Gastrointestinal Pathology in Samples from Coronavirus Disease 2019 (COVID-19)-Positive Patients
Archives of pathology & laboratory medicine
Westerhoff, M;Jones, D;Hrycaj, SM;Chan, MP;Pantanowitz, L;Tu, H;Choi, K;Greenson, J;Lamps, L;
PMID: 33961007 | DOI: 10.5858/arpa.2021-0137-SA
-Although primarily considered a respiratory illness, coronavirus disease 2019 (COVID-19) can cause gastrointestinal manifestations. -To evaluate histopathology and in situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal samples from patients with recent and remote COVID-19. -Patients with positive SARS-CoV-2 nasopharyngeal tests and a gastrointestinal tissue specimen were included. SARS-CoV-2 in situ hybridization (ISH) was performed on each sample. A subset had SARS-CoV-2 next generation sequencing (NGS) performed. -Twenty-five patients met inclusion criteria. Five had positive SARS-CoV-2 nasopharyngeal tests within 7 days of their gastrointestinal procedure. Two were ulcerative colitis patients on steroid therapy who lacked typical COVID-19 symptoms. Their colectomies showed severe ulcerative colitis; one demonstrated SARS-CoV-2 by NGS but a negative ISH. Another had an ischemic colon resected as a complication of the COVID-19 course; however, both ISH and NGS were negative. A fourth had a normal-appearing terminal ileum but positive ISH and NGS. The fifth patient had ileal ulcers with SARS-CoV-2 negativity by both modalities. The remaining 20 patients had positive nasopharyngeal tests an average of 53 days prior to procedure. None of their samples demonstrated SARS-CoV-2 ISH positivity, but one was positive on NGS despite a negative nasopharyngeal test. -Gastrointestinal findings from SARS-CoV-2-infected patients ranged from normal with virus detected by ISH and NGS, to bowel ischemia secondary to systemic viral effects, without evidence of virus in the tissue. No distinct histologic finding was identified in those with gastrointestinal tissue specimens demonstrating SARS-CoV-2 positivity in this cohort.
Signal transduction and targeted therapy
Song, Z;Bao, L;Deng, W;Liu, J;Ren, E;Lv, Q;Liu, M;Qi, F;Chen, T;Deng, R;Li, F;Liu, Y;Wei, Q;Gao, H;Yu, P;Han, Y;Zhao, W;Zheng, J;Liang, X;Yang, F;Qin, C;
PMID: 35091528 | DOI: 10.1038/s41392-022-00891-6
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.
Vanderheiden, A;Thomas, J;Soung, AL;Davis-Gardner, ME;Floyd, K;Jin, F;Cowan, DA;Pellegrini, K;Shi, PY;Grakoui, A;Klein, RS;Bosinger, SE;Kohlmeier, JE;Menachery, VD;Suthar, MS;
PMID: 34749524 | DOI: 10.1128/mBio.02749-21
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Single-cell RNA sequencing (scRNA-Seq) analysis of lung homogenates identified a hyperinflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a potential CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts the viral burden in the lung. We find that SARS-CoV-2 triggers an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using RNA sequencing and flow cytometry approaches, we demonstrate that SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Mechanistically, CCR2 signaling promoted the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified that the CCR2 pathway is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.
Röltgen, K;Nielsen, S;Silva, O;Younes, S;Maxim Zaslavsky, ;Costales, C;Yang, F;Wirz, O;Solis, D;Hoh, R;Wang, A;Arunachalam, P;Colburg, D;Zhao, S;Haraguchi, E;Lee, A;Shah, M;Manohar, M;Chang, I;Gao, F;Mallajosyula, V;Li, C;Liu, J;Shoura, M;Sindher, S;Parsons, E;Dashdorj, N;Dashdorj, N;Monroe, R;Serrano, G;Beach, T;Chinthrajah, R;Charville, G;Wilbur, J;Wohlstadter, J;Davis, M;Pulendran, B;Troxell, M;Sigal, G;Natkunam, Y;Pinsky, B;Nadeau, K;Boyd, S;
| DOI: 10.1016/j.cell.2022.01.018
During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including 3rd dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is less after infection compared to all vaccines evaluated, but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks post-vaccination in some cases. SARS-CoV-2 antibody specificity, breadth and maturation are affected by imprinting from exposure history, and distinct histological and antigenic contexts in infection compared to vaccination.
