The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

Abstract

In COVID-19 neurological alterations are noticed during the systemic viral infection. Various pathophysiological mechanisms on the central nervous system (CNS) have been suggested in the past two years, including the viral neurotropism hypothesis. Nevertheless, neurological complications can also occur independent of neurotropism and at different stages of the disease and may be persistent. Previous autopsy studies of the CNS from patients with severe COVID-19 show infiltration of macrophages and T lymphocytes, especially in the perivascular regions as well as pronounced microglial activation, but without signs of viral encephalitis. However, there is an ongoing debate about long-term changes and cytotoxic effects in the CNS due to the systemic inflammation. Here, we show the brain-specific host response during and after COVID-19. We profile single-nucleus transcriptomes and proteomes of brainstem tissue from deceased COVID-19 patients who underwent rapid autopsy. We detect a disease phase-dependent inflammatory type-I interferon response in acute COVID-19 cases. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation. One neuronal with direct focus on cranial nerve nuclei and one diffusely affecting the whole brainstem, the latter reflecting a bystander effect that spreads throughout the vascular unit and alters the transcriptional state of oligodendrocytes, microglia and astrocytes. Our results indicate that even without persistence of SARS-CoV-2 in the CNS, the tissue activates highly protective mechanisms, which also cause functional disturbances that may explain the neurological symptoms of COVID-19, triggered by strong systemic type-I IFN signatures in the periphery.

Vagus nerve inflammation contributes to dysautonomia in COVID-19

“…1 a). Notably, this is in line with a recent study that demonstrated a strong inflammatory response in brain stems of deceased COVID-19 patients [ 24 ]. Next, we investigated whether the vagus nerve is directly affected by COVID-19.…”

“…This is supported by our findings of strong endothelial inflammatory responses in vagus nerves of COVID-19 patients similar to the transcriptional profiles of the neurovascular units in the CNS [ 15 , 29 ]. Thereby, the vagus nerve might serve as additional gateway for SARS-CoV-2 infiltration of the brain stem and CNS [ 24 ]. Across different cell types, SARS-CoV-2 induced a strong interferon response independent of the viral load.…”

“…Thus, we cannot exclude spatial differences of the transcriptional response to SARS-CoV-2 and whether the SARS-CoV-2 viral load is different along the vagus nerve. SARS-CoV-2 RNA has been identified at the entry site of the vagus nerve into the brainstem of COVID-19 patients [ 24 ] which implies that SARS-CoV-RNA is detectable along the entire route of the vagus nerve. Additionally, the axonal transcriptomes strongly correlate with the somatic transcriptomes in neurons and even stronger reflect protein synthesis since these mRNAs are transported to axons to be locally translated [ 23 ].…”

Targeting MCAM for next-generation modulation of leucocyte trafficking

“… 3 Interestingly, focal upregulation of EC MCAM was recently observed in the context of neuroCOVID. 10 …”