrand; Michelangelo Campanella; Edward M Campbell; François-Xavier Campbell-Valois; Silvia Campello; Ilaria Campesi; Juliane C Campos; Olivier Camuzard; Jorge Cancino; Danilo Candido de Almeida; Laura Canesi; Isabella Caniggia; Barbara Canonico; Carles Cantí; Bin Cao; Michele Caraglia; Beatriz Caramés; Evie H Carchman; Elena Cardenal-Muñoz; Cesar Cardenas; Luis Cardenas; Sandra M Cardoso; Jennifer S Carew; Georges F Carle; Gillian Carleton; Silvia Carloni; Didac Carmona-Gutierrez; Leticia A Carneiro; Oliana Carnevali; Julian M Carosi; Serena Carra; Alice Carrier; Lucie Carrier; Bernadette Carroll; A Brent Carter; Andreia Neves Carvalho; Magali Casanova; Caty Casas; Josefina Casas; Chiara Cassioli; Eliseo F Castillo; Karen Castillo; Sonia Castillo-Lluva; Francesca Castoldi; Marco Castori; Ariel F Castro; Margarida Castro-Caldas; Javier Castro-Hernandez; Susana Castro-Obregon; Sergio D Catz; Claudia Cavadas; Federica Cavaliere; Gabriella Cavallini; Maria Cavinato; Maria L Cayuela; Paula Cebollada Rica; Valentina Cecarini; Francesco Cecconi; Marzanna Cechowska-Pasko; Simone Cenci; Victòria Ceperuelo-Mallafré; João J Cerqueira; Janete M Cerutti; Davide Cervia; Vildan Bozok Cetintas; Silvia Cetrullo; Han-Jung Chae; Andrei S Chagin; Chee-Yin Chai; Gopal Chakrabarti; Oishee Chakrabarti; Tapas Chakraborty; Trinad Chakraborty; Mounia Chami; Georgios Chamilos; David W Chan; Edmond Y W Chan; Edward D Chan; H Y Edwin Chan; Helen H Chan; Hung Chan; Matthew T V Chan; Yau Sang Chan; Partha K Chandra; Chih-Peng Chang; Chunmei Chang; Hao-Chun Chang; Kai Chang; Jie Chao; Tracey Chapman; Nicolas Charlet-Berguerand; Samrat Chatterjee; Shail K Chaube; Anu Chaudhary; Santosh Chauhan; Edward Chaum; Frédéric Checler; Michael E Cheetham; Chang-Shi Chen; Guang-Chao Chen; Jian-Fu Chen; Liam L Chen; Leilei Chen; Lin Chen; Mingliang Chen; Mu-Kuan Chen; Ning Chen; Quan Chen; Ruey-Hwa Chen; Shi Chen; Wei Chen; Weiqiang Chen; Xin-Ming Chen; Xiong-Wen Chen; Xu Chen; Yan Chen; Ye-Guang Chen; Yingyu Chen; Yongqiang Chen; Yu-Jen Chen; Yue-Qin Chen; Zhefan Stephen Chen; Zhi Chen; Zhi-Hua Chen; Zhijian J Chen; Zhixiang Chen; Hanhua Cheng; Jun Cheng; Shi-Yuan Cheng; Wei Cheng; Xiaodong Cheng; Xiu-Tang Cheng; Yiyun Cheng; Zhiyong Cheng; Zhong Chen; Heesun Cheong; Jit Kong Cheong; Boris V Chernyak; Sara Cherry; Chi Fai Randy Cheung; Chun Hei Antonio Cheung; King-Ho Cheung; Eric Chevet; Richard J Chi; Alan Kwok Shing Chiang; Ferdinando Chiaradonna; Roberto Chiarelli; Mario Chiariello; Nathalia Chica; Susanna Chiocca; Mario Chiong; Shih-Hwa Chiou; Abhilash I Chiramel; Valerio Chiurchiù; Dong-Hyung Cho; Seong-Kyu Choe; Augustine M K Choi; Mary E Choi; Kamalika Roy Choudhury; Norman S Chow; Charleen T Chu; Jason P Chua; John Jia En Chua; Hyewon Chung; Kin Pan Chung; Seockhoon Chung; So-Hyang Chung; Yuen-Li Chung; Valentina Cianfanelli; Iwona A Ciechomska; Mariana Cifuentes; Laura Cinque; Sebahattin Cirak; Mara Cirone; Michael J Clague; Robert Clarke; Emilio Clementi; Eliana M Coccia; Patrice Codogno; Ehud Cohen; Mickael M Cohen; Tania Colasanti; Fiorella Colasuonno; Robert A Colbert; Anna Colell; Miodrag Čolić; Nuria S Coll; Mark O Collins; María I Colombo; Daniel A Colón-Ramos; Lydie Combaret; Sergio Comincini; Márcia R Cominetti; Antonella Consiglio; Andrea Conte; Fabrizio Conti; Viorica Raluca Contu; Mark R Cookson; Kevin M Coombs; Isabelle Coppens; Maria Tiziana Corasaniti; Dale P Corkery; Nils Cordes; Katia Cortese; Maria do Carmo Costa; Sarah Costantino; Paola Costelli; Ana Coto-Montes; Peter J Crack; Jose L Crespo; Alfredo Criollo; Valeria Crippa; Riccardo Cristofani; Tamas Csizmadia; Antonio Cuadrado; Bing Cui; Jun Cui; Yixian Cui; Yong Cui; Emmanuel Culetto; Andrea C Cumino; Andrey V Cybulsky; Mark J Czaja; Stanislaw J Czuczwar; Stefania D'Adamo; Marcello D'Amelio; Daniela D'Arcangelo; Andrew C D'Lugos; Gabriella D'Orazi; James A da Silva; Hormos Salimi Dafsari; Ruben K Dagda; Yasin Dagdas; Maria Daglia; Xiaoxia Dai; Yun Dai; Yuyuan Dai; Jessica Dal Col; Paul Dalhaimer; Luisa Dalla Valle; Tobias