Kidney allograft biopsy findings after COVID-19

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

2021 Aug 17

Daniel, E;Sekulic, M;Kudose, S;Kubin, C;Ye, X;Shayan, K;Patel, A;Cohen, DJ;Ratner, L;Santoriello, D;Stokes, MB;Markowitz, GS;Pereira, MR;D'Agati, VD;Batal, I;
PMID: 34403563 | DOI: 10.1111/ajt.16804

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of eleven (45%) biopsies obtained within one month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n=2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n=2), infarction (n=1), and transplant glomerulopathy (n=1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n=1), acute tubular injury (n=1), and non-specific histologic findings (n=5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis.This article is protected by

Insights from a Rapidly Implemented COVID-19 Biobank Using Electronic Consent and Informatics Tools

Biopreservation and biobanking

2022 Jun 30

Higgs, EF;Flood, BA;Pyzer, AR;Rouhani, SJ;Trujillo, JA;Gajewski, TF;
PMID: 35771982 | DOI: 10.1089/bio.2021.0169

Biobanking during the COVID-19 pandemic presented unique challenges regarding patient enrollment, sample collection, and experimental analysis. This report details the ways in which we rapidly overcame those challenges to create a robust database of clinical information and patient samples while maintaining clinician and researcher safety. We developed a pipeline using REDCap (Research Electronic Data Capture) to coordinate electronic informed consent, sample collection, immunological assay execution, and data analysis for biobanking samples from patients with COVID-19. We then integrated immunological assay data with clinical data extracted from the electronic health record to link study parameters with clinical readouts. Of the 193 inpatients who participated in this study, 138 consented electronically and 56 provided paper consent. We collected and banked blood samples to measure circulating cytokines and chemokines, peripheral immune cell composition and activation status, anti-COVID-19 antibodies, and germline gene polymorphisms. In addition, we collected DNA and RNA from nasopharyngeal swabs to assess viral titer and microbiome composition by 16S sequencing. The rapid spread and contagious nature of COVID-19 required special considerations and innovative solutions to biobank samples quickly while protecting researchers and clinicians. Overall, this workflow and computational pipeline allowed for comprehensive immune profiling of 193 inpatients infected with COVID-19, as well as 89 outpatients, 157 patients receiving curbside COVID-19 testing, and 86 healthy controls. We describe a novel electronic framework for biobanking and analyzing patient samples during COVID-19, and present insights and strategies that can be applied more broadly to other biobank studies.

The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies

Placenta

2022 May 01

Ward, JD;Cornaby, C;Kato, T;Gilmore, RC;Bunch, D;Miller, MB;Boucher, RC;Schmitz, JL;Askin, FA;Scanga, LR;
PMID: 35512490 | DOI: 10.1016/j.placenta.2022.04.006

The effect of SARS-CoV-2 severity or the trimester of infection in pregnant mothers, placentas, and infants is not fully understood.A retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021 via chart review to document the infants' weight, length, head circumference, survival, congenital abnormalities, hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria.Of the 115 mothers, 85.2% were asymptomatic (n = 37) or had mild (n = 61) symptoms, 13.0% had moderate (n = 9) or severe (n = 6) COVID-19, and 1.74% (n = 2) did not have symptoms recorded. Moderate and severe maternal infections were associated with increased C-section, premature delivery, infant NICU admission, and were more likely to occur in Type 1 (p = 0.0055) and Type 2 (p = 0.0285) diabetic mothers. Only one infant (0.870%) became infected with SARS-CoV-2, which was not via the placenta. Most placentas (n = 63, 54.8%) did not show specific histologic findings; however, a subset showed mild maternal vascular malperfusion (n = 26, 22.6%) and/or mild microscopic ascending intrauterine infection (n = 28, 24.3%). The infants had no identifiable congenital abnormalities, and all infants and mothers survived.Most mothers and their infants had a routine clinical course; however, moderate and severe COVID-19 maternal infections were associated with pregnancy complications and premature delivery. Mothers with pre-existing, non-gestational diabetes were at greatest risk of developing moderate or severe COVID-19. The placental injury patterns of maternal vascular malperfusion and/or microscopic ascending intrauterine infection were not associated with maternal COVID-19 severity.

