COVID-19 News: Study Shockingly Finds That Innate Immune Response To SARS-CoV-2 Infection Contributes To Neuronal Damage!

COVID-19 News: The global impact of the COVID-19 pandemic has been unprecedented, affecting millions of individuals worldwide. Beyond respiratory complications, emerging evidence suggests a link between SARS-CoV-2 infection and neurological diseases. In a groundbreaking study covered in this COVID-19 News report, conducted at Hannover Medical School, Institute of Virology in Germany, researchers delved into the intricate relationship between the innate immune response and neuronal damage in the context of SARS-CoV-2 infection.


SARS-CoV-2 efficiently infects PNS neurons and induces robust type III IFN responses and ISG expression. (A) Immunoblot showing SARS-CoV-2 NC and MAPK in PNS neurons lysed at 3 dpi. NC levels were measured relative to MAPK using ImageJ. A representative blot is shown from three independent experiments. (B) Graph showing relative expression of SARS-CoV-2 Membrane and Nucleocapsid mRNA in PNS neurons at 3 dpi. (C) Immunoblot showing TUJ1 and MAPK in cell lysates of PNS neurons at 3 dpi. TUJ1 levels were measured relative to MAPK using ImageJ. One representative blot, out of three independent ones, is shown. (D) Immunofluorescence of PNS neurons fixed at 3 dpi and stained with anti-SARS-CoV-2 NC, anti-TUJ1, and DAPI. The right panels show a zoom in of 4x, applied using ImageJ. Scale bar = 100 µm; amplification: ×20. (E, G, I) Graphs showing relative expression of host genes in PNS neurons at 3 dpi. (F) Protein concentrations of released cytokines determined by ELISA. (H) Immunoblot showing ISG15 and MAPK in lysates of PNS neurons at 3 dpi. ISG15 levels were measured relative to MAPK using ImageJ. One representative blot, out of three independent ones, is shown. (J) Protein concentrations of released cytokines determined by cytometric bead array multiplex analysis in the supernatant of infected PNS neurons. In all immunoblots, the numbers at the bottom of the blot represent the fold-change to mock-infected, untreated control. In all graphs showing gene expression, this was quantified by RT-qPCR and set relative to β-actin. Fold-change is relative to mock-infected, untreated control. In all graphs, error bars represent standard deviation of the arithmetic mean from three independent experiments. Statistical analyses for all experiments were determined using one-way ANOVA followed by the Dunnetts multiple comparison posttest. *p < 0.03; **p < 0.002; ***p < 0.0002; ****p < 0.0001; not significant comparisons are not indicated. IFN, interferon; PNS, peripheral nervous system; SARS-CoV-2, severe acute respiratory coronavirus 2.

Neurological Complications in COVID-19
Clinical studies have reported cases of neurological diseases in COVID-19 patients affecting both the central nervous system (CNS) and peripheral nervous system (PNS). These complications range from nerve pain and Guillain−Barré syndrome to myasthen ia gravis, neurosensory disorders, and peripheral neuropathy. Moreover, individuals with long-term COVID-19 symptoms often experience neurological disorders, suggesting persistent damage or potential progression to neurodegenerative diseases.
 
The Unanswered Question: Infection or Immune Response?
One of the critical questions in understanding COVID-19-related neurological complications is whether they result from the direct effects of viral infection on the nervous system or from the subsequent immune response. The researchers at Hannover Medical School set out to address this question by infecting human induced pluripotent stem cell-derived CNS and PNS neurons with SARS-CoV-2.
 
Differential Response in CNS and PNS Neurons
Surprisingly, the study revealed distinct responses in CNS and PNS neurons to SARS-CoV-2 infection. While a low number of CNS neurons were infected, they did not exhibit a robust innate immune response. On the contrary, a higher number of PNS neurons were infected, leading to the expression of interferon (IFN) λ1, several IFN-stimulated genes, and proinflammatory cytokines. Notably, the PNS neurons displayed alterations indicative of neuronal damage.
 
The Role of Innate Immune Response
The researchers observed that the innate immune response played a significant role in the pathogenesis of SARS-CoV-2 infection in the PNS. Blockade of the Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway by Ruxolitinib did not increase the virus's infection but significantly reduced neuronal damage. This suggests that an exacerbated neuronal innate immune response contributes to the development of pathology in the PNS.
 