Dallenga; Guillaume Dalmasso; Markus Damme; Ilaria Dando; Nico P Dantuma; April L Darling; Hiranmoy Das; Srinivasan Dasarathy; Santosh K Dasari; Srikanta Dash; Oliver Daumke; Adrian N Dauphinee; Jeffrey S Davies; Valeria A Dávila; Roger J Davis; Tanja Davis; Sharadha Dayalan Naidu; Francesca De Amicis; Karolien De Bosscher; Francesca De Felice; Lucia De Franceschi; Chiara De Leonibus; Mayara G de Mattos Barbosa; Guido R Y De Meyer; Angelo De Milito; Cosimo De Nunzio; Clara De Palma; Mauro De Santi; Claudio De Virgilio; Daniela De Zio; Jayanta Debnath; Brian J DeBosch; Jean-Paul Decuypere; Mark A Deehan; Gianluca Deflorian; James DeGregori; Benjamin Dehay; Gabriel Del Rio; Joe R Delaney; Lea M D Delbridge; Elizabeth Delorme-Axford; M Victoria Delpino; Francesca Demarchi; Vilma Dembitz; Nicholas D Demers; Hongbin Deng; Zhiqiang Deng; Joern Dengjel; Paul Dent; Donna Denton; Melvin L DePamphilis; Channing J Der; Vojo Deretic; Albert Descoteaux; Laura Devis; Sushil Devkota; Olivier Devuyst; Grant Dewson; Mahendiran Dharmasivam; Rohan Dhiman; Diego di Bernardo; Manlio Di Cristina; Fabio Di Domenico; Pietro Di Fazio; Alessio Di Fonzo; Giovanni Di Guardo; Gianni M Di Guglielmo; Luca Di Leo; Chiara Di Malta; Alessia Di Nardo; Martina Di Rienzo; Federica Di Sano; George Diallinas; Jiajie Diao; Guillermo Diaz-Araya; Inés Díaz-Laviada; Jared M Dickinson; Marc Diederich; Mélanie Dieudé; Ivan Dikic; Shiping Ding; Wen-Xing Ding; Luciana Dini; Jelena Dinić; Miroslav Dinic; Albena T Dinkova-Kostova; Marc S Dionne; Jörg H W Distler; Abhinav Diwan; Ian M C Dixon; Mojgan Djavaheri-Mergny; Ina Dobrinski; Oxana Dobrovinskaya; Radek Dobrowolski; Renwick C J Dobson; Jelena Đokić; Serap Dokmeci Emre; Massimo Donadelli; Bo Dong; Xiaonan Dong; Zhiwu Dong; Gerald W Dorn Ii; Volker Dotsch; Huan Dou; Juan Dou; Moataz Dowaidar; Sami Dridi; Liat Drucker; Ailian Du; Caigan Du; Guangwei Du; Hai-Ning Du; Li-Lin Du; André du Toit; Shao-Bin Duan; Xiaoqiong Duan; Sónia P Duarte; Anna Dubrovska; Elaine A Dunlop; Nicolas Dupont; Raúl V Durán; Bilikere S Dwarakanath; Sergey A Dyshlovoy; Darius Ebrahimi-Fakhari; Leopold Eckhart; Charles L Edelstein; Thomas Efferth; Eftekhar Eftekharpour; Ludwig Eichinger; Nabil Eid; Tobias Eisenberg; N Tony Eissa; Sanaa Eissa; Miriam Ejarque; Abdeljabar El Andaloussi; Nazira El-Hage; Shahenda El-Naggar; Anna Maria Eleuteri; Eman S El-Shafey; Mohamed Elgendy; Aristides G Eliopoulos; María M Elizalde; Philip M Elks; Hans-Peter Elsasser; Eslam S Elsherbiny; Brooke M Emerling; N C Tolga Emre; Christina H Eng; Nikolai Engedal; Anna-Mart Engelbrecht; Agnete S T Engelsen; Jorrit M Enserink; Ricardo Escalante; Audrey Esclatine; Mafalda Escobar-Henriques; Eeva-Liisa Eskelinen; Lucile Espert; Makandjou-Ola Eusebio; Gemma Fabrias; Cinzia Fabrizi; Antonio Facchiano; Francesco Facchiano; Bengt Fadeel; Claudio Fader; Alex C Faesen; W Douglas Fairlie; Alberto Falcó; Bjorn H Falkenburger; Daping Fan; Jie Fan; Yanbo Fan; Evandro F Fang; Yanshan Fang; Yognqi Fang; Manolis Fanto; Tamar Farfel-Becker; Mathias Faure; Gholamreza Fazeli; Anthony O Fedele; Arthur M Feldman; Du Feng; Jiachun Feng; Lifeng Feng; Yibin Feng; Yuchen Feng; Wei Feng; Thais Fenz Araujo; Thomas A Ferguson; Álvaro F Fernández; Jose C Fernandez-Checa; Sonia Fernández-Veledo; Alisdair R Fernie; Anthony W Ferrante; Alessandra Ferraresi; Merari F Ferrari; Julio C B Ferreira; Susan Ferro-Novick; Antonio Figueras; Riccardo Filadi; Nicoletta Filigheddu; Eduardo Filippi-Chiela; Giuseppe Filomeni; Gian Maria Fimia; Vittorio Fineschi; Francesca Finetti; Steven Finkbeiner; Edward A Fisher; Paul B Fisher; Flavio Flamigni; Steven J Fliesler; Trude H Flo; Ida Florance; Oliver Florey; Tullio Florio; Erika Fodor; Carlo Follo; Edward A Fon; Antonella Forlino; Francesco Fornai; Paola Fortini; Anna Fracassi; Alessandro Fraldi; Brunella Franco; Rodrigo Franco; Flavia Franconi; Lisa B Frankel; Scott L Friedman; Leopold F Fröhlich; Gema Frühbeck; Jose M Fuentes; Yukio Fujiki; Naonobu Fujita; Yuuki Fujiwara; Mitsunori Fukuda; Simone