Jansen, J;Reimer, K;Nagai, J;Varghese, F;Overheul, G;de Beer, M;Roverts, R;Daviran, D;Fermin, L;Willemsen, B;Beukenboom, M;Djudjaj, S;von Stillfried, S;van Eijk, L;Mastik, M;Bulthuis, M;Dunnen, W;van Goor, H;Hillebrands, J;Triana, S;Alexandrov, T;Timm, M;Tideman van den Berge, B;van den Broek, M;Nlandu, Q;Heijnert, J;Bindels, E;Hoogenboezem, R;Mooren, F;Kuppe, C;Miesen, P;Grünberg, K;Ijzermans, T;Steenbergen, E;Czogalla, J;Schreuder, M;Sommerdijk, N;Akiva, A;Boor, P;Puelles, V;Floege, J;Huber, T;van Rij, R;Costa, I;Schneider, R;Smeets, B;Kramann, R;
| DOI: 10.1016/j.stem.2021.12.010
Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID.
Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19
Li, Z;Wang, Z;Dinh, PC;Zhu, D;Popowski, KD;Lutz, H;Hu, S;Lewis, MG;Cook, A;Andersen, H;Greenhouse, J;Pessaint, L;Lobo, LJ;Cheng, K;
PMID: 34140674 | DOI: 10.1038/s41565-021-00923-2
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.
One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine INO-4800 protects against respiratory tract disease burden in nonhuman primate challenge model
Gooch, K;Smith, T;Salguero, F;Fotheringham, S;Watson, R;Dennis, M;Handley, A;Humphries, H;Longet, S;Tipton, T;Sarfas, C;Sibley, L;Slack, G;Rayner, E;Ryan, K;Schultheis, K;Ramos, S;White, A;Charlton, S;Sharpe, S;Gleeson, F;Humeau, L;Hall, Y;Broderick, K;Carroll, M;
| DOI: 10.1016/j.vaccine.2021.06.057
Safe and effective vaccines will provide essential medical countermeasures to tackle the COVID-19 pandemic. Here, we assessed the safety, immunogenicity and efficacy of the intradermal delivery of INO-4800, a synthetic DNA vaccine candidate encoding the SARS-CoV-2 spike protein in the rhesus macaque model. Single and 2 dose vaccination regimens were evaluated. Vaccination induced both binding and neutralizing antibodies, along with IFN-γ-producing T cells against SARS-CoV-2. Upon administration of a high viral dose (5 x 106 pfu) via the intranasal and intratracheal routes we observed significantly reduced virus load in the lung and throat, in the vaccinated animals compared to controls. 2 doses of INO-4800 was associated with more robust vaccine-induced immune responses and improved viral protection. Importantly, histopathological examination of lung tissue provided no indication of vaccine-enhanced disease following SARS-CoV-2 challenge in INO-4800 immunized animals. This vaccine candidate is currently under clinical evaluation as a 2 dose regimen.
Wendisch, D;Dietrich, O;Mari, T;von Stillfried, S;Ibarra, I;Mittermaier, M;Mache, C;Chua, R;Knoll, R;Timm, S;Brumhard, S;Krammer, T;Zauber, H;Hiller, A;Pascual-Reguant, A;Mothes, R;Bülow, R;Schulze, J;Leipold, A;Djudjaj, S;Erhard, F;Geffers, R;Pott, F;Kazmierski, J;Radke, J;Pergantis, P;Baßler, K;Conrad, C;Aschenbrenner, A;Sawitzki, B;Landthaler, M;Wyler, E;Horst, D;Hippenstiel, S;Hocke, A;Heppner, F;Uhrig, A;Garcia, C;Machleidt, F;Herold, S;Elezkurtaj, S;Thibeault, C;Witzenrath, M;Cochain, C;Suttorp, N;Drosten, C;Goffinet, C;Kurth, F;Schultze, J;Radbruch, H;Ochs, M;Eils, R;Müller-Redetzky, H;Hauser, A;Luecken, M;Theis, F;Conrad, C;Wolff, T;Boor, P;Selbach, M;Saliba, A;Sander, L;
| DOI: 10.1016/j.cell.2021.11.033
COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
Peripheral and lung resident memory T cell responses against SARS-CoV-2
Grau-Expósito, J;Sánchez-Gaona, N;Massana, N;Suppi, M;Astorga-Gamaza, A;Perea, D;Rosado, J;Falcó, A;Kirkegaard, C;Torrella, A;Planas, B;Navarro, J;Suanzes, P;Álvarez-Sierra, D;Ayora, A;Sansano, I;Esperalba, J;Andrés, C;Antón, A;Ramón Y Cajal, S;Almirante, B;Pujol-Borrell, R;Falcó, V;Burgos, J;Buzón, MJ;Genescà, M;
PMID: 34021148 | DOI: 10.1038/s41467-021-23333-3
Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.
Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection
Diao, B;Wang, C;Wang, R;Feng, Z;Zhang, J;Yang, H;Tan, Y;Wang, H;Wang, C;Liu, L;Liu, Y;Liu, Y;Wang, G;Yuan, Z;Hou, X;Ren, L;Wu, Y;Chen, Y;
PMID: 33947851 | DOI: 10.1038/s41467-021-22781-1
It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect human kidney, thus leading to acute kidney injury (AKI). Here, we perform a retrospective analysis of clinical parameters from 85 patients with laboratory-confirmed coronavirus disease 2019 (COVID-19); moreover, kidney histopathology from six additional COVID-19 patients with post-mortem examinations was performed. We find that 27% (23/85) of patients exhibited AKI. The elderly patients and cases with comorbidities (hypertension and heart failure) are more prone to develop AKI. Haematoxylin & eosin staining shows that the kidneys from COVID-19 autopsies have moderate to severe tubular damage. In situ hybridization assays illustrate that viral RNA accumulates in tubules. Immunohistochemistry shows nucleocapsid and spike protein deposits in the tubules, and immunofluorescence double staining shows that both antigens are restricted to the angiotensin converting enzyme-II-positive tubules. SARS-CoV-2 infection triggers the expression of hypoxic damage-associated molecules, including DP2 and prostaglandin D synthase in infected tubules. Moreover, it enhances CD68+ macrophages infiltration into the tubulointerstitium, and complement C5b-9 deposition on tubules is also observed. These results suggest that SARS-CoV-2 directly infects human kidney to mediate tubular pathogenesis and AKI.
Stenton, S;McPartland, J;Shukla, R;Turner, K;Marton, T;Hargitai, B;Bamber, A;Pryce, J;Peres, CL;Burguess, N;Wagner, B;Ciolka, B;Simmons, W;Hurrell, D;Sekar, T;Moldovan, C;Trayers, C;Bryant, V;Palm, L;Cohen, MC;
PMID: 35465646 | DOI: 10.1016/j.eclinm.2022.101389
Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis.The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected.59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described.SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation.There was not funding associated with this study.
Liver histopathology in COVID-19 patients: A mono-Institutional series of liver biopsies and autopsy specimens
Pathology, research and practice
Fassan, M;Mescoli, C;Sbaraglia, M;Guzzardo, V;Russo, FP;Fabris, R;Trevenzoli, M;Pelizzaro, F;Cattelan, AM;Basso, C;Navalesi, P;Farinati, F;Vettor, R;Dei Tos, AP;
PMID: 33932720 | DOI: 10.1016/j.prp.2021.153451
Few studies have focused on COVID-19 patients' hepatic histopathological features. Many of the described morphological landscapes are non-specific and possibly due to other comorbidities or to Sars-CoV-2-related therapies. We describe the hepatic histopathological findings of 3 liver biopsies obtained from living COVID-19 patients in which active SARS-CoV-2 infection was molecularly confirmed and biopsied because of significant alterations of liver function tests and 25 livers analyzed during COVID-19-related autopsies. Main histopathological findings were (i) the absence of significant biliary tree or vascular damages, (ii) mild/absent lymphocytic hepatitis; (iii) activation of (pigmented) Kupffer cells, (iv) hepatocellular regenerative changes, (v) the presence of steatosis, (vi) sinusoidal ectasia, micro-thrombosis and acinar atrophy in autopsy specimens No viral particle actively infecting the hepatic or endothelial cells was detected at in situ hybridization. The morphological features observed within the hepatic parenchyma are not specific and should be considered as the result of an indirect insult resulting from the viral infection or the adopted therapeutic protocols.
