Catch me if you can: SARS-CoV-2 detection in brains of deceased patients with COVID-19
Authors: Stephan Frank
Journal: The Lancet Neurology (2020)

In the American biographical crime film Catch Me If You Can, FBI agent Carl Hanratty goes all out to catch the notorious impostor and cheque counterfeiter Frank Abagnale Jr. Hanratty's dogged pursuit of the culprit bears striking resemblance to current COVID-19 research efforts to find evidence of changes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might leave in the brain. In The Lancet Neurology, Jakob Matschke and colleagues1Matschke J Lütgehetmann M Hagel C et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; (published online Oct 5.)https://doi.org/10.1016/S1474-4422(20)30308-2Summary Full Text Full Text PDF PubMed Scopus (849) Google Scholar give a detailed account of the histological alterations related to COVID-19 in the CNS. Through meticulous detective work, they mapped the brain's immunoinflammatory response to viral infection and detected SARS-CoV-2 protein expression in a substantial percentage of autoptic brains of patients with COVID-19. Matschke and colleagues analysed 43 brains from a large cohort of patients who died with COVID-19,2Edler C Schröder AS Aepfelbacher M et al.Dying with SARS-CoV-2 infection—an autopsy study of the first consecutive 80 cases in Hamburg, Germany.Int J Legal Med. 2020; 134: 1275-1284Crossref PubMed Scopus (329) Google Scholar focusing on inflammatory changes and detection of SARS-CoV-2. To find out which CNS cell types are prone to SARS-CoV-2 infection, the authors screened gene expression datasets for signatures related to viral entry and persistence. Their in-silico analysis showed high expression of angiotensin-converting enzyme 2 (ACE2) in oligodendrocytes and of transmembrane serine proteases 2 and 4 (TMPRSS2 and TMPRSS4) in neurons—genes that code for proteins crucially implicated in SARS-CoV-2 host-cell entry (ACE2) and proteolytic priming of the virus-decorating spikes (TMPRSS2).3Hoffmann M Kleine-Weber H Schroeder S et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Summary Full Text Full Text PDF PubMed Scopus (13431) Google Scholar Interestingly, a study using human brain organoids, published in September, 2020,4Ramani A Müller L Ostermann PN et al.SARS-CoV-2 targets neurons of 3D human brain organoids.EMBO J. 2020; (published online Sept 2.)DOI: 10.15252/embj.2020106230Crossref PubMed Scopus (330) Google Scholar showed that SARS-CoV-2 can readily infect and kill neurons. The neuronal cell death upon viral infection was preceded by aberrant intraneuronal localisation and hyperphosphorylation of Tau protein,4Ramani A Müller L Ostermann PN et al.SARS-CoV-2 targets neurons of 3D human brain organoids.EMBO J. 2020; (published online Sept 2.)DOI: 10.15252/embj.2020106230Crossref PubMed Scopus (330) Google Scholar similar to the pathogenesis of Alzheimer's disease and other neurodegenerative diseases. Matschke and colleagues used quantitative RT-PCR (qRT-PCR) and immunohistochemistry with antibodies against nucleocapsid and spike proteins to detect SARS-CoV-2. Whereas viral RNA was detected in 48% of cases, viral protein detection was positive in 40%. Overall, the authors found SARS-CoV-2, either viral RNA or viral protein (or both), in 51% of the brains investigated. Remarkably, SARS-CoV-2 presence did not correlate with the severity of neuropathological alterations. While the replicative and infective potential of the viral RNA remains unclear, the in-situ detection of SARS-CoV-2 proteins is an important finding, as it confirms the presence of the virus in the brain. In this context, concerns5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar, 6Solomon IH Normandin E Bhattacharyya S et al.Neuropathological features of COVID-19.N Engl J Med. 2020; 383: 989-992Crossref PubMed Scopus (595) Google Scholar that the comparably low viral genome levels detectable by qRT-PCR in brain tissue might be blood-derived deserve mention. Of note, the authors found virus protein expression to be confined to the medulla oblongata and to cranial nerves originating from the lower brainstem (most likely glossopharyngeal or vagal nerve). Considering the capability of SARS-CoV-2 to infect human gut enterocytes as well as pneumocytes,7Lamers MM Beumer J van der Vaart J et al.SARS-CoV-2 productively infects human gut enterocytes.Science. 2020; 369: 50-54Crossref PubMed Scopus (1159) Google Scholar, 8Schaefer IM Padera RF Solomon IH et al.In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19.Mod Pathol. 2020; (published online June 19.)https://doi.org/10.1038/s41379-020-0595-zCrossref Scopus (218) Google Scholar this finding is of particular interest, warranting future investigations of vagal nerve tissue as a potential viral CNS access route in COVID-19. The study also identified pronounced, brainstem-accentuated microglia activation, confirming previous work.5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar As these brain-resident macrophage-like innate immune cells are highly heterogeneous with regard to gene expression, regional abundance, and perhaps functions,9Masuda T Sankowski R Staszewski O Prinz M Microglia Heterogeneity in the Single-Cell Era.Cell Rep. 2020; 30: 1271-1281Summary Full Text Full Text PDF PubMed Scopus (365) Google Scholar it seems worth testing whether microglia activated in a COVID-19 context correspond to a specific subtype,10Böttcher C Schlickeiser S Sneeboer MAM et al.Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry.Nat Neurosci. 2019; 22: 78-90Crossref PubMed Scopus (258) Google Scholar expressing sets of genes reflective of particular functional states. Given the complex pathophysiology of COVID-19, any autopsy study is bound to have limitations (varying post-mortem intervals, incomplete or lacking clinical data, etc) and the present study is no exception in that regard. Confounding factors, such as the multiple comorbidities present among older patients with COVID-19 and, equally important, common COVID-19 treatment modalities, such as invasive ventilation (which might promote cerebral microbleeds) or dexamethasone medication (known to modulate immune responses), have to be considered when interpreting neuropathological findings. In the context of dexamethasone, it is unfortunate that no data on steroid medication were used to investigate correlations between some of the findings. Likewise, in the absence of appropriate control cohorts, it remains unclear to what extent microglia activation and brain infiltration by cytotoxic T-lymphocytes represent COVID-19-specific findings. Both sparse lymphocytic infiltrates and microglia activation were recently documented in the brains of individuals without COVID-19, and they appeared to be particularly pronounced in septic cases.5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar At a time when a potential second wave of infections is increasingly becoming of global concern, the question of whether the neuropathological alterations in COVID-19 directly result from SARS-CoV-2 brain infection as opposed to reflecting sequelae of an overstimulated systemic immune response is of high clinical importance. Whereas the first scenario would support the use of remdesevir or other antivirals, anti-inflammatory modalities appear to be the treatment of choice once damaging immunoinflammatory mechanisms take over. Teasing apart these fundamentally different scenarios is an ongoing task for neuropathology experts. The work by Matschke and colleagues1Matschke J Lütgehetmann M Hagel C et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; (published online Oct 5.)https://doi.org/10.1016/S1474-4422(20)30308-2Summary Full Text Full Text PDF PubMed Scopus (849) Google Scholar represents an important step towards navigating the complex pathophysiology of COVID-19 in the brain. Just like agent Hanratty, the authors have done a superb job closing in on the culprit. SF reports grants from the Botnar Research Centre for Child Health. Neuropathology of patients with COVID-19 in Germany: a post-mortem case seriesIn general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included. Full-Text PDF