Fulda; Luc Furic; Norihiko Furuya; Carmela Fusco; Michaela U Gack; Lidia Gaffke; Sehamuddin Galadari; Alessia Galasso; Maria F Galindo; Sachith Gallolu Kankanamalage; Lorenzo Galluzzi; Vincent Galy; Noor Gammoh; Boyi Gan; Ian G Ganley; Feng Gao; Hui Gao; Minghui Gao; Ping Gao; Shou-Jiang Gao; Wentao Gao; Xiaobo Gao; Ana Garcera; Maria Noé Garcia; Verónica E Garcia; Francisco García-Del Portillo; Vega Garcia-Escudero; Aracely Garcia-Garcia; Marina Garcia-Macia; Diana García-Moreno; Carmen Garcia-Ruiz; Patricia García-Sanz; Abhishek D Garg; Ricardo Gargini; Tina Garofalo; Robert F Garry; Nils C Gassen; Damian Gatica; Liang Ge; Wanzhong Ge; Ruth Geiss-Friedlander; Cecilia Gelfi; Pascal Genschik; Ian E Gentle; Valeria Gerbino; Christoph Gerhardt; Kyla Germain; Marc Germain; David A Gewirtz; Elham Ghasemipour Afshar; Saeid Ghavami; Alessandra Ghigo; Manosij Ghosh; Georgios Giamas; Claudia Giampietri; Alexandra Giatromanolaki; Gary E Gibson; Spencer B Gibson; Vanessa Ginet; Edward Giniger; Carlotta Giorgi; Henrique Girao; Stephen E Girardin; Mridhula Giridharan; Sandy Giuliano; Cecilia Giulivi; Sylvie Giuriato; Julien Giustiniani; Alexander Gluschko; Veit Goder; Alexander Goginashvili; Jakub Golab; David C Goldstone; Anna Golebiewska; Luciana R Gomes; Rodrigo Gomez; Rubén Gómez-Sánchez; Maria Catalina Gomez-Puerto; Raquel Gomez-Sintes; Qingqiu Gong; Felix M Goni; Javier González-Gallego; Tomas Gonzalez-Hernandez; Rosa A Gonzalez-Polo; Jose A Gonzalez-Reyes; Patricia González-Rodríguez; Ing Swie Goping; Marina S Gorbatyuk; Nikolai V Gorbunov; Kıvanç Görgülü; Roxana M Gorojod; Sharon M Gorski; Sandro Goruppi; Cecilia Gotor; Roberta A Gottlieb; Illana Gozes; Devrim Gozuacik; Martin Graef; Markus H Gräler; Veronica Granatiero; Daniel Grasso; Joshua P Gray; Douglas R Green; Alexander Greenhough; Stephen L Gregory; Edward F Griffin; Mark W Grinstaff; Frederic Gros; Charles Grose; Angelina S Gross; Florian Gruber; Paolo Grumati; Tilman Grune; Xueyan Gu; Jun-Lin Guan; Carlos M Guardia; Kishore Guda; Flora Guerra; Consuelo Guerri; Prasun Guha; Carlos Guillén; Shashi Gujar; Anna Gukovskaya; Ilya Gukovsky; Jan Gunst; Andreas Günther; Anyonya R Guntur; Chuanyong Guo; Chun Guo; Hongqing Guo; Lian-Wang Guo; Ming Guo; Pawan Gupta; Shashi Kumar Gupta; Swapnil Gupta; Veer Bala Gupta; Vivek Gupta; Asa B Gustafsson; David D Gutterman; Ranjitha H B; Annakaisa Haapasalo; James E Haber; Aleksandra Hać; Shinji Hadano; Anders J Hafrén; Mansour Haidar; Belinda S Hall; Gunnel Halldén; Anne Hamacher-Brady; Andrea Hamann; Maho Hamasaki; Weidong Han; Malene Hansen; Phyllis I Hanson; Zijian Hao; Masaru Harada; Ljubica Harhaji-Trajkovic; Nirmala Hariharan; Nigil Haroon; James Harris; Takafumi Hasegawa; Noor Hasima Nagoor; Jeffrey A Haspel; Volker Haucke; Wayne D Hawkins; Bruce A Hay; Cole M Haynes; Soren B Hayrabedyan; Thomas S Hays; Congcong He; Qin He; Rong-Rong He; You-Wen He; Yu-Ying He; Yasser Heakal; Alexander M Heberle; J Fielding Hejtmancik; Gudmundur Vignir Helgason; Vanessa Henkel; Marc Herb; Alexander Hergovich; Anna Herman-Antosiewicz; Agustín Hernández; Carlos Hernandez; Sergio Hernandez-Diaz; Virginia Hernandez-Gea; Amaury Herpin; Judit Herreros; Javier H Hervás; Daniel Hesselson; Claudio Hetz; Volker T Heussler; Yujiro Higuchi; Sabine Hilfiker; Joseph A Hill; William S Hlavacek; Emmanuel A Ho; Idy H T Ho; Philip Wing-Lok Ho; Shu-Leong Ho; Wan Yun Ho; G Aaron Hobbs; Mark Hochstrasser; Peter H M Hoet; Daniel Hofius; Paul Hofman; Annika Höhn; Carina I Holmberg; Jose R Hombrebueno; Chang-Won Hong Yi-Ren Hong; Lora V Hooper; Thorsten Hoppe; Rastislav Horos; Yujin Hoshida; I-Lun Hsin; Hsin-Yun Hsu; Bing Hu; Dong Hu; Li-Fang Hu; Ming Chang Hu; Ronggui Hu; Wei Hu; Yu-Chen Hu; Zhuo-Wei Hu; Fang Hua; Jinlian Hua; Yingqi Hua; Chongmin Huan; Canhua Huang; Chuanshu Huang; Chuanxin Huang; Chunling Huang; Haishan Huang; Kun Huang; Michael L H Huang; Rui Huang; Shan Huang; Tianzhi Huang; Xing Huang; Yuxiang Jack Huang; Tobias B Huber; Virginie Hubert; Christian A Hubner; Stephanie M Hughes; William