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Specific immune response to SARS-CoV-2 nucleocapsid protein in individuals with neurological manifestations of post-acute COVID syndrome

More than three years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long-COVID or post-acute COVID syndrome (PACS). In this study, Australian authors investigated immunological signatures that distinguish patients diagnosed with post-acute COVID syndrome and neurological manifestations (neuro-PASC) from healthy COVID convalescents, especially, the immune responses specific to SARS-CoV-2 nucleocapsid (N) protein. 

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. Much attention has been focused on the S protein, which appears to be a major pathogenic factor that contributes to the unique pathogenesis of SARS-CoV-2. However, many other SARS-CoV-2 proteins play equally critical roles in the viral life cycle. The SARS-CoV-2 N protein is the basis of viral RNA genome packaging, but it is also the most abundant protein in virions and a high immunogenicity antigen.

PASC or long-COVID syndrome is more common in hospitalization survivors, but, even those who have experienced mild acute COVID-19 have a wide range of persistent and disabling symptoms. The most frequent symptoms of long COVID are neurological. Despite extensive mapping of the spectrum of neurological sequelae, no significant progress has been made in comprehending the underlying mechanisms.

About the study

The study investigated activation signatures that distinguish patients diagnosed with neuro-PASC from healthy COVID convalescents. Three groups of participants were included: patients who developed neuro-PASC, healthy COVID convalescents, and healthy individuals who were not infected with SARS-CoV-2.The authors focused on a group of patients who developed neuro-PASC syndrome after a mild acute COVID-19. Patients with neuro-PASC had positive polymerase chain reaction (PCR) tests or seropositive IgG results for SARS-CoV-2. Healthy COVID convalescents had positive PCR tests or seropositive IgG results for SARS-CoV-2 before vaccination. Healthy controls had negative PCR tests or seronegative IgG results for SARS-CoV-2 before the vaccination.

The second version of the National Institutes of Health Toolbox test that measures processing speed, attention, executive functions, and working memory was used to assess cognitive deficits in patients diagnosed with neuro-PASC. The PROMIS-57 questionnaire was used to evaluate quality of life.

Results

The study included 94 patients who developed neuro-PASC, 44 healthy COVID convalescents, and 34 healthy uninfected individuals.

77 participants diagnosed with neuro-PASC had mild acute COVID-19 and were not hospitalized. They experienced persistent neurological symptoms, such as headaches, fatigue, brain fog, and myalgia for more than six weeks after the acute COVID-19. The group of healthy COVID convalescent controls did not experience neurological symptoms for more than four weeks after the acute COVID-19. 

30 subjects across all three groups were vaccinated with the Pfizer BNT162B2 or Moderna mRNA-1273 vaccines.

The assessment of cognitive functions using The second version of the National Institutes of Health Toolbox showed lower scores in the attention domain in patients diagnosed with neuro-PASC. In addition, the same group of patients scored higher on anxiety, depression, fatigue, sleep disturbance, and pain. 

 

Immunological signatures in patients with post-acute COVID syndrome and neurological manifestations

The immunological analysis has shown that individuals with neuro-PASC had distinct immunological signatures compared to convalescent and healthy controls.

Patients diagnosed with neuro-PASC had a higher titer of specific anti-SARS-CoV-2 N protein IgG antibodies than healthy COVID convalescents and healthy controls.

CD4+T cells from neuro-PASC patients were more activated by the SARS-CoV-2 N antigen and produced more tumor necrosis factor-alpha than those from healthy COVID convalescents.

Patients diagnosed with neuro-PASC had a higher percentage of CD8+ terminal effector memory T-cells (TEMRA) than control groups. However, CD8+T cell subsets, CD8+ effector memory (TEM), and CD8+ TEMRA cells from neuro-PASC patients were less activated by the SARS-CoV-2 N antigen than those from COVID convalescents.

Interestingly, reduced functionality of CD8+ TEM cells correlated with high depression scores. 

Although CD8+memory T cells showed reduced activation in response to the SARS-CoV-2 N protein, they exhibited enhanced interleukin (IL)-6 production. IL-6 production by CD8+T cells correlated with the severity of neurologic symptoms, including pain.

The interferon-gamma response specific for the C-terminal region of the N protein (N3) correlated negatively with cognitive test scores, and positively with anxiety scores. Neuro-PASC patients with lower scores in attention and executive functions had higher interferon-gamma response specific for N3.

Patients with neuro-PASC had increased levels of proteins associated with immunoregulatory pathways. These levels correlated with the severity of symptoms and cognitive scores. In contrast, healthy controls had increased levels of proteins related to pro-inflammatory and antiviral pathways.

Conclusion

This study has shown that immunological signatures and changes in immune responses specific to the SARS-CoV-2 N protein distinguish patients with post-acute COVID-19 syndrome and neurological manifestations from controls in individuals. The authors hypothesized that functionally anergic CD8+TEMRA cells observed in patients diagnosed with neuro-PASC might contribute to the pathogenesis of PASC.

This article was published in Frontiers in Immunology.

Journal Reference

Visvabharathy L et al. Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein. Front Immunol, 29 May 2023. Sec. Viral Immunology. Volume 14, 2023. (Open Access)  https://doi.org/10.3389/fimmu.2023.1155770

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