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.
We present a comprehensive vaccine strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by combining antigen optimization and nanoparticle display. We first developed a receptor binding domain (RBD)-specific antibody column for purification and displayed the RBD on self-assembling protein nanoparticles (SApNPs) using the SpyTag/SpyCatcher system. We then identified the heptad repeat 2 (HR2) stalk as a major cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on three SApNPs with high yield, purity, and antigenicity. Compared to the RBD, the RBD-ferritin SApNP elicited a more potent murine neutralizing antibody (NAb) response on par with the spike. S2GΔHR2 elicited two-fold-higher NAb titers than the proline-capped spike (S2P), while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T-cell immunity, thereby providing a next-generation vaccine candidate to battle the COVID-19 pandemic.
ore than 100 million people have been infected with SARS-CoV-2, including nearly 2 million children in the US. 1 Although respiratory disease in pediatric COVID-19 is generally mild, parainfectious and postinfectious neurologic sequelae are increasingly recognized. 2,3 These include encephalitis, seizures, aseptic meningitis, and confusion-found in about 20% of cases of multisystem inflammatory syndrome in children. 4 Notably, rates of new and recurrent psychiatric illness are significantly increased in adults after SARS-CoV-2 infection compared with influenza and other respiratory infections. 5 SARS-CoV-2 RNA is rarely detected in the cerebrospinal fluid (CSF) of patients with COVID-19, but intrathecal anti-SARS-CoV-2 antibodies have been reported, 6,7 suggesting possible neuroinvasion. Although some neurologically impaired adults with COVID-19 have intrathecal antineural autoantibodies, 8 to our knowledge, neither intrathecal anti-SARS-CoV-2 nor antineural antibodies have been reported in pediatric patients with COVID-19 and neuropsychiatric presentations. Methods Case IdentificationPatients younger than 21 years who presented over 5 months in 2020 to the University of California, San Francisco (UCSF) Benioff Children's Hospital with neuropsychiatric symptoms prompting a neurology consultation who also had evidence of a recent SARS-CoV-2 infection (positive findings on reverse transcriptase-polymerase chain reaction [RT-PCR] or serology with clinical history consistent with recent exposure) were IMPORTANCE Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population.OBJECTIVE To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. DESIGN, SETTING, AND PARTICIPANTSThis case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptasepolymerase chain reaction or rapid antigen test.MAIN OUTCOMES AND MEASURES Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies. RESULTSOf 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. CONCLUSIONS AND RELEVANCEPediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their C...
A subset of patients with COVID-19 display neurologic symptoms but it remains unknown whether SARS-CoV-2 damages the central nervous system (CNS) directly through neuroinvasion, or if neurological symptoms are due to secondary mechanisms, including immune-mediated effects. Here, we examined the immune milieu in the CNS through the analysis of cerebrospinal fluid (CSF) and in circulation through analysis of peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with neurological symptoms. Single cell sequencing with paired repertoire sequencing of PBMCs and CSF cells show evidence for unique immune response to SARS-CoV-2 in the CNS. Strikingly, anti-SARS-CoV-2 antibodies are present in the CSF of all patients studied, but the antibody epitope specificity in the CSF and relative prevalence of B cell receptor sequences markedly differed when compared to those found in paired serum. Finally, using a mouse model of SARS-CoV-2 infection, we demonstrate that localized CNS immune responses occur following viral neuroinvasion, and that the CSF is a faithful surrogate for responses occurring uniquely in the CNS. These results illuminate CNS compartment-specific immune responses to SARS-CoV-2, forming the basis for informed treatment of neurological symptoms associated with COVID-19.
Neuronal progenitors in the developing forebrain undergo dynamic competence states. This process ensures timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the dorsal forebrain. At early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent intracellular inhibitor of SHH signaling, can alter the transcriptomic landscape of neocortical progenitors. Ectopic activation of SHH signaling in neocortical progenitors increase expression of Fibroblast Growth Factor 15 (FGF15), consequently activating FGF and MAPK signaling and inducing expression of genes characteristic of ventral forebrain progenitors. Ultimately, neocortical progenitors differentiate into misspecified excitatory neurons or surprisingly, inhibitory neurons. Thus, our studies underscore the importance of modulating extrinsic niche signals in early corticogenesis to maintain the competency and specification program of neocortical progenitors.
Background: Many researchers have studied differences in conditions of ethnic skin using biophysical measurements. However, few studies to date have focused on the antioxidative capacity of the skin. Methods: We measured two parameters of oxidative stress in the stratum corneum, catalase activity and protein carbonylation of the stratum corneum (SCCP), in two ethnic groups, Japanese and French subjects, to characterize the susceptibility to oxidative stress. We also measured several physiological parameters at three different skin sites, two sun-exposed sites (cheek and dorsal aspect of the hand) and a sun-protected site (inner upper arm), in both ethnic groups. Results: Transepidermal water loss (TEWL), the size of corneocytes and skin color showed differences between sun-exposed and sun-protected sites regardless of ethnicity. Regarding ethnic differences, catalase activities and parameters of skin hydration and barrier function of Japanese subjects were higher than those of French subjects. However, SCCP values showed a trend contrary to catalase activity. The difference in the b* value indicated that the melanin content of Japanese skin was higher than that of French skin. Pearson’s correlation analyses showed that catalase activity and SCCP values had weak relationships with water content, TEWL and skin color in both ethnic groups. Conclusion: Differences in susceptibility to oxidative stress, namely melanin content and catalase activity in the skin, induce the better skin condition of Japanese compared with French subjects.
Neuronal progenitors in the developing forebrain undergo dynamic competence states. This process ensures timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the dorsal forebrain. At early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent intracellular inhibitor of SHH signaling, can alter the transcriptomic landscape of neocortical progenitors. Ectopic activation of SHH signaling in neocortical progenitors increase expression of Fibroblast Growth Factor 15 (FGF15), consequently activating FGF and MAPK signaling and inducing expression of genes characteristic of ventral forebrain progenitors. Ultimately, neocortical progenitors differentiate into misspecified excitatory neurons or surprisingly, inhibitory neurons. Thus, our studies underscore the importance of modulating extrinsic niche signals in early corticogenesis to maintain the competency and specification program of neocortical progenitors.Figure 1. Specification defects are evident in discrete regions of the neocortex of the E12.5 mice lacking Sufu. A-B, Immunostaining using dorsal forebrain progenitor marker, Pax6, and DAPI counterstain, show high Pax6 expression in the dorsal forebrain (cx) compared to the lateral (LGE) or medial (MGE) ganglionic eminence in both the E12.5 control and Sufu-cKO embryonic forebrains. Scale bar = 500 mm. C-D, Higher magnification of boxed regions in A and B show low or absent Pax6 expression in specific areas of the rostral neocortex of Sufu-cKO forebrains (D, arrows) but not in controls (C). Sections are counterstained with DAPI. Scale bar = 250 mm.
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