The pathogenesis of gastrointestinal, hepatic and pancreatic injury in acute and long COVID-19 infection

Gastroenterology Clinics of North America

2022 Dec 01

Meringer, H;Wang, A;Mehandru, S;
| DOI: 10.1016/j.gtc.2022.12.001

The gastrointestinal tract (GI) is targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The present review examines GI involvement in patients with long COVID and discusses the underlying pathophysiological mechanisms that include viral persistence, mucosal and systemic immune dysregulation, microbial dysbiosis, insulin resistance and metabolic abnormalities. Due to the complex and potentially multifactorial nature of this syndrome, rigorous clinical definitions and pathophysiology-based therapeutic approaches are warranted

SARS-CoV-2 Doggybone DNA Vaccine Produces Cross-Variant Neutralizing Antibodies and Is Protective in a COVID-19 Animal Model

Vaccines

2022 Jul 09

Mucker, EM;Brocato, RL;Principe, LM;Kim, RK;Zeng, X;Smith, JM;Kwilas, SA;Kim, S;Horton, H;Caproni, L;Hooper, JW;
PMID: 35891268 | DOI: 10.3390/vaccines10071104

To combat the COVID-19 pandemic, an assortment of vaccines has been developed. Nucleic acid vaccines have the advantage of rapid production, as they only require a viral antigen sequence and can readily be modified to detected viral mutations. Doggybone DNA vaccines targeting the spike protein of SARS-CoV-2 have been generated and compared with a traditionally manufactured, bacterially derived plasmid DNA vaccine that utilizes the same spike sequence. Administered to Syrian hamsters by jet injection at two dose levels, the immunogenicity of both DNA vaccines was compared following two vaccinations. Immunized hamsters were then immunosuppressed and exposed to SARS-CoV-2. Significant differences in body weight were observed during acute infection, and lungs collected at the time of euthanasia had significantly reduced viral RNA, infectious virus, and pathology compared with irrelevant DNA-vaccinated controls. Moreover, immune serum from vaccinated animals was capable of neutralizing SARS-CoV-2 variants of interest and importance in vitro. These data demonstrate the efficacy of a synthetic DNA vaccine approach to protect hamsters from SARS-CoV-2.

Cell culture systems for isolation of SARS-CoV-2 clinical isolates and generation of recombinant virus

iScience

2023 May 19

Chen, DY;Turcinovic, J;Feng, S;Kenney, DJ;Chin, CV;Choudhary, MC;Conway, HL;Semaan, M;Close, BJ;Tavares, AH;Seitz, S;Khan, N;Kapell, S;Crossland, NA;Li, JZ;Douam, F;Baker, SC;Connor, JH;Saeed, M;
PMID: 37095858 | DOI: 10.1016/j.isci.2023.106634

A simple and robust cell culture system is essential for generating authentic SARS-CoV-2 stocks for evaluation of viral pathogenicity, screening of antiviral compounds, and preparation of inactivated vaccines. Evidence suggests that Vero E6, a cell line commonly used in the field to grow SARS-CoV-2, does not support efficient propagation of new viral variants and triggers rapid cell culture adaptation of the virus. We generated a panel of 17 human cell lines overexpressing SARS-CoV-2 entry factors and tested their ability to support viral infection. Two cell lines, Caco-2/AT and HuH-6/AT, demonstrated exceptional susceptibility, yielding highly concentrated virus stocks. Notably, these cell lines were more sensitive than Vero E6 cells in recovering SARS-CoV-2 from clinical specimens. Further, Caco-2/AT cells provided a robust platform for producing genetically reliable recombinant SARS-CoV-2 through a reverse genetics system. These cellular models are a valuable tool for the study of SARS-CoV-2 and its continuously emerging variants.

Intrinsic host susceptibility among multiple species to intranasal SARS-CoV-2 identifies diverse virological, biodistribution and pathological outcomes

Scientific reports

2022 Nov 04

Berry, N;Ferguson, D;Kempster, S;Hall, J;Ham, C;Jenkins, A;Rannow, V;Giles, E;Leahy, R;Goulding, S;Fernandez, A;Adedeji, Y;Vessillier, S;Rajagopal, D;Prior, S;Le Duff, Y;Hurley, M;Gilbert, S;Fritzsche, M;Mate, R;Rose, N;Francis, RJ;MacLellan-Gibson, K;Suarez-Bonnet, A;Priestnall, S;Almond, N;
PMID: 36333445 | DOI: 10.1038/s41598-022-23339-x

