Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy
Meliambro, K;Li, X;Salem, F;Yi, Z;Sun, Z;Chan, L;Chung, M;Chancay, J;Vy, HMT;Nadkarni, G;Wong, JS;Fu, J;Lee, K;Zhang, W;He, JC;Campbell, KN;
PMID: 33942030 | DOI: 10.1016/j.xkme.2021.02.012
Recent Case reports suggest COVID-19 is associated with collapsing glomerulopathy in African Americans with APOL1 risk alleles, however, it is unclear if disease pathogenesis is similar to HIVAN. Here RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19-associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and ACE2 mRNA transcripts as compared to 12 control kidney samples downloaded from the GTEx Portal. Whole genome sequencing of the COVID-19-associated collapsing glomerulopathy kidney sample identified four indel gene variants, three of which are of unknown significance with respect to chronic kidney disease and/or FSGS. Molecular profiling of the kidney demonstrated activation of COVID-19-associated cell injury pathways such as inflammation and coagulation. Evidence for direct SARS-CoV-2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 in both COVID-19-associated collapsing glomerulopathy and HIVAN as compared to control kidney tissue. Importantly, IL-6-induced activation of STAT3 may be a targetable mechanism driving COVID-19-associated acute kidney injury.
Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages
Lv, J;Wang, Z;Qu, Y;Zhu, H;Zhu, Q;Tong, W;Bao, L;Lv, Q;Cong, J;Li, D;Deng, W;Yu, P;Song, J;Tong, WM;Liu, J;Liu, Y;Qin, C;Huang, B;
PMID: 33850112 | DOI: 10.1038/s41421-021-00258-1
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.
Journal of the American Society of Nephrology : JASN
Kudose, S;Santoriello, D;Bomback, AS;Sekulic, M;Batal, I;Stokes, MB;Ghavami, IA;Kim, JS;Marasa, M;Xu, K;Peleg, Y;Barasch, J;Canetta, P;Rasouly, HM;Gharavi, AG;Markowitz, GS;D'Agati, VD;
PMID: 34670811 | DOI: 10.1681/ASN.2021070931
The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown.We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2.The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected.Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.
Bewley, D;Lee, J;Popescu, O;Oviedo, A;
| DOI: 10.7759/cureus.20833
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Favre, G;Mazzetti, S;Gengler, C;Bertelli, C;Schneider, J;Laubscher, B;Capoccia, R;Pakniyat, F;Ben Jazia, I;Eggel-Hort, B;de Leval, L;Pomar, L;Greub, G;Baud, D;Giannoni, E;
PMID: 34960786 | DOI: 10.3390/v13122517
Neonatal COVID-19 is rare and mainly results from postnatal transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, can infect the placenta and compromise its function. We present two cases of decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation, and leading to brain injury. Placental examination revealed extensive and multifocal chronic intervillositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic peri-ventricular leukomalacia.
Pathogenic Characterization of a Porcine Circovirus Type 3 Isolate from Heilongjiang, China
Wang, M;Yu, Y;Wu, J;Meng, F;Tang, Y;Wang, S;Wang, Y;Cui, H;He, X;Tu, Y;Wang, G;Cai, X;
| DOI: 10.1155/2021/9434944
The clinical outcome of porcine circovirus 3 (PCV3) infection is still controversial. Herein, a novel PCV3 isolate (PCV3-China/DB-1/2017) with the molecular characterization of 24A and 27K in the Cap protein was used to inoculate three-week-old cesarean-derived, colostrum-deprived piglets. The nine PCV3 DB-1 inoculated piglets exhibited no obvious clinical symptoms or macroscopic lesions. PCV3 displayed a broad histotropism, including the heart, liver, spleen, lung, kidney, brain, lymph nodes, and tonsil, and the lungs and lymph nodes contained a higher quantity of viral genomes compared to that of the other organs. From 7 days after PCV3 DB-1 inoculation, the piglets showed obvious IgG antibody responses against PCV3 rCap-VLPs. The cumulative results demonstrated that PCV3 trend to low pathogenicity.
Park, J;Foox, J;Hether, T;Danko, D;Warren, S;Kim, Y;Reeves, J;Butler, D;Mozsary, C;Rosiene, J;Shaiber, A;Afshin, E;MacKay, M;Rendeiro, A;Bram, Y;Chandar, V;Geiger, H;Craney, A;Velu, P;Melnick, A;Hajirasouliha, I;Beheshti, A;Taylor, D;Saravia-Butler, A;Singh, U;Wurtele, E;Schisler, J;Fennessey, S;Corvelo, A;Zody, M;Germer, S;Salvatore, S;Levy, S;Wu, S;Tatonetti, N;Shapira, S;Salvatore, M;Westblade, L;Cushing, M;Rennert, H;Kriegel, A;Elemento, O;Imielinski, M;Rice, C;Borczuk, A;Meydan, C;Schwartz, R;Mason, C;
| DOI: 10.1016/j.xcrm.2022.100522
The molecular mechanisms underlying the clinical manifestations of COVID-19 and what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome, remains poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match this data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue compartment-specific damage wrought by SARS-CoV-2 infection, evident as a function of varying viral loads during the clinical course of infection and tissue type specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.
