SARS-CoV-2 infection and persistence in the human body and brain at autopsy
Sydney R Stein, Sabrina C Ramelli, Alison Grazioli, Joon-Yong Chung, Manmeet Singh, Claude Kwe Yinda, Clayton W Winkler, Junfeng Sun, James M Dickey, Kris Ylaya, Sung Hee Ko, Andrew P Platt, Peter D Burbelo, Martha Quezado, Stefania Pittaluga, Madeleine Purcell, Vincent J Munster, Frida Belinky, Marcos J Ramos-Benitez, Eli A Boritz, Izabella A Lach, Daniel L Herr, Joseph Rabin, Kapil K Saharia, Ronson J Madathil, Ali Tabatabai, Shahabuddin Soherwardi, Michael T Mccurdy, Ashley L Babyak, Luis J Perez Valencia, Shelly J Curran, Mary E Richert, Willie J Young, Sarah P Young, Billel Gasmi, Michelly Sampaio De Melo, Sabina Desar, Saber Tadros, Nadia Nasir, Xueting Jin, Sharika Rajan, Esra Dikoglu, Neval Ozkaya, Grace Smith, Elizabeth R Emanuel, Brian L Kelsall, Justin A Olivera, Megan Blawas, Robert A Star, Nicole Hays, Shreya Singireddy, Jocelyn Wu, Katherine Raja, Ryan Curto, Jean E Chung, Amy J Borth, Kimberly A Bowers, Anne M Weichold, Paula A Minor, Mir Ahmad N Moshref, Emily E Kelly, Mohammad M Sajadi, Thomas M Scalea, Douglas Tran, Siamak Dahi, Kristopher B Deatrick, Eric M Krause, Joseph A Herrold, Eric S Hochberg, Christopher R Cornachione, Andrea R Levine, Justin E Richards, John Elder, Allen P Burke, Michael A Mazzeffi, Robert H Christenson, Zackary A Chancer, Mustafa Abdulmahdi, Sabrina Sopha, Tyler Goldberg, Yashvir Sangwan, Kristen Sudano, Diane Blume, Bethany Radin, Madhat Arnouk, James W Eagan, Robert Palermo, Anthony D Harris, Thomas Pohida, Marcial Garmendia-Cedillos, George Dold, Eric Saglio, Phuoc Pham, Karin E Peterson, Jeffrey I Cohen, Emmie De Wit, Kevin M Vannella, Stephen M Hewitt, David E Kleiner, Daniel S Chertow
Nature, doi:10.1038/s41586-022-05542-y
Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction 1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of 5 ). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain 3,6-14 . Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months. COVID-19 has respiratory and non-respiratory manifestations 1-3 , including multi-organ failure and shock among patients with severe and fatal disease. Some individuals who survive experience post-acute sequelae of SARS-CoV-2, also known as long COVID 4, 5 . Although autopsy studies of fatal COVID-19 cases support the ability of SARS-CoV-2 to infect multiple organs 3, [7] [8] [9] [10] [11] [12] , extrapulmonary organs often lack histopathological evidence of virally mediated injury or inflammation [10] [11] [12] [13] [14] . The paradox of infection outside the respiratory tract without injury or inflammation raises many pathogen-and host-related questions. To investigate the cellular tropism, replication competence, persistence and evolution of SARS-CoV-2 in humans, and to look for associated histopathology in infected tissues, we carried out autopsies on 44 COVID-19 cases. Our approach focused on timely, systematic and comprehensive tissue sampling and preservation for complementary
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Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Data availability The datasets that support the findings of this study are available in Supplementary Data 1, 2 and 3. Positive and negative controls for ISH, IF and IHC are available in Supplementary Data 3. The sequencing data of SARS-CoV-2 isolated from Vero E6-TMPRSS2-T2A-ACE2 cell culture of thalamus of P38 have been deposited to GenBank (OP125352).
Article Extended Data Table 1 | Autopsy cohort demographics, comorbidities, and clinical intervention summary
Article
Extended Data Table 3 | SARS-CoV-2 cellular tropism Summary of tissues with cell types that were identified as SARS-CoV-2 positive by in situ hybridization (ISH) with the associated panels demonstrating the cellular tropism within Fig. 2 , Fig. 3 , and Supplementary Data 3. NOS/not otherwise specified.
Extended Data Table 4 | Histopathologic findings of COVID-19 autopsy cases Summary of histopathologic findings across organ system across 44 autopsy cases. Central nervous system findings are reported for the 11 cases in which consent for sampling was obtained. Includes one case in which the COVID lungs were transplanted and data from explanted lungs used in table. 2 Individual lung weights were missing in 4 cases. 3 Findings..