E Hughes; Magali Humbert; Gerhard Hummer; James H Hurley; Sabah Hussain; Salik Hussain; Patrick J Hussey; Martina Hutabarat; Hui-Yun Hwang; Seungmin Hwang; Antonio Ieni; Fumiyo Ikeda; Yusuke Imagawa; Yuzuru Imai; Carol Imbriano; Masaya Imoto; Denise M Inman; Ken Inoki; Juan Iovanna; Renato V Iozzo; Giuseppe Ippolito; Javier E Irazoqui; Pablo Iribarren; Mohd Ishaq; Makoto Ishikawa; Nestor Ishimwe; Ciro Isidoro; Nahed Ismail; Shohreh Issazadeh-Navikas; Eisuke Itakura; Daisuke Ito; Davor Ivankovic; Saška Ivanova; Anand Krishnan V Iyer; José M Izquierdo; Masanori Izumi; Marja Jäättelä; Majid Sakhi Jabir; William T Jackson; Nadia Jacobo-Herrera; Anne-Claire Jacomin; Elise Jacquin; Pooja Jadiya; Hartmut Jaeschke; Chinnaswamy Jagannath; Arjen J Jakobi; Johan Jakobsson; Bassam Janji; Pidder Jansen-Dürr; Patric J Jansson; Jonathan Jantsch; Sławomir Januszewski; Alagie Jassey; Steve Jean; Hélène Jeltsch-David; Pavla Jendelova; Andreas Jenny; Thomas E Jensen; Niels Jessen; Jenna L Jewell; Jing Ji; Lijun Jia; Rui Jia; Liwen Jiang; Qing Jiang; Richeng Jiang; Teng Jiang; Xuejun Jiang; Yu Jiang; Maria Jimenez-Sanchez; Eun-Jung Jin; Fengyan Jin; Hongchuan Jin; Li Jin; Luqi Jin; Meiyan Jin; Si Jin; Eun-Kyeong Jo; Carine Joffre; Terje Johansen; Gail V W Johnson; Simon A Johnston; Eija Jokitalo; Mohit Kumar Jolly; Leo A B Joosten; Joaquin Jordan; Bertrand Joseph; Dianwen Ju; Jeong-Sun Ju; Jingfang Ju; Esmeralda Juárez; Delphine Judith; Gábor Juhász; Youngsoo Jun; Chang Hwa Jung; Sung-Chul Jung; Yong Keun Jung; Heinz Jungbluth; Johannes Jungverdorben; Steffen Just; Kai Kaarniranta; Allen Kaasik; Tomohiro Kabuta; Daniel Kaganovich; Alon Kahana; Renate Kain; Shinjo Kajimura; Maria Kalamvoki; Manjula Kalia; Danuta S Kalinowski; Nina Kaludercic; Ioanna Kalvari; Joanna Kaminska; Vitaliy O Kaminskyy; Hiromitsu Kanamori; Keizo Kanasaki; Chanhee Kang; Rui Kang; Sang Sun Kang; Senthilvelrajan Kaniyappan; Tomotake Kanki; Thirumala-Devi Kanneganti; Anumantha G Kanthasamy; Arthi Kanthasamy; Marc Kantorow; Orsolya Kapuy; Michalis V Karamouzis; Md Razaul Karim; Parimal Karmakar; Rajesh G Katare; Masaru Kato; Stefan H E Kaufmann; Anu Kauppinen; Gur P Kaushal; Susmita Kaushik; Kiyoshi Kawasaki; Kemal Kazan; Po-Yuan Ke; Damien J Keating; Ursula Keber; John H Kehrl; Kate E Keller; Christian W Keller; Jongsook Kim Kemper; Candia M Kenific; Oliver Kepp; Stephanie Kermorgant; Andreas Kern; Robin Ketteler; Tom G Keulers; Boris Khalfin; Hany Khalil; Bilon Khambu; Shahid Y Khan; Vinoth Kumar Megraj Khandelwal; Rekha Khandia; Widuri Kho; Noopur V Khobrekar; Sataree Khuansuwan; Mukhran Khundadze; Samuel A Killackey; Dasol Kim; Deok Ryong Kim; Do-Hyung Kim; Dong-Eun Kim; Eun Young Kim; Eun-Kyoung Kim; Hak-Rim Kim; Hee-Sik Kim; Jeong Hun Kim; Jin Kyung Kim; Jin-Hoi Kim; Joungmok Kim; Ju Hwan Kim; Keun Il Kim; Peter K Kim; Seong-Jun Kim; Scot R Kimball; Adi Kimchi; Alec C Kimmelman; Tomonori Kimura; Matthew A King; Kerri J Kinghorn; Conan G Kinsey; Vladimir Kirkin; Lorrie A Kirshenbaum; Sergey L Kiselev; Shuji Kishi; Katsuhiko Kitamoto; Yasushi Kitaoka; Kaio Kitazato; Richard N Kitsis; Josef T Kittler; Ole Kjaerulff; Peter S Klein; Thomas Klopstock; Jochen Klucken; Helene Knævelsrud; Roland L Knorr; Ben C B Ko; Fred Ko; Jiunn-Liang Ko; Hotaka Kobayashi; Satoru Kobayashi; Ina Koch; Jan C Koch; Ulrich Koenig; Donat Kögel; Young Ho Koh; Masato Koike; Sepp D Kohlwein; Nur M Kocaturk; Masaaki Komatsu; Jeannette König; Toru Kono; Benjamin T Kopp; Tamas Korcsmaros; Gözde Korkmaz; Viktor I Korolchuk; Mónica Suárez Korsnes; Ali Koskela; Janaiah Kota; Yaichiro Kotake; Monica L Kotler; Yanjun Kou; Michael I Koukourakis; Evangelos Koustas; Attila L Kovacs; Tibor Kovács; Daisuke Koya; Tomohiro Kozako; Claudine Kraft; Dimitri Krainc; Helmut Krämer; Anna D Krasnodembskaya; Carole Kretz-Remy; Guido Kroemer; Nicholas T Ktistakis; Kazuyuki Kuchitsu; Sabine Kuenen; Lars Kuerschner; Thomas Kukar; Ajay Kumar; Ashok Kumar; Deepak Kumar; Dhiraj Kumar; Sharad Kumar; Shinji Kume; Caroline Kumsta; Chanakya N Kundu; Mondira