SARS-CoV-2 exhibits a diverse host species range with variable outcomes, enabling differential host susceptibility studies to assess suitability for pre-clinical countermeasure and pathogenesis studies. Baseline virological, molecular and pathological outcomes were determined among multiple species-one Old World non-human primate (NHP) species (cynomolgus macaques), two New World NHP species (red-bellied tamarins; common marmosets) and Syrian hamsters-following single-dose, atraumatic intranasal administration of SARS-CoV-2/Victoria-01. After serial sacrifice 2, 10 and 28-days post-infection (dpi), hamsters and cynomolgus macaques displayed differential virus biodistribution across respiratory, gastrointestinal and cardiovascular systems. Uniquely, New World tamarins, unlike marmosets, exhibited high levels of acute upper airway infection, infectious virus recovery associated with mild lung pathology representing a host previously unrecognized as susceptible to SARS-CoV-2. Across all species, lung pathology was identified post-clearance of virus shedding (antigen/RNA), with an association of virus particles within replication organelles in lung sections analysed by electron microscopy. Disrupted cell ultrastructure and lung architecture, including abnormal morphology of mitochondria 10-28 dpi, represented on-going pathophysiological consequences of SARS-CoV-2 in predominantly asymptomatic hosts. Infection kinetics and host pathology comparators using standardized methodologies enables model selection to bridge differential outcomes within upper and lower respiratory tracts and elucidate longer-term consequences of asymptomatic SARS-CoV-2 infection.

BCG vaccination provides protection against IAV but not SARS-CoV-2

Cell reports

2022 Feb 21

Kaufmann, E;Khan, N;Tran, KA;Ulndreaj, A;Pernet, E;Fontes, G;Lupien, A;Desmeules, P;McIntosh, F;Abow, A;Moorlag, SJCFM;Debisarun, P;Mossman, K;Banerjee, A;Karo-Atar, D;Sadeghi, M;Mubareka, S;Vinh, DC;King, IL;Robbins, CS;Behr, MA;Netea, MG;Joubert, P;Divangahi, M;
PMID: 35235831 | DOI: 10.1016/j.celrep.2022.110502

Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism.

Society on NeuroImmune Pharmacology COVID-19 Virtual Workshop

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

2021 Jun 28

Kumar, S;Pendyala, G;Yelamanchili, SV;Seth, P;Maggirwar, S;Bidlack, JM;Chang, SL;
PMID: 34181181 | DOI: 10.1007/s11481-021-10001-y

This brief report collects the program and abstracts of the Society on NeuroImmune Pharmacology (SNIP) COVID-19 Virtual Workshop held on April 9, 2021. The workshop consisted of four symposia: Symposium 1: Molecular approaches to COVID-19 pathogenesis and underlying mechanisms; Symposium 2: Therapeutic and vaccine approaches to COVID-19; Symposium 3: Early Career Investigator talks; and Symposium 4: Diversity and Inclusion SNIP Committee (DISC) program: Well-being and reflections. The workshop also featured four special talks on COVID-19 and funding opportunities from the National Institute on Alcohol Abuse and Alcoholism (NIAAA); COVID-19 and funding opportunities from the National Institute on Drug Abuse (NIDA); opportunities from NIH for early career investigator (ECI) fellows; and neurologic and psychiatric complications of SARS-CoV-2 infection. Presenters included NIH officials, SNIP members, and non-member scientists whose abstracts were submitted and accepted for inclusion in the virtual event hosted by the University of Nebraska Medical Center via Zoom webinar. A special theme issue of SNIP's official journal, the Journal of Neuroimmune Pharmacology (JNIP), will collect select papers from the workshop along with other related manuscripts in a special theme issue titled "Neuroimmune Pharmacology of SARS-CoV-2."

Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy

Kidney medicine

2021 Apr 28

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

Cell discovery

2021 Apr 13

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.

Direct mechanisms of SARS-CoV-2-induced cardiomyocyte damage: an update

Virology journal

2022 Jun 25

Yang, Y;Wei, Z;Xiong, C;Qian, H;
PMID: 35752810 | DOI: 10.1186/s12985-022-01833-y

Myocardial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reportedly related to disease severity and mortality, attracting attention to exploring relevant pathogenic mechanisms. Limited by insufficient evidence, myocardial injury caused by direct viral invasion of cardiomyocytes (CMs) is not fully understood. Based on recent studies, endosomal dependence can compensate for S protein priming to mediate SARS-CoV-2 infection of CMs, damage the contractile function of CMs, trigger electrical dysfunction, and tip the balance of the renin-angiotensin-aldosterone system to exert a myocardial injury effect. In this review, we shed light on the direct injury caused by SARS-CoV-2 to provide a comprehensive understanding of the cardiac manifestations of coronavirus disease 2019 (COVID-19).

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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