Background: The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features.

Globally 118 319 confirmed (4620 new) 4292 deaths (280 new) China 80 955 confirmed (31 new) 3162 deaths (22 new) Outside of China 37 364 confirmed (4589 new) 1130 deaths (258 new) 113 countries/territories/ areas (4 new)

Background Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS. MethodsIn this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions. Findings 43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70-86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltra tion by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes.Interpretation In 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.

The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targetstreated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARSCoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion.

The human coronaviruses (CoVs) severe acute respiratory syndrome (SARS)-CoV and NL63 employ angiotensin-converting enzyme 2 (ACE2) for cell entry. It was shown that recombinant SARS-CoV spike protein (SARS-S) downregulates ACE2 expression and thereby promotes lung injury. Whether NL63-S exerts a similar activity is yet unknown. We found that recombinant SARS-S bound to ACE2 and induced ACE2 shedding with higher efficiency than NL63-S. Shedding most likely accounted for the previously observed ACE2 downregulation but was dispensable for viral replication. Finally, SARS-CoV but not NL63 replicated efficiently in ACE2-positive Vero cells and reduced ACE2 expression, indicating robust receptor interference in the context of SARS-CoV but not NL63 infection.

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock.

Bats may host emerging viruses, including coronaviruses (CoV). We conducted an evaluation of CoV in

Hipposideros spp. bats harbor a coronavirus that shares common ancestry with human viruses.