Kundu; Ajaikumar B Kunnumakkara; Lukasz Kurgan; Tatiana G Kutateladze; Ozlem Kutlu; SeongAe Kwak; Ho Jeong Kwon; Taeg Kyu Kwon; Yong Tae Kwon; Irene Kyrmizi; Albert La Spada; Patrick Labonté; Sylvain Ladoire; Ilaria Laface; Frank Lafont; Diane C Lagace; Vikramjit Lahiri; Zhibing Lai; Angela S Laird; Aparna Lakkaraju; Trond Lamark; Sheng-Hui Lan; Ane Landajuela; Darius J R Lane; Jon D Lane; Charles H Lang; Carsten Lange; Ülo Langel; Rupert Langer; Pierre Lapaquette; Jocelyn Laporte; Nicholas F LaRusso; Isabel Lastres-Becker; Wilson Chun Yu Lau; Gordon W Laurie; Sergio Lavandero; Betty Yuen Kwan Law; Helen Ka-Wai Law; Rob Layfield; Weidong Le; Herve Le Stunff; Alexandre Y Leary; Jean-Jacques Lebrun; Lionel Y W Leck; Jean-Philippe Leduc-Gaudet; Changwook Lee; Chung-Pei Lee; Da-Hye Lee; Edward B Lee; Erinna F Lee; Gyun Min Lee; He-Jin Lee; Heung Kyu Lee; Jae Man Lee; Jason S Lee; Jin-A Lee; Joo-Yong Lee; Jun Hee Lee; Michael Lee; Min Goo Lee; Min Jae Lee; Myung-Shik Lee; Sang Yoon Lee; Seung-Jae Lee; Stella Y Lee; Sung Bae Lee; Won Hee Lee; Ying-Ray Lee; Yong-Ho Lee; Youngil Lee; Christophe Lefebvre; Renaud Legouis; Yu L Lei; Yuchen Lei; Sergey Leikin; Gerd Leitinger; Leticia Lemus; Shuilong Leng; Olivia Lenoir; Guido Lenz; Heinz Josef Lenz; Paola Lenzi; Yolanda León; Andréia M Leopoldino; Christoph Leschczyk; Stina Leskelä; Elisabeth Letellier; Chi-Ting Leung; Po Sing Leung; Jeremy S Leventhal; Beth Levine; Patrick A Lewis; Klaus Ley; Bin Li; Da-Qiang Li; Jianming Li; Jing Li; Jiong Li; Ke Li; Liwu Li; Mei Li; Min Li; Min Li; Ming Li; Mingchuan Li; Pin-Lan Li; Ming-Qing Li; Qing Li; Sheng Li; Tiangang Li; Wei Li; Wenming Li; Xue Li; Yi-Ping Li; Yuan Li; Zhiqiang Li; Zhiyong Li; Zhiyuan Li; Jiqin Lian; Chengyu Liang; Qiangrong Liang; Weicheng Liang; Yongheng Liang; YongTian Liang; Guanghong Liao; Lujian Liao; Mingzhi Liao; Yung-Feng Liao; Mariangela Librizzi; Pearl P Y Lie; Mary A Lilly; Hyunjung J Lim; Thania R R Lima; Federica Limana; Chao Lin; Chih-Wen Lin; Dar-Shong Lin; Fu-Cheng Lin; Jiandie D Lin; Kurt M Lin; Kwang-Huei Lin; Liang-Tzung Lin; Pei-Hui Lin; Qiong Lin; Shaofeng Lin; Su-Ju Lin; Wenyu Lin; Xueying Lin; Yao-Xin Lin; Yee-Shin Lin; Rafael Linden; Paula Lindner; Shuo-Chien Ling; Paul Lingor; Amelia K Linnemann; Yih-Cherng Liou; Marta M Lipinski; Saška Lipovšek; Vitor A Lira; Natalia Lisiak; Paloma B Liton; Chao Liu; Ching-Hsuan Liu; Chun-Feng Liu; Cui Hua Liu; Fang Liu; Hao Liu; Hsiao-Sheng Liu; Hua-Feng Liu; Huifang Liu; Jia Liu; Jing Liu; Julia Liu; Leyuan Liu; Longhua Liu; Meilian Liu; Qin Liu; Wei Liu; Wende Liu; Xiao-Hong Liu; Xiaodong Liu; Xingguo Liu; Xu Liu; Xuedong Liu; Yanfen Liu; Yang Liu; Yang Liu; Yueyang Liu; Yule Liu; J Andrew Livingston; Gerard Lizard; Jose M Lizcano; Senka Ljubojevic-Holzer; Matilde E LLeonart; David Llobet-Navàs; Alicia Llorente; Chih Hung Lo; Damián Lobato-Márquez; Qi Long; Yun Chau Long; Ben Loos; Julia A Loos; Manuela G López; Guillermo López-Doménech; José Antonio López-Guerrero; Ana T López-Jiménez; Óscar López-Pérez; Israel López-Valero; Magdalena J Lorenowicz; Mar Lorente; Peter Lorincz; Laura Lossi; Sophie Lotersztajn; Penny E Lovat; Jonathan F Lovell; Alenka Lovy; Péter Lőw; Guang Lu; Haocheng Lu; Jia-Hong Lu; Jin-Jian Lu; Mengji Lu; Shuyan Lu; Alessandro Luciani; John M Lucocq; Paula Ludovico; Micah A Luftig; Morten Luhr; Diego Luis-Ravelo; Julian J Lum; Liany Luna-Dulcey; Anders H Lund; Viktor K Lund; Jan D Lünemann; Patrick Lüningschrör; Honglin Luo; Rongcan Luo; Shouqing Luo; Zhi Luo; Claudio Luparello; Bernhard Lüscher; Luan Luu; Alex Lyakhovich; Konstantin G Lyamzaev; Alf Håkon Lystad; Lyubomyr Lytvynchuk; Alvin C Ma; 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Sascha Martens; Alexandre P J Martin; Katie R Martin; Sara Martin; Shaun Martin; Adrián Martín-Segura; Miguel A Martín-Acebes; Inmaculada Martin-Burriel; Marcos Martin-Rincon; Paloma Martin-Sanz; José A Martina; Wim Martinet; Aitor Martinez; Ana Martinez; Jennifer Martinez; Moises Martinez Velazquez; Nuria Martinez-Lopez; Marta