Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

Abstract

COVID-19 patients frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single cell RNA-seq and cytokine analyses of CSF and blood from COVID-19 patients with neurological symptoms, we find compartmentalized, CNS specific T cell activation and B cell responses. All COVID-19 cases had CSF anti-SARS-CoV-2 antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are found only during brain infection, and are not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from a COVID-19 patient, and find that these mAbs target both anti-viral and anti-neural antigens—including one mAb that reacted to both spike protein and neural tissue. Overall, CSF IgG from 5/7 patients contains anti-neural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of COVID-19 patients and suggests a role for autoimmunity in neurologic sequelae of COVID-19.

Intrathecal inflammatory responses in the absence of SARS-CoV-2 nucleic acid in the CSF of COVID-19 hospitalized patients

“…For example, in the case of WNV neuroinvasive disease which is characterized by CSF pleocytosis and elevated total protein in 95% of patients, CSF RT-qPCR is relatively insensitive (57–70%) compared to WNV IgM [ 43 ]. Prior work with animal models expressing humanized ACE2 in brain and lung tissue and infected intranasally with SARS-CoV-2 demonstrated anti-SARS-CoV-2 antibodies in CSF and the brain [ 44 ], and a few reports in humans have shown high-titer anti-SARS-CoV-2 IgG in patients with COVID-19 and neurologic symptoms (reviewed in 9 ). Specifically, an 8-person case series showed high-titers of CSF IgG in a subgroup of hospitalized patients with COVID-19 and encephalopathy despite absence of CSF SARS-CoV-2 RNA or intrathecal pleocytosis [ 31 ].…”

“…We did not quantify CSF anti-SARS-CoV-2 IgG and in the absence of paired serology, this would limit our ability to comment on CNS compartmentalization. Given recent literature also demonstrating that autoantibodies may be present in the CSF of patients with COVID-19 [ [44] , [45] , [46] , [47] , [48] , [49] ], further studies are required to determine whether compartmentalized anti-SARS-CoV-2 antibodies are present and if so, whether the presence of antibodies is associated with intrathecal inflammatory responses or blood brain barrier disruption despite absent pleocytosis or elevated protein.…”

“…Prior case series which examined CSF cytokine changes have shown elevated levels of IL-6, IL-1β, and IL-10 in some but not all patients with COVID-19 [ 11 , 36 , 50 ], though none of these included a control dataset for comparison. Rare studies [ 44 , 51 , 52 ] that included pre-pandemic CSF samples as controls have mixed results on COVID-specific compartmentalized immune responses. In this cohort, a relative increase in CSF cytokines (IL-6, IL-8, IL-15, MIP-1β) was observed in COVID-19 patients compared to controls and HIV suppressed patients, driven by a small subset of individuals.…”

Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions

“…Central and peripheral immunological responses to SARS-CoV-2 infection are distinct. Immune analysis of mononuclear cells from COVID-19 patients with neurological symptoms revealed unique B cell responses that markedly differed between the CSF and peripheral blood [ 162 ]. Furthermore, a mouse model of SARS-CoV-2 infection found that antibody responses can occur separately in the brain without being evident in the systemic circulation.…”

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

“…To decipher the underpinnings of neurological symptoms, Song et al. ( 33 ) performed single-cell transcriptomics on immune cells from the CSF and blood of neuro-COVID-19 patients and healthy donors. They found and increased activation of CSF T cells, that strongly interacted with overactive NK and dendritic cells, displaying upregulation of IL-1 and IL-12 pathways and suggesting a coordinated and compartmentalized T-cell based response to CNS antigens.…”