Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses, 2023, Spatola et al

[SNT Gatchaman]

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses
Spatola, Marianna; Nziza, Nadège; Jung, Wonyeong; Deng, Yixiang; Yuan, Dansu; Dinoto, Alessandro; Bozzetti, Silvia; Chiodega, Vanessa; Ferrari, Sergio; Lauffenburger, Douglas A; Mariotto, Sara; Alter, Galit

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the central nervous system (CNS), can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations, and persistence of SARS-CoV-2 reservoirs.

In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common Coronaviruses - 229E, HKU1, NL63, OC43) in the serum and cerebrospinal fluid (CSF) from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC, compared to serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2; IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).

These data argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 vs 66.5 years, respectively, p = 0.55; females 33% vs 44%, p = 0.52), but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors.

However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common Coronaviruses, including 229E, HKU1, NL63, and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an original antigenic sin (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to current infection, as a key prognostic marker of neuroPASC disease.

Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

PubMed | Link | PDF (Brain)

 

[SNT Gatchaman]

Selected quotes —

Using a high throughput systems serology approach, we identified distinctive humoral signatures across individuals with and without neuroPASC. Individuals with neuroPASC were characterized by a diminished systemic response to SARS-CoV-2, in contrast with an expanded systemic response to common Coronaviruses. These features were also observed in CSF and were particularly enriched in individuals with poor outcome.

Moreover, neuroPASC was marked by a distinct CSF and systemic humoral response, characterized by a highly compartmentalized brain-specific antibody signature, pointing to limited evidence of intrathecal SARS-CoV-2 antibody production.

Next, we aimed to understand whether lower SARS-CoV-2 specific antibody responses in neuroPASC were uniquely diminished to SARS-CoV-2, or whether individuals with neuroPASC might have deficient humoral responses to other viruses as well. Thus, we profiled responses to Epstein Barr virus (EBV), Influenza virus (Flu), herpes simplex virus (HSV1) and additional common Coronaviruses. No difference in the antibody responses to EBV, Flu or HSV1 were observed between no PASC and neuroPASC

However, surprisingly, antibody responses to other related common Coronaviruses (in particular 229E), including IgG1 titers and FcɣR binding levels, were enriched in individuals with NeuroPASC. These data argue that individuals with neuroPASC generate equivalent responses to common viruses, but exhibit a significant bias towards elevated responses to other non-SARS-CoV-2 Coronaviruses, potentially a marker of imprinting or original antigenic sin.

 

[SNT Gatchaman]

Emerging studies in individuals with PASC have begun to collectively point to anomalous immune mechanisms, marked by perturbated inflammatory cytokine profiles, altered cellular transcriptional signatures, and auto-antibodies production. However, given the heterogeneity of PASC clinical manifestations, including individuals with neurologic, respiratory, vascular, or rheumatologic complications, it is possible that unique pathways may be triggered during SARS-CoV-2 infection that may lead to distinct PASC phenotypes.

Moreover, these common Coronaviruses immune responses were likely transferred from the circulation into the CSF, rather than generated within the CNS, and were directly associated with neuroPASC outcome. Taken together, these data point to a potentially incomplete maturation of the SARSCoV-2 response, biased by a pre-existing humoral immunity to common Coronaviruses, that may lead to development of neuroPASC due to partial or delayed viral clearance and persistent neuroinflammation.

While it has been speculated that a persistent reservoir of SARS-CoV-2 in the CNS could contribute to neuronal damage in neuroPASC, analyses of CSF from living individuals as well as autopsy studies, have rarely detected active viral replication in the brain. Moreover, viral replication in the CNS would likely be accompanied by recruitment of B cells in the brain, that would convert to antibody-secreting plasma cells capable to switch and locally generate large numbers of polyclonal antibodies of various Ig subclasses, in response to the local presence of antigen. Instead, individuals with neuroPASC had highly compartmentalized CSF-antibody profiles, characterized by lower levels, but highly focused IgG1 phagocytic profiles.

 

[SNT Gatchaman]

The role of dysregulated immune mechanisms in the development of neurological complications of SARS-CoV-2 infection has become increasingly accepted.

Our data show that individuals with neuroPASC exhibited a biased immune response across coronaviruses, with an expanded common Coronaviruses response (in particular 229E, NL63 and OC43) at the expense of an attenuated SARS-CoV-2 response in the serum and CSF. This suggests a mechanism of original antigenic sin, in which previous immune responses to common Coronaviruses might shape subsequent responses to other related viruses, such as SARS-CoV-2, which share high epitope homology. This mechanism, also known as immunologic imprinting [...]

The lack of CSF antibody profiles from PASC individuals without neurological manifestations is a limitation of our study, as it does not allow direct comparison of antibody profiles in the CSF of individuals with neuroPASC and PASC to confirm whether these antibody responses are unique to neuroPASC or are common also to PASC individuals without neurological complications. However, given our observation that CSF-profiles highly correlated with disease severity/outcome in neuroPASC, it seems unlikely that PASC individuals might present similar responses in the CSF and be neurologically asymptomatic.

Overall, our data suggest a previously unappreciated role for immunologic imprinting from other Coronaviruses that may induce a defective antibody-mediated control of SARS-CoV-2 infection, resulting in incomplete or delayed virus clearance, and persistence of systemic immune activation and neuroinflammation involved in the pathogenesis of neuroPASC. Whether the markers identified here are simply biomarkers or mechanistic players in neuroPASC remains unknown

 

[Hutan]

Original antigenic sin, also known as antigenic imprinting, the Hoskins effect,[1]or immunological imprinting,[2] is the propensity of the immune system to preferentially use immunological memory based on a previous infection when a second slightly different version of that foreign pathogen (e.g. a virus or bacterium) is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to repertoire freeze, a form of original antigenic sin.

The phenomenon has been described in relation to influenza virus, SARS-CoV-2,[2]dengue fever, human immunodeficiency virus (HIV) [3] and to several other viruses.[4]

So, if I'm understanding correctly, a previous infection resulted in the body's recipe for fighting that infection (would that be in the long lived plasma cells in the bone marrow?) Then, when another infection comes along that is similar but different, the body is stuck on the old response and doesn't effectively deal with the infection. The result is ineffective clearance - so it's basically the 'viral persistence' hypothesis, with a bit of upstream elaboration.

So, it leaves the question 'why are the infections that result in Long Covid so often mild, rather than more severe, if the viral response is inadequate?'.

I can't read the paper right now.

 

[Hutan]

I still haven't read this paper and probably won't get to it today, but I think it could be interesting to read in the light of the MS B cells in the brain idea.

These data argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.

 

[SNT Gatchaman]

There's also a commentary on this paper in Can immunological imprinting drive neurological dysfunction in long COVID? (2023, Brain)