Martinez-Vicente; Daniel O Martins; Joilson O Martins; Waleska K Martins; Tania Martins-Marques; Emanuele Marzetti; Shashank Masaldan; Celine Masclaux-Daubresse; Douglas G Mashek; Valentina Massa; Lourdes Massieu; Glenn R Masson; Laura Masuelli; Anatoliy I Masyuk; Tetyana V Masyuk; Paola Matarrese; Ander Matheu; Satoaki Matoba; Sachiko Matsuzaki; Pamela Mattar; Alessandro Matte; Domenico Mattoscio; José L Mauriz; Mario Mauthe; Caroline Mauvezin; Emanual Maverakis; Paola Maycotte; Johanna Mayer; Gianluigi Mazzoccoli; Cristina Mazzoni; Joseph R Mazzulli; Nami McCarty; Christine McDonald; Mitchell R McGill; Sharon L McKenna; BethAnn McLaughlin; Fionn McLoughlin; Mark A McNiven; 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Soledad Porte Alcon; Eliana Portilla-Fernandez; Martin Post; Malia B Potts; Joanna Poulton; Ted Powers; Veena Prahlad; Tomasz K Prajsnar; Domenico Praticò; Rosaria Prencipe; Muriel Priault; Tassula Proikas-Cezanne; Vasilis J Promponas; Christopher G Proud; Rosa Puertollano; Luigi Puglielli; Thomas Pulinilkunnil; Deepika Puri; Rajat Puri; Julien Puyal; Xiaopeng Qi; Yongmei Qi; Wenbin Qian; Lei Qiang; Yu Qiu; Joe Quadrilatero; Jorge Quarleri; Nina Raben; Hannah Rabinowich; Debora Ragona; Michael J Ragusa; Nader Rahimi; Marveh Rahmati; Valeria Raia; Nuno Raimundo; Namakkal-Soorappan Rajasekaran; Sriganesh Ramachandra Rao; Abdelhaq Rami; Ignacio Ramírez-Pardo; David B Ramsden; Felix Randow; Pundi N Rangarajan; Danilo Ranieri; Hai Rao; Lang Rao; Rekha Rao; Sumit Rathore; J Arjuna Ratnayaka; Edward A Ratovitski; Palaniyandi Ravanan; Gloria Ravegnini; Swapan K Ray; Babak Razani; Vito Rebecca; Fulvio Reggiori; Anne Régnier-Vigouroux; Andreas S Reichert; David Reigada; Jan H Reiling; Theo Rein; 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Peter B Stathopulos; Katja Stefan; Sven Marcel Stefan; Leonidas Stefanis; Joan S Steffan; Alexander Steinkasserer; Harald Stenmark; Jared Sterneckert; Craig Stevens; Veronika Stoka; Stephan Storch; Björn Stork; Flavie Strappazzon; Anne Marie Strohecker; Dwayne G Stupack; Huanxing Su; Ling-Yan Su; Longxiang Su; Ana M Suarez-Fontes; Carlos S Subauste; Selvakumar Subbian; Paula V Subirada; Ganapasam Sudhandiran; Carolyn M Sue; Xinbing Sui; Corey Summers; Guangchao Sun; Jun Sun; Kang Sun; Meng-Xiang Sun; Qiming Sun; Yi Sun; Zhongjie Sun; Karen K S Sunahara; Eva Sundberg; Katalin Susztak; Peter Sutovsky; Hidekazu Suzuki; Gary Sweeney; J David Symons; Stephen Cho Wing Sze; Nathaniel J Szewczyk; Anna Tabęcka-Łonczynska; Claudio Tabolacci; Frank Tacke; Heinrich Taegtmeyer; Marco Tafani; Mitsuo Tagaya; Haoran Tai; Stephen W G Tait; Yoshinori Takahashi; Szabolcs Takats; Priti Talwar; Chit Tam; Shing Yau Tam; Davide Tampellini; Atsushi Tamura; Chong Teik Tan; Eng-King Tan; Ya-Qin Tan; Masaki Tanaka; Motomasa Tanaka; Daolin Tang; Jingfeng Tang; Tie-Shan Tang; Isei Tanida; Zhipeng Tao; Mohammed Taouis; Lars Tatenhorst; Nektarios Tavernarakis; Allen Taylor; Gregory A Taylor; Joan M Taylor; Elena Tchetina; Andrew R Tee; Irmgard Tegeder; David Teis; Natercia Teixeira; Fatima Teixeira-Clerc; Kumsal A Tekirdag; Tewin Tencomnao; Sandra Tenreiro; Alexei V Tepikin; Pilar S Testillano; Gianluca Tettamanti; Pierre-Louis Tharaux; Kathrin Thedieck; Arvind A Thekkinghat; Stefano Thellung; Josephine W Thinwa; V P Thirumalaikumar; Sufi Mary Thomas; Paul G Thomes; Andrew Thorburn; Lipi Thukral; Thomas Thum; Michael Thumm; Ling Tian; Ales Tichy; Andreas Till; Vincent Timmerman; Vladimir I Titorenko; Sokol V Todi; Krassimira Todorova; Janne M Toivonen; Luana Tomaipitinca; Dhanendra Tomar; Cristina Tomas-Zapico; Sergej Tomić; Benjamin Chun-Kit Tong; Chao Tong; Xin Tong; Sharon A Tooze; Maria L Torgersen; Satoru Torii; Liliana Torres-López; Alicia Torriglia; Christina G Towers; Roberto Towns; Shinya Toyokuni; Vladimir Trajkovic; Donatella Tramontano; Quynh-Giao Tran; Leonardo H Travassos; Charles B Trelford; Shirley Tremel; Ioannis P Trougakos; Betty P Tsao; Mario P Tschan; Hung-Fat Tse; Tak Fu Tse; Hitoshi Tsugawa; Andrey S Tsvetkov; David