References
Al-Aly, Xie, Bowe, High-dimensional characterization of post-acute sequelae of COVID-19, Nature
Alexandersen, Chamings, Bhatta, SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication, Nat. Commun
Beyer, Forero, Mechanisms of antiviral immune evasion of SARS-CoV-2, J. Mol. Biol
Bhatnagar, Evidence of severe acute respiratory syndrome coronavirus 2 replication and tropism in the lungs, airways, and vascular endothelium of patients with fatal coronavirus disease 2019: an autopsy case series, J. Infect. Dis
Binnicker, Can testing predict SARS-CoV-2 infectivity? The potential for certain methods to be surrogates for replication-competent virus, J. Clin. Microbiol
Bourgonje, Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19), J. Pathol
Brioschi, Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS border, Science
Burbelo, Goldman, Mattson, A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins, BMC Biotechnol
Burbelo, Sensitivity in detection of antibodies to nucleocapsid and spike proteins of severe acute respiratory syndrome coronavirus 2 in patients with coronavirus disease 2019, J. Infect. Dis
Carossino, Detection of SARS-CoV-2 by RNAscope® in situ hybridization and immunohistochemistry techniques, Arch. Virol
Corman, Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR, Euro Surveill
Crook, Raza, Nowell, Young, Edison, Long covid-mechanisms, risk factors, and management, Brit. Med. J
Desai, Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection, Nat. Commun
Diamond, Kanneganti, Innate immunity: the first line of defense against SARS-CoV-2, Nat. Immunol
Dimcheff, Severe acute respiratory syndrome coronavirus 2 total and subgenomic RNA viral load in hospitalized patients, J. Infect. Dis
Dorward, Tissue-specific immunopathology in fatal COVID-19, Am. J. Respir. Crit. Care Med
Huang, SARS-CoV-2 infection of the oral cavity and saliva, Nat. Med
Jacobs, SARS-CoV-2 viremia is associated with COVID-19 severity and predicts clinical outcomes, Clin. Infect. Dis
Ko, High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19, PLoS Pathog
Langmead, Salzberg, Fast gapped-read alignment with Bowtie 2, Nat. Methods
Lythgoe, SARS-CoV-2 within-host diversity and transmission, Science
Martin, Cutadapt removes adapter sequences from high-throughput sequence reads, EMBnet J
Martines, Pathology and pathogenesis of SARS-CoV-2 associated with fatal coronavirus disease, United States, Emerg. Infect. Dis
Matschke, Neuropathology of patients with COVID-19 in Germany: a post-mortem case series, Lancet Neurol
Matsuyama, Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells, Proc. Natl Acad. Sci. USA
Mukerji, Solomon, What can we learn from brain autopsies in COVID-19, Neurosci. Lett
Munster, Respiratory disease in rhesus macaques inoculated with SARS-CoV-2, Nature
Puelles, Multiorgan and renal tropism of SARS-CoV-2, N. Engl. J. Med
Remmelink, Unspecific post-mortem findings despite multiorgan viral spread in COVID-19 patients, Crit. Care
Rosenke, Hydroxychloroquine prophylaxis and treatment is ineffective in macaque and hamster SARS-CoV-2 disease models, JCI Insight
Salamanna, Maglio, Landini, Fini, Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2, Front. Med
Schurink, Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study, Lancet Microbe
Sidhu, Defective measles virus in human subacute sclerosing panencephalitis brain, Virology
Song, Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms, Cell Rep. Med
Speranza, Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys, Sci. Transl. Med
Sridhar, Nicholls, Pathophysiology of infection with SARS-CoV-2-what is known and what remains a mystery, Respirology
Tonkin-Hill, Patterns of within-host genetic diversity in SARS-CoV-2, Elife
Valesano, Temporal dynamics of SARS-CoV-2 mutation accumulation within and across infected hosts, PLoS Pathog
Van Kampen, Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019, Nat. Commun
Vannella, Evidence of SARS-CoV-2-specific T-cell-mediated myocarditis in a MIS-A case, Front. Imunol
Wang, Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges, Immunity
Williamson, Clinical benefit of Remdesivir in rhesus macaques infected with SARS-CoV-2, Nature
Wong, Perlman, Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses -are we our own worst enemy?, Nat. Rev. Immunol
Wölfel, Virological assessment of hospitalized patients with COVID-19, Nature
Yao, A cohort autopsy study defines COVID-19 systemic pathogenesis, Cell Res
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