Investigating Mechanisms in Neuronal Models
To unravel the mechanisms underlying neurological symptoms in COVID-19 patients, researchers employed human neurons and neuronal models derived from stem cells. The study focused on human induced pluripotent stem cell (iPSC)-derived CNS neurons and PNS neurons. Previous research had shown varying efficiency of viral replication in human CNS and differences in the types of cells that are productively infected. Most studies, however, concentrated on CNS neurons, leaving the PNS neurons less explored.
 
Neuronal Responses to Viral Infection
Neurons possess intricate mechanisms to detect viruses through pattern recognition receptors and respond to interferons to combat infections. The innate and intrinsic responses of neurons to viral infections can lead to various outcomes, including neurodegenerative processes. The researchers aimed to understand how CNS and PNS neurons respond to SARS-CoV-2 infection and whether these responses contribute to neuronal damage.
 
Differential Expression of SARS-CoV-2 Entry Factors
Analysis of SARS-CoV-2 entry factors in iPSC-derived CNS and PNS neurons revealed low expression levels of ACE2, TMPRSS2, and NRP-1. Surprisingly, despite these low expression levels, SARS-CoV-2 efficiently infected PNS neurons, indicating a potential ACE2-independent entry mechanism. This finding challenges previous assumptions about the primary entry factors for SARS-CoV-2.
 
Distinct Responses in CNS and PNS Neurons
Infection of CNS neurons with SARS-CoV-2 resulted in low viral replication and a limited innate immune response. Conversely, PNS neurons displayed higher susceptibility to infection, leading to the activation of the type III IFN response and increased expression of proinflammatory cytokines. Additionally, PNS neurons showed signs of neuronal damage, including altered levels of specific proteins associated with neurodegeneration.
 
Role of JAK/STAT Pathway in Neuronal Damage
The researchers explored the impact of the JAK/STAT pathway on SARS-CoV-2 infection and subsequent neuronal damage. Ruxolitinib, a JAK/STAT pathway inhibitor, did not affect the virus's infection efficiency in CNS neurons but significantly reduced neuronal damage. This highlights the crucial role of the innate immune response, particularly the JAK/STAT pathway, in the pathogenesis of SARS-CoV-2 in the PNS.
 
Distinct Molecular Responses in CNS and PNS Neurons
Detailed molecular analyses revealed unique responses in CNS and PNS neurons to SARS-CoV-2 infection. In CNS neurons, there was no induction of a robust innate immune response, endoplasmic reticulum (ER) stress, or signs of neuronal damage. Instead, an increase in BiP, a chaperone associated with ER homeostasis, suggested a potential protective role against cytopathic effects.
 
Conversely, SARS-CoV-2 infection of PNS neurons triggered a type III IFN response, increased expression of neurodegeneration-related genes, and signs of axonal degeneration. The JAK/STAT pathway played a crucial role in mediating these responses, linking the innate immune response to neuronal damage in the PNS.
 
Implications for COVID-19-Related Neuronal Pathology
The study provides a foundation for understanding COVID-19-related neuronal pathology, particularly the differential impact on CNS and PNS neurons. The findings suggest that while CNS neurons exhibit resilience to SARS-CoV-2 infection, PNS neurons are more susceptible, leading to an exacerbated innate immune response and subsequent neuronal damage.
 
Future Preventive and Therapeutic Strategies
The identification of the JAK/STAT pathway as a key player in the neuronal damage process opens avenues for future preventive and therapeutic strategies. Inhibition of this pathway with Ruxolitinib showed promise in reducing neuronal damage in PNS neurons without compromising SARS-CoV-2 infection efficiency. This implies that targeted interventions could mitigate neurological complications in COVID-19 patients.
 
Conclusion
In unraveling the complexities of SARS-CoV-2 infection in human iPSC-derived CNS and PNS neurons, this study sheds light on the intricate interplay between the virus, the innate immune response, and neuronal damage. The differential responses observed in CNS and PNS neurons provide valuable insights into the mechanisms underlying COVID-19-related neurological complications. As research progresses, these findings may contribute to the development of targeted therapies and preventive measures to alleviate the impact of SARS-CoV-2 on the nervous system.
 
The study findings were published in the peer reviewed Journal of medical Virology.
https://onlinelibrary.wiley.com/doi/10.1002/jmv.29455
 
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