A Tumbarello; Yasin Tumtas; María J Tuñón; Sandra Turcotte; Boris Turk; Vito Turk; Bradley J Turner; Richard I Tuxworth; Jessica K Tyler; Elena V Tyutereva; Yasuo Uchiyama; Aslihan Ugun-Klusek; Holm H Uhlig; Marzena Ułamek-Kozioł; Ilya V Ulasov; Midori Umekawa; Christian Ungermann; Rei Unno; Sylvie Urbe; Elisabet Uribe-Carretero; Suayib Üstün; Vladimir N Uversky; Thomas Vaccari; Maria I Vaccaro; Björn F Vahsen; Helin Vakifahmetoglu-Norberg; Rut Valdor; Maria J Valente; Ayelén Valko; Richard B Vallee; Angela M Valverde; Greet Van den Berghe; Stijn van der Veen; Luc Van Kaer; Jorg van Loosdregt; Sjoerd J L van Wijk; Wim Vandenberghe; Ilse Vanhorebeek; Marcos A Vannier-Santos; Nicola Vannini; M Cristina Vanrell; Chiara Vantaggiato; Gabriele Varano; Isabel Varela-Nieto; Máté Varga; M Helena Vasconcelos; Somya Vats; Demetrios G Vavvas; Ignacio Vega-Naredo; Silvia Vega-Rubin-de-Celis; Guillermo Velasco; Ariadna P Velázquez; Tibor Vellai; Edo Vellenga; Francesca Velotti; Mireille Verdier; Panayotis Verginis; Isabelle Vergne; Paul Verkade; Manish Verma; Patrik Verstreken; Tim Vervliet; Jörg Vervoorts; Alexandre T Vessoni; Victor M Victor; Michel Vidal; Chiara Vidoni; Otilia V Vieira; Richard D Vierstra; Sonia Viganó; Helena Vihinen; Vinoy Vijayan; Miquel Vila; Marçal Vilar; José M Villalba; Antonio Villalobo; Beatriz Villarejo-Zori; Francesc Villarroya; Joan Villarroya; Olivier Vincent; Cecile Vindis; Christophe Viret; Maria Teresa Viscomi; Dora Visnjic; Ilio Vitale; David J Vocadlo; Olga V Voitsekhovskaja; Cinzia Volonté; Mattia Volta; Marta Vomero; Clarissa Von Haefen; Marc A Vooijs; Wolfgang Voos; Ljubica Vucicevic; Richard Wade-Martins; Satoshi Waguri; Kenrick A Waite; Shuji Wakatsuki; David W Walker; Mark J Walker; Simon A Walker; Jochen Walter; Francisco G Wandosell; Bo Wang; Chao-Yung Wang; Chen Wang; Chenran Wang; Chenwei Wang; Cun-Yu Wang; Dong Wang; Fangyang Wang; Feng Wang; Fengming Wang; Guansong Wang; Han Wang; Hao Wang; Hexiang Wang; Hong-Gang Wang; Jianrong Wang; Jigang Wang; Jiou Wang; Jundong Wang; Kui Wang; Lianrong Wang; Liming Wang; Maggie Haitian Wang; Meiqing Wang; Nanbu Wang; Pengwei Wang; Peipei Wang; Ping Wang; Ping Wang; Qing Jun Wang; Qing Wang; Qing Kenneth Wang; Qiong A Wang; Wen-Tao Wang; Wuyang Wang; Xinnan Wang; Xuejun Wang; Yan Wang; Yanchang Wang; Yanzhuang Wang; Yen-Yun Wang; Yihua Wang; Yipeng Wang; Yu Wang; Yuqi Wang; Zhe Wang; Zhenyu Wang; Zhouguang Wang; Gary Warnes; Verena Warnsmann; Hirotaka Watada; Eizo Watanabe; Maxinne Watchon; Anna Wawrzyńska; Timothy E Weaver; Grzegorz Wegrzyn; Ann M Wehman; Huafeng Wei; Lei Wei; Taotao Wei; Yongjie Wei; Oliver H Weiergräber; Conrad C Weihl; Günther Weindl; Ralf Weiskirchen; Alan Wells; Runxia H Wen; Xin Wen; Antonia Werner; Beatrice Weykopf; Sally P Wheatley; J Lindsay Whitton; Alexander J Whitworth; Katarzyna Wiktorska; Manon E Wildenberg; Tom Wileman; Simon Wilkinson; Dieter Willbold; Brett Williams; Robin S B Williams; Roger L Williams; Peter R Williamson; Richard A Wilson; Beate Winner; Nathaniel J Winsor; Steven S Witkin; Harald Wodrich; Ute Woehlbier; Thomas Wollert; Esther Wong; Jack Ho Wong; Richard W Wong; Vincent Kam Wai Wong; W Wei-Lynn Wong; An-Guo Wu; Chengbiao Wu; Jian Wu; Junfang Wu; Kenneth K Wu; Min Wu; Shan-Ying Wu; Shengzhou Wu; Shu-Yan Wu; Shufang Wu; William K K Wu; Xiaohong Wu; Xiaoqing Wu; Yao-Wen Wu; Yihua Wu; Ramnik J Xavier; Hongguang Xia; Lixin Xia; Zhengyuan Xia; Ge Xiang; Jin Xiang; Mingliang Xiang; Wei Xiang; Bin Xiao; Guozhi Xiao; Hengyi Xiao; Hong-Tao Xiao; Jian Xiao; Lan Xiao; Shi Xiao; Yin Xiao; Baoming Xie; Chuan-Ming Xie; Min Xie; Yuxiang Xie; Zhiping Xie; Zhonglin Xie; Maria Xilouri; Congfeng Xu; En Xu; Haoxing Xu; Jing Xu; JinRong Xu; Liang Xu; Wen Wen Xu; Xiulong Xu; Yu Xue; Sokhna M S Yakhine-Diop; Masamitsu Yamaguchi; Osamu Yamaguchi; Ai Yamamoto; Shunhei Yamashina; Shengmin Yan; Shian-Jang Yan; Zhen Yan; Yasuo Yanagi; Chuanbin Yang; Dun-Sheng Yang; Huan Yang; Huang-Tian Yang; Hui Yang; Jin-Ming Yang; Jing Yang; Jingyu Yang; Ling Yang; Liu