NeuroCOVID manifestations in post infections are determined by immunologic imprinting from previous Coronaviruses


A new study lead by researchers from Ragon Institute of MGH, MIT and Harvard Medical School, Cambridge – USA has found that NeuroCOVID manifestations in post infections are determined by immunologic imprinting from previous coronaviruses.

The study findings were published on a preprint server and are currently being peer reviewed.

Post-acute neurological complications (neuroPASC) occur in a significant portion of the patients with SARS-CoV-2 infection.

These symptoms often occur in previously healthy individuals, even in the setting of asymptomatic or mild disease, and can persist for several months with significant impact on functional and work capacity.32

However, both biomarkers and mechanisms that explain these debilitating secondary effects of SARS-CoV-2 infection remain ill defined, but could revolutionize patient care and the development of disease-modifying therapies.

Emerging studies in individuals with PASC have begun to collectively point to anomalous immune mechanisms, marked by perturbated inflammatory cytokine profiles,33-35 altered cellular transcriptional signatures,36,37 and auto-antibodies production.36,38,39

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.

In the setting of neuroPASC, new data point towards immune-mediated mechanisms as a driver of disease. Thus, here we applied a systems serology approach and identified distinctive antibody signatures in neuroPASC individuals, characterized by compromised SARS-CoV-2 specific humoral responses in association with enhanced common Coronaviruses immunity.

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. These data, collectively, point to a potentially incomplete maturation of the SARS-CoV-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 individuals7,40 as well as autopsy studies,41 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.

This is in line with previous observations in patients with acute COVID-19 and neurological manifestations, reporting CSF SARS-CoV-2 specific antibodies, whose target epitopes were different from serum antibodies,42 and were associated with compartmentalized cytokine production.43

While CSF-specific antibody profiles that we observed in neuroPASC were also present in the systemic circulation, the systemic response was much more diverse, arguing for the selective transfer of antibodies into the CNS. In homeostatic conditions, antibodies are thought to circulate into the brain through an FcRn-mediated transcytosis mechanism across the blood-brain barrier.44,45 FcRn binds to IgG1 with higher affinity than to other antibody subclasses, but additional selectivity was observed across antigen-specificity and FcγR binding capacities, arguing for the additional role of activating, but not inhibitory, FcγRs as co-transporters of antibodies into the CNS, potentially as a shield against any virus that should breach the blood-brain-barrier.

Similarly to our previous reports on HIV,46 these data suggest the presence of novel antibody transport mechanisms into the brain, but also point to limited immunologic evidence of persistent active viral replication, and antigen generation, into the brain.

The role of dysregulated immune mechanisms in the development of neurological complications of SARS-CoV-2 infection has become increasingly accepted. Most studies have focused on neurologic manifestations during the acute phase of COVID-19, and have shown the enrichment of both systemic immune activation47-49 and CSF-specific increased cytokine levels.50,51

Moreover, studies have shown evidence of higher levels of SARS-CoV-2 specific antibodies, especially in the CSF, in individuals with more severe neurological disease and CNS damage.43,52-53 These data point towards a role for a hyperinflammatory state and neuroinflammation in the development of neurological manifestations during acute SARS-CoV-2 infection.51

However, the role of humoral and other immune responses in the persistence (or delayed onset) of neurological symptoms beyond acute COVID-19 disease is yet to be clarified. 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, has been observed also for other pathogens, such as influenza virus30 and more recently HIV.54

These studies demonstrated that, during secondary exposure to pathogens, circulating antibodies produced during the primary humoral response modulate naïve B cell recruitment, blocking or skewing the maturation of the humoral response to the new pathogen. Likewise, in our study we observed a bias towards common Coronaviruses-specific immunity as a marker of neuroPASC, that may inhibit the evolution of new B cell responses to SARS-CoV-2, that may ultimately lead to decreased or delayed viral clearance.

Interestingly, this antibody signature was amplified in individuals with poor clinical outcome, across both compartments. These 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, but may support the more effective identification, management, and potential treatment of individuals suffering from neuroPASC.

Neuroinvasion of SARS-CoV-2
Several well-controlled studies and case series or case reports have documented SARS-CoV-2, albeit in low quantities, in the CNS of patients dying from or with COVID-19 [2,16,17,18,19]. The presence may only be transient and may only occur in a subset of patients, yet it raises an important question about how the virus gains access to the CNS.

COVID-19 leads to viremia and SARS-CoV-2 may target brain endothelial cells where SARS-CoV-2 proteins can be found [20,21,22]. Thus, the entry of SARS-CoV-2, present in blood, into the CNS via the neurovascular system passing through the blood–brain barrier, is a conceivable route of neuroinvasion. In fact, studies using animal models of the disease have suggested this possibility early in the pandemic [23]. Recent data using human-induced pluripotent stem cell-derived brain capillary endothelial-like cells not only show the transcellular transport of SARS-CoV-2 through brain endothelial cells, but also that the virus can replicate in these cells [24].

