BREAKING COVID-19 News! SARS-CoV-2 Also Targets Human Motor Neurons! Expect More Neuromuscular Issues In Post COVID Phase!

COVID-19 News: The COVID-19 pandemic has sparked a global scientific quest to understand the intricacies of the novel coronavirus, SARS-CoV-2. While the respiratory implications have taken center stage, a remarkable number of COVID-19 patients have reported neurological and neuromuscular symptoms, leading researchers to explore the virus's impact on the central nervous system (CNS) and peripheral nervous system (PNS). A recent study conducted by the University of Milan-Italy, in collaboration with IRCCS Istituto Auxologico Italiano and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan-Italy, is shedding light on an uncharted territory - the virus's ability to infect human motor neurons derived from induced pluripotent stem cells (iPSC-MNs).


Graphical representation of the study workflow. SARS-CoV-2 host receptor gene expression was assessed on iPSC-derived motor neurons (iPSC-MNs) by RT-qPCR and immunofluorescence. iPSC-MN were then in vitro infected by SARS-CoV-2 and viral infection/replication was assessed by a multidisciplinary approach using RT-qPCR, TCID50, immunofluorescence and quantigene Plex techniques. The effect of viral infection on iPSC-MN homeostasis was determined by analyzing the alteration of their transcriptome
 
Neurological Complexity in COVID-19
The respiratory nature of COVID-19 is well-documented in numerous studies and COVID-19 News coverages, but the virus's diverse neurological manifestations have raised significant questions. From cerebrovascular diseases and seizures to sensory impairments like anosmia and ageusia, the spectrum of neurological symptoms is broad. Furthermore, the lingering effects of COVID-19, commonly referred to as "Long COVID-19," exhibit persistent issues such as memory deficits, attention problems, insomnia, anxiety, depression, and various neuromuscular disorders. The study aims to bridge the gap in understanding how SARS-CoV-2 directly impacts motor neuronal cells, a crucial aspect that has been largely unexplored.
 
Neurological Link to SARS-CoV-2
Various studies have suggested that SARS-CoV-2 can infect different neuronal populations, potentially contributing to neurodegenerative disorders. The documented neurological abnormalities in COVID-19 patients indicate alterations in both the CNS and PNS, raising concerns about the development or exacerbation of neurodegenerative disorders. Despite these observations, the specific impact of SARS-CoV-2 on motor neuronal cells has not been thoroughly investigated.
 
Investigating Motor Neurons' Susceptibility
To unravel the mysteries surrounding SARS-CoV-2 and its potential impact on motor neurons, researchers utilized an innovative in vitro model involving human motor neurons derived from induced pluripotent stem cells (iPSC-MNs). This unique model allowed researchers to address three critical questions: the expression of SARS-CoV-2 main receptors, the susceptibility of iPSC-MNs to SARS-CoV-2 infection, and the impact of viral exposure on iPSC-MN transcriptome.
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Expression of SARS-CoV-2 Receptors in iPSC-derived MNs
The study discovered that iPSC-MNs expressed all major SARS-CoV-2 receptors, with CD147 and NRP1 being the most prominently represented. This finding challenges previous assumptions and suggests that these receptors may play a pivotal role in facilitating SARS-CoV-2 entry into motor neurons. Interestingly, ACE2, a well-known receptor associated with SARS-CoV-2 infection, displayed low expression levels in human motor neurons, prompting a reconsideration of the assumed exclusive role of ACE2 in viral entry.
 
SARS-CoV-2 Viral Replication in iPSC-MNs
The researchers demonstrated that human iPSC-MNs were indeed susceptible to productive SARS-CoV-2 infection. Evidence included the presence of viral nucleocapsid proteins and the ability of infected iPSC-MNs to release infectious viral particles. While the levels of viral replication were modest compared to susceptible cells, this discovery highlights the potential for SARS-CoV-2 to infect and replicate within motor neuronal cells.
 
Effect of SARS-CoV-2 Infection on iPSC-MN Gene Expression
The study delved into the transcriptome of iPSC-MNs after exposure to SARS-CoV-2, revealing a significant alteration in gene expression associated with cell survival, metabolism, antiviral response, and inflammatory processes. Notable changes included upregulation of IL-6, MX1, and CD147, suggesting an induction of inflammatory and antiviral responses. Additionally, the study observed changes in genes involved in apoptosis, indicating a potential manipulation of host defense mechanisms by the virus.
 
Implications and Future Directions
The groundbreaking findings of this study suggest, for the first time, that SARS-CoV-2 can productively infect human motor neurons, possibly through the binding of CD147 and NRP1 receptors. These revelations have profound implications for understanding the biological underpinnings of neuromuscular disorders associated with SARS-CoV-2 infection and long-term COVID-19 symptoms.
 
The study acknowledges certain limitations, such as the absence of an immune system component in the in vitro model, heterogeneity in cell differentiation, and a restricted number of subjects. However, the results pave the way for further investigations into the neuroinvasive routes of SARS-CoV-2 entry within the gray matter of the spinal cord. A recent preprint publication suggests that SARS-CoV-2 can infect spinal cord neurons in mice models, emphasizing the need for additional research to comprehensively understand the impact of the virus on the nervous system.
 
Unraveling the Neurological Enigma
As we delve deeper into the complexities of SARS-CoV-2, the study findings from the University of Milan-Italy emerges as a beacon, guiding our understanding of the virus's affinity for human motor neurons. This Italian research not only unravels the previously unexplored territory of SARS-CoV-2's impact on motor neuronal cells but also challenges existing paradigms regarding the virus's preferred receptors.
 
The intricate interplay between SARS-CoV-2 and the nervous system becomes more nuanced as we consider the expressed receptors in motor neurons. CD147 and NRP1 take center stage, potentially serving as the gateway for the virus to enter these crucial cells. The study's meticulous exploration of gene expression changes in iPSC-MNs post-SARS-CoV-2 exposure opens a window into the host-virus interaction, revealing alterations in inflammatory responses, antiviral mechanisms, and apoptosis.
 
In the quest to understand the implications of SARS-CoV-2 on the nervous system, the iPSC-MN model offers a valuable tool, allowing researchers to dissect the virus's impact at the cellular level. However, the study's acknowledgment of limitations underscores the need for further research, particularly in in vivo models that can more accurately represent the complex interplay between the virus, the immune system, and the nervous system.
 
Looking Ahead - Implications for Therapy and Intervention
As we uncover more about SARS-CoV-2's interaction with motor neurons, the implications for therapy and intervention become increasingly apparent. The study's identification of CD147 and NRP1 as potential receptors for SARS-CoV-2 in motor neurons suggests new avenues for targeted therapies. Future research may explore interventions that block these receptors, hindering the virus's entry into motor neurons and potentially mitigating neurological complications in COVID-19 patients.
 
Understanding the transcriptomic changes induced by SARS-CoV-2 in motor neurons provides a roadmap for potential therapeutic targets. The upregulation of IL-6, MX1, and CD147, coupled with alterations in apoptosis-related genes, suggests that modulating these pathways could influence the course of SARS-CoV-2 infection in the nervous system. Targeted therapies aimed at mitigating inflammation, enhancing antiviral responses, and preserving cell survival mechanisms may prove beneficial
 
The study findings were published in the peer reviewed journal: Frontiers in Cellular Neuroscience.
https://www.frontiersin.org/articles/10.3389/fncel.2023.1285836/full
 
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