Chen, Z;Chen, J;Wei, X;Hua, H;Hu, R;Ding, N;Zhang, J;Song, D;Ye, Y;Tang, Y;Ding, Z;Ke, S;
PMID: 34960796 | DOI: 10.3390/v13122527
Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, causes neonatal pig acute gastrointestinal infection with a characterization of severe diarrhea, vomiting, high morbidity, and high mortality, resulting in tremendous damages to the swine industry. Neither specific antiviral drugs nor effective vaccines are available, posing a high priority to screen antiviral drugs. The aim of this study is to investigate anti-PEDV effects of carbazole alkaloid derivatives. Eighteen carbazole derivatives (No.1 to No.18) were synthesized, and No.5, No.7, and No.18 were identified to markedly reduce the replication of enhanced green fluorescent protein (EGFP) inserted-PEDV, and the mRNA level of PEDV N. Flow cytometry assay, coupled with CCK8 assay, confirmed No.7 and No.18 carbazole derivatives displayed high inhibition effects with low cell toxicity. Furthermore, time course analysis indicated No.7 and No.18 carbazole derivatives exerted inhibition at the early stage of the viral life cycle. Collectively, the analysis underlines the benefit of carbazole derivatives as potential inhibitors of PEDV, and provides candidates for the development of novel therapeutic agents.
Establishment of a Three-Dimensional In Vitro Model of Equine Papillomavirus Type 2 Infection
Ramsauer, A;Wachoski-Dark, G;Fraefel, C;Ackermann, M;Brandt, S;Grest, P;Knight, C;Favrot, C;Tobler, K;
| DOI: 10.3390/v13071404
There is growing evidence that equine papillomavirus type 2 (EcPV2) infection is etiologically associated with the development of genital squamous cell carcinoma (SCC) and precursor lesions in equids. However, the precise mechanisms underlying neoplastic progression remain unknown. To allow the study of EcPV2-induced carcinogenesis, we aimed to establish a primary equine cell culture model of EcPV2 infection. Three-dimensional (3D) raft cultures were generated from equine penile perilesional skin, plaques and SCCs. Using histological, molecular biological and immunohistochemical methods, rafts versus corresponding natural tissue sections were compared with regard to morphology, presence of EcPV2 DNA, presence and location of EcPV2 gene transcripts and expression of epithelial, mesenchymal and tumor/proliferation markers. Raft cultures from perilesional skin harboring only a few EcPV2-positive (EcPV2+) cells accurately recapitulated the differentiation process of normal skin, whilst rafts from EcPV2+ penile plaques were structurally organized but showed early hyperplasia. Rafts from EcPV2+ SCCs exhibited pronounced hyperplasia and marked dysplasia. Raft levels of EcPV2 oncogene transcription (E6/E7) and expression of tumor/proliferation markers p53, Ki67 and MCM7 expression positively correlated with neoplastic progression, again reflecting the natural situation. Three-dimensional raft cultures accurately reflected major features of corresponding ex vivo material, thus constituting a valuable new research model to study EcPV2-induced carcinogenesis.
Chen, Q;Huang, XY;Tian, Y;Fan, C;Sun, M;Zhou, C;Li, R;Zhang, RR;Wu, G;Qin, CF;
PMID: 34569016 | DOI: 10.1007/s12250-021-00452-1
HISTOLOGICAL FINDINGS IN TRANSBRONCHIAL CRYOBIOPSIES OBTAINED FROM PATIENTS AFTER COVID-19
Culebras, M;Loor, K;Sansano, I;Persiva, Ó;Clofent, D;Polverino, E;Felipe, A;Osorio, J;Muñoz, X;Álvarez, A;Se-COVID-19 team, ;
PMID: 34582842 | DOI: 10.1016/j.chest.2021.09.016
Immunological and pathological outcomes of SARS-CoV-2 challenge following formalin-inactivated vaccine in ferrets and rhesus macaques
Bewley, KR;Gooch, K;Thomas, KM;Longet, S;Wiblin, N;Hunter, L;Chan, K;Brown, P;Russell, RA;Ho, C;Slack, G;Humphries, HE;Alden, L;Allen, L;Aram, M;Baker, N;Brunt, E;Cobb, R;Fotheringham, S;Harris, D;Kennard, C;Leung, S;Ryan, K;Tolley, H;Wand, N;White, A;Sibley, L;Sarfas, C;Pearson, G;Rayner, E;Xue, X;Lambe, T;Charlton, S;Gilbert, S;Sattentau, QJ;Gleeson, F;Hall, Y;Funnell, S;Sharpe, S;Salguero, FJ;Gorringe, A;Carroll, M;
PMID: 34516768 | DOI: 10.1126/sciadv.abg7996
[Figure: see text].