Using a human-induced pluripotent stem-cell-derived blood–brain barrier model in this study, the ultrastructural data map attachment of the virus to the apical side and the release of virus particles from the basolateral side of capillary endothelial-like cells in vitro [25]. The role of the highly vascularized choroid plexus, a structure with key roles not just in the blood–brain barrier maintenance, but also in blood–CSF barrier maintenance, has been highlighted in COVID-19, where its barrier functions are impaired, thus, further suggesting that there is a role for the blood–brain barrier in SARS-CoV-2 CNS entry [25].

SARS-CoV-2 is found in high quantities in the nasal cavity. Since dysfunction of the olfactory system, manifesting as hyposmia, is a prevalent and early symptom of COVID-19, the speculation on an olfactory route of SARS-CoV-2 neuroinvasion was raised very early in the pandemic. This scenario is openly discussed within the scientific community. In fact, there are patient- and animal-experiment-derived data showing that the virus, present in the olfactory mucosa, transits to the olfactory and sensory nerve endings contained within the olfactory mucosa, thereby gaining access to the CNS via the olfactory tract [22,26]. On the other hand, others contest this route of neuroinvasion; patient data show that, within the nasal cavity, SARS-CoV-2 is mainly found in the sustentacular cells within the respiratory mucosa; these studies neither found evidence of olfactory sensory neuron infection, nor of entry via the olfactory bulb [27,28].

Within the CNS, SARS-CoV-2-associated neuropathological alterations are most commonly seen in the brain stem [17]. In fact, in some patients dying with COVID-19, glial and neuroinflammatory reactions could be mapped to respiratory centers within the brain stem containing the nuclei of the vagal nerve [29]. These morphological data, together with clinical data suggesting vagal nerve dysfunction, led to the hypothesis that the vagal nerve may be involved in SARS-CoV-2 neuroinvasion. Moreover, the lung, as the prime target of SARS-CoV-2, is densely innervated by the vagal nerve. Although data from animal models are lacking, the fact that SARS-CoV-2 viral proteins can be found in the vagal nerve of patients dying with COVID-19 suggests a vagal route of SARS-CoV-2 CNS entry [17,29]. However, at present, no data demonstrate the involvement of the vagal nerve innervating in the gastrointestinal tract in SARS-CoV-2 neuroinvasion—although, since SARS-CoV-2 has been detected in rectal swabs, this additional possibility cannot be excluded [24].

The neuroinvasion of pathogens is a complex matter as it involves transitioning between different tissue compartments with tissue- and cell-type-specific replication cycles occurring in a well-defined spatial and temporal manner. Therefore, it is likely that further, more detailed studies of SARS-CoV-2 transport, and replication may yield novel routes of neuroinvasion; it is conceivable that the preferred route SARS-CoV-2 takes to gain access to the CNS very much depends on host- and pathogen-encoded factors, and redundancy may occur. Furthermore, it should be stressed that a considerable number of novel insights into SARS-CoV-2 neuroinvasion come from autopsy studies. As mentioned above, this population (i.e., patients having died from/with SARS-CoV-2) may not be fully representative of the milder clinical courses of COVID-19 seen in the vast majority of patients and rarely pictures the acute phase of SARS-CoV-2 infection.

The Pathophysiology of NeuroCOVID
Clinical and virological data argue in favor of CNS involvement in COVID-19, at least in a subset of patients; yet, mechanistic insights into the pathophysiology of neurological symptoms have not yet been fully elucidated. Indeed, even the key question has not been answered: is the observed CNS damage directly caused by SARS-CoV-2, or is this rather an indirectly mediated effect caused by an overshooting neuroimmune response? A putative sequence of events leading to both acute and long NeuroCOVID, backed by scientific data, could be as follows: In severe cases of COVID-19, SARS-CoV-2 is present in the blood, where it gains access to the CNS through the blood–brain barrier; alternatively or additionally, it can travel to the CNS using one of the aforementioned nerve-associated routes.
Once in the CNS, presence of the SARS-CoV-2 initiates several events (Figure 1). All of the below-mentioned pathways are corroborated by the experimental data, but need to be confirmed by other independent studies in a greater number of models and human participants.

Figure 1. Possible routes of SARS-CoV-2 neuroinvasion and potential modes of action concerning CNS damage, as seen in NeuroCOVID.
  • The main SARS-CoV-2 protease Mpro (identical with Nsp5 or 3CLpro) proteolytically processes the host protein nuclear factor (NF)-κB essential modulator (NEMO), thereby disturbing NEMO-mediated signaling cascades, some of them being critical for the survival of brain endothelial cells [30]. This signaling impairment has multiple consequences, one of which is necroptotic cell death of endothelial cells and, consequently, microvascular damage [30].
  • The presence of SARS-CoV-2 in the CNS, specifically in the neurovascular unit, leads to neuroimmune activation of both the innate immune system (manifested as microglial activation with microglial nodules) but also of the adaptive immune system (presenting with an enhanced presence in the CNS of monocytes and T helper cells) [18,24,31,32].
  • SARS-CoV-2 leads to the breakdown of the blood–brain barrier, either caused by CNS-specific effects or as a consequence of peripheral inflammation and/or peripheral overshooting immune responses [24,31,33].
  • A misleading immune reaction against SARS-CoV-2 may initiate the production of autoantibodies targeting neural antigens [34,35].

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