Wenzel J, Lampe J, Müller-Fielitz H, Schuster R, Zille M, Müller K, Krohn M, Körbelin J, Zhang L, Özorhan Ü, Neve V, Wagner JU, Bojkova D, Shumliakivska M, Jiang Y, Fähnrich A, Ott F, Sencio V, Robil C, Pfefferle S, Sauve F, Coêlho CF, Franz J, Spiecker F, Lembrich B, Binder S, Feller N, König P, Busch H, Collin L, Villaseñor R, Jöhren O, Altmeppen HC, Pasparakis M, Dimmeler S, Cinatl J, Püschel K, Zelic M, Ofengeim D, Stadelmann C, Trottein F, Nogueiras R, Hilgenfeld R, Glatzel M, Prevot V, Schwaninger M. The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat Neurosci. 2021 Oct 21; PubMed.

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  1. CNS complications are common in acute severe COVID-19, and as SARS-CoV-2 infection also is linked to a substantial increased risk of thrombotic events, microvascular thromboembolic and hypoxic causes have been suggested as pathogenic mechanisms behind neurological complications in COVID-19.

    Whether SARS-CoV-2 is neurotropic and directly infects cells in the brain is controversial and still not proven. During COVID-19 infection, SARS-CoV-2 is normally not detected in the cerebrospinal fluid, and pleocytosis (increased cell count) is normally absent, contrary to many other viral CNS infections.

    In this impressive study, Markus Schwaninger and colleagues found indications of SARS-CoV-2 infection of endothelial cells in the brain and a possible link between infection and microvascular pathology by protease-mediated cleavage of NEMO, a major modulator of nuclear factor-κB. If these interesting findings hold, it may guide future research toward possible therapeutic interventions to treat neuropathology of COVID-19.

    View all comments by Magnus Gisslen

  2. This elegant work illustrates a possible mechanism of neurological damage. However, the data reported does not document persistence of the virus within the central nervous system, but only a possible tropism for the cerebral endothelium documented in few cases. Indeed, as previously illustrated (Iadecola et al., 2020), the expression of ACE-2 in the brain appears quite low.

    In my opinion, the "brain fog" phenomenon is not the result of a simple mechanism, such as direct SARS-CoV-2 invasion of the brain. Instead, it derives from a complex interaction between several biological (i.e., brain inflammation and hypoxia) and psychosocial factors (i.e., isolation and lockdown), which may accelerate neurodegeneration.

    From a clinical point of view, a proper long-COVID definition, especially regarding the neuropsychiatric symptoms of what is commonly called brain fog, will be clarified through longitudinal studies that follow patients' courses. It should be considered that the recovery from COVID-19 requires termination of both viral infection and its associated inflammatory processes, which in severe cases takes much longer than four weeks.

    Notwithstanding, some of the biological and psychosocial detrimental effects are at least partially reversible and "brain fog" can resolve.

    References:

    Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the Nervous System. Cell. 2020 Oct 1;183(1):16-27.e1. Epub 2020 Aug 19 PubMed.

    View all comments by Tino Emanuele Poloni

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  1. Losing NEMO: Could This Protein Explain COVID Brain Fog?