Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients

Remšík, Ján; Wilcox, Jessica; Babady, N. Esther; McMillen, Tracy; Vachha, Behroze; Halpern, Neil A.; Dhawan, Vikram; Rosenblum, Marc K.; Iacobuzio‐Donahue, Christine A.; Avila, Edward K.; Santomasso, Bianca; Boire, Adrienne

doi:10.1016/j.ccell.2021.01.007

Cited by 63 publications

(73 citation statements)

References 45 publications

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“…TNFRSF1B showed consistent expression changes in AD or AD-related pathologies, as well as in COVID-19 patient CSF samples. We also found that CXCL10 protein level was increased in CSF of COVID-19 patients [ 93 ] (Fig. 3 b).…”

Section: Resultsmentioning

confidence: 73%

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

et al. 2021

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Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. Methods In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

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Section: Resultsmentioning

confidence: 73%

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

et al. 2021

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Section: Resultsmentioning

confidence: 74%

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Zhou

Hou

et al. 2021

Preprint

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Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. Methods: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.

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“…Similarly, a study of 13 “COVID-19 encephalitis” cases found increases in CXCL8 as well as markers of glial activation such as GFAP [ 58 ]. Another study of CSF in 18 subjects with cancer who exhibited a variety of neurological manifestations after COVID-19 used target proteomic assays to identify relative increases in subsets of chemokines such as CXCL8, CXCL10, as well as IFNγ and MMP-10, a metalloproteinase associated with neuronal dysfunction [ 59 ]. Although suggestive of activation of inflammatory markers, such findings are not necessarily indicative of “cytokine storms” or specific adaptive immune responses within the CNS but rather reflect the pattern of activation and homeostatic neuroglial responses to pathogenic processes such as ischemia, hypoxemia and sepsis [ 56 , [60] , [61] , [62] ].…”

Section: Discussionmentioning

confidence: 99%

“…The paucity of inflammatory changes in COVID-19 CSF undermines the hypothesis that conventional neuroinflammation, encephalitic processes or SARS-CoV2 neurovirulence play major roles in the pathogenesis of the most common neurological complications in COVID-19 that were studied here. The previously identified “neuroinflammatory” processes in the CSF of COVID-19 [ 23 , 24 , 59 , 65 ] or changes described in the so-called “COVID-19 encephalitis” [ 58 ] could be derived from homeostatic neuroglial responses by microglia and astroglia to systemic pathology such as ischemia, hypoxia or systemic critical illnesses [ 56 , [66] , [67] , [68] ] rather than adaptive immune mediated, “cytokine storm” or inflammation driven by neurovirulence. Evidence from our study of increases in NF-L further supports the evidence of injury of neuronal cell populations in severe cases of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm

García

Barreras

Lewis

et al. 2021

Journal of the Neurological Sciences

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Objective To study in cerebrospinal fluid (CSF) of COVID-19 subjects if a “cytokine storm” or neuroinflammation are implicated in pathogenesis of neurological complications. Methods Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity. COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls ( n = 82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. Results CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls. Conclusion The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. The role of CSF SARS-CoV2 IgG antibodies and mechanisms of neuronal damage are still undetermined.

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Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients

Cited by 63 publications

References 45 publications

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm

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