Yang; Ming Yang; Pei-Ming Yang; Qian Yang; Seungwon Yang; Shu Yang; Shun-Fa Yang; Wannian Yang; Wei Yuan Yang; Xiaoyong Yang; Xuesong Yang; Yi Yang; Ying Yang; Honghong Yao; Shenggen Yao; Xiaoqiang Yao; Yong-Gang Yao; Yong-Ming Yao; Takahiro Yasui; Meysam Yazdankhah; Paul M Yen; Cong Yi; Xiao-Ming Yin; Yanhai Yin; Zhangyuan Yin; Ziyi Yin; Meidan Ying; Zheng Ying; Calvin K Yip; Stephanie Pei Tung Yiu; Young H Yoo; Kiyotsugu Yoshida; Saori R Yoshii; Tamotsu Yoshimori; Bahman Yousefi; Boxuan Yu; Haiyang Yu; Jun Yu; Jun Yu; Li Yu; Ming-Lung Yu; Seong-Woon Yu; Victor C Yu; W Haung Yu; Zhengping Yu; Zhou Yu; Junying Yuan; Ling-Qing Yuan; Shilin Yuan; Shyng-Shiou F Yuan; Yanggang Yuan; Zengqiang Yuan; Jianbo Yue; Zhenyu Yue; Jeanho Yun; Raymond L Yung; David N Zacks; Gabriele Zaffagnini; Vanessa O Zambelli; Isabella Zanella; Qun S Zang; Sara Zanivan; Silvia Zappavigna; Pilar Zaragoza; Konstantinos S Zarbalis; Amir Zarebkohan; Amira Zarrouk; Scott O Zeitlin; Jialiu Zeng; Ju-Deng Zeng; Eva Žerovnik; Lixuan Zhan; Bin Zhang; Donna D Zhang; Hanlin Zhang; Hong Zhang; Hong Zhang; Honghe Zhang; Huafeng Zhang; Huaye Zhang; Hui Zhang; Hui-Ling Zhang; Jianbin Zhang; Jianhua Zhang; Jing-Pu Zhang; Kalin Y B Zhang; Leshuai W Zhang; Lin Zhang; Lisheng Zhang; Lu Zhang; Luoying Zhang; Menghuan Zhang; Peng Zhang; Sheng Zhang; Wei Zhang; Xiangnan Zhang; Xiao-Wei Zhang; Xiaolei Zhang; Xiaoyan Zhang; Xin Zhang; Xinxin Zhang; Xu Dong Zhang; Yang Zhang; Yanjin Zhang; Yi Zhang; Ying-Dong Zhang; Yingmei Zhang; Yuan-Yuan Zhang; Yuchen Zhang; Zhe Zhang; Zhengguang Zhang; Zhibing Zhang; Zhihai Zhang; Zhiyong Zhang; Zili Zhang; Haobin Zhao; Lei Zhao; Shuang Zhao; Tongbiao Zhao; Xiao-Fan Zhao; Ying Zhao; Yongchao Zhao; Yongliang Zhao; Yuting Zhao; Guoping Zheng; Kai Zheng; Ling Zheng; Shizhong Zheng; Xi-Long Zheng; Yi Zheng; Zu-Guo Zheng; Boris Zhivotovsky; Qing Zhong; Ao Zhou; Ben Zhou; Cefan Zhou; Gang Zhou; Hao Zhou; Hong Zhou; Hongbo Zhou; Jie Zhou; Jing Zhou; Jing Zhou; Jiyong Zhou; Kailiang Zhou; Rongjia Zhou; Xu-Jie Zhou; Yanshuang Zhou; Yinghong Zhou; Yubin Zhou; Zheng-Yu Zhou; Zhou Zhou; Binglin Zhu; Changlian Zhu; Guo-Qing Zhu; Haining Zhu; Hongxin Zhu; Hua Zhu; Wei-Guo Zhu; Yanping Zhu; Yushan Zhu; Haixia Zhuang; Xiaohong Zhuang; Katarzyna Zientara-Rytter; Christine M Zimmermann; Elena Ziviani; Teresa Zoladek; Wei-Xing Zong; Dmitry B Zorov; Antonio Zorzano; Weiping Zou; Zhen Zou; Zhengzhi Zou; Steven Zuryn; Werner Zwerschke; Beate Brand-Saberi; X Charlie Dong; Chandra Shekar Kenchappa; Zuguo Li; Yong Lin; Shigeru Oshima; Yueguang Rong; Judith C Sluimer; Christina L Stallings; Chun-Kit Tong
Journal:  Autophagy       Date:  2021-02-08       Impact factor: 13.391

Review 4.  Autophagy in the immune system.

Authors:  Daniel J Puleston; Anna Katharina Simon
Journal:  Immunology       Date:  2014-01       Impact factor: 7.397

Review 5.  Assessing Autophagy in Mouse Models and Patients with Systemic Autoimmune Diseases.

Authors:  Fengjuan Wang; Baihui Li; Nicolas Schall; Maud Wilhelm; Sylviane Muller
Journal:  Cells       Date:  2017-06-28       Impact factor: 6.600

Review 6.  Autophagy and the Immune Response.

Authors:  Bing Cui; Heng Lin; Jinmei Yu; Jiaojiao Yu; Zhuowei Hu
Journal:  Adv Exp Med Biol       Date:  2019       Impact factor: 2.622

7.  Circulating Cytokines and Lymphocyte Subsets in Patients Who Have Recovered from COVID-19.

Authors:  Xinri Zhang; Xin Li; Xin Li; Dongyan Li
Journal:  Biomed Res Int       Date:  2020-11-26       Impact factor: 3.411

8.  Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway.

Authors:  Shahla Shojaei; Madhumita Suresh; Daniel J Klionsky; Hagar Ibrahim Labouta; Saeid Ghavami
Journal:  Virulence       Date:  2020-12       Impact factor: 5.882

9.  Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study.

Authors:  Li Tan; Qi Wang; Duanyang Zhang; Jinya Ding; Qianchuan Huang; Yi-Quan Tang; Qiongshu Wang; Hongming Miao
Journal:  Signal Transduct Target Ther       Date:  2020-03-27
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