Methods:
- Bulk/single-cell RNA-seq, differential gene analysis, and algorithm prediction techniques have been used to compare and identify the interaction between pulmonary immune cells and sensory neuron transcriptomics. 

Sampling:

- Public and private datasets from patient samples of bronchial alveolar lavage fluid (BALF) & human dorsal root ganglion neurons (hDRGNs), and ligand-receptor signaling & mice sensory tissue databases, have been used for analysis.

The image below shows a sample workflow for ligand-receptor analyses of COVID-19 BALF and DRG samples, in support of the neuro-immune hypothesis (Ray et. al).

Technical Methods for Research of the SARS-CoV-2 Neuro-Immune Hypothesis.

Not only do patients with MS have a higher chance of infection and complications and mortality due to infection than the normal population but SARS-CoV-2 has been accused of triggering the disease as well. SARS-CoV-2 may trigger this disease as a result of its adverse modifying effect on immune cells certain immune cells. In severe COVID-19 patients, the aggressive cytokine storms along with other over-exaggerated immune responses may affect the CNS, especially if the patient is predisposed with a weakened blood-brain barrier. 

COVID-19 Immunopathology and the Central Nervous System: Implication for Multiple Sclerosis and Other Autoimmune Diseases with Associated Demyelination

Hypothesis:

- SARS-CoV2 infection of immune-cells and the subsequent upregulation of cytokines and chemokines may interact with lung-innervating sensory neurons, providing a neurological model for COVID-19 severity.

The image below shows a proposed mechanism of the neuro-immune interactome; SARS-CoV-2 activation of the immune cell results in an inflammatory cytokine storm, along with the upregulation of COVID-19 inflammatory ligands that bind to sensory neurons receptors; neurologic inflammation may occur following the release of neuropeptides, forming a positive-feedback loop that could exacerbate lung inflammation (Ray et. al).

Smith College

- Autoimmune Response Contribution to Neurological Symptoms.
- Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Indirect/Downstream effects of SARS-CoV-2 on the CNS.

Infection by SARS-CoV-2, as is with other viral infections, induces a two-phased immune response in the human body, described in the figure below: 
- Innate (rapid, natural, non-specific) 
- Adaptive (slow, acquired, specific)

Those two branches of the immune system cooperate with one another, and can be distinguished based on the cell-types involved (immune response vs white blood cells). However, the adaptive system is further broken down by the type of mechanism:

- Cell-mediated
- Antibody-mediated

Current research around COVID-19 immunity aims at uncovering the interaction between SARS-CoV-2 and the host's immune response, with questions related to pathogenesis, severity, and intervention.

Immune Response to COVID-19 

The lungs are innervated by two autonomic nervous system components:
- parasympathetic/vagus nerves (origin: cranial and sacral nerves)
- sympathetic nerves (origin: thoracolumbar region of the spinal cord)


The image below shows a schematic of pulmonary nerve innervation: afferent fibers transmit information from peripheral organs back to the CNS, while efferent fibers send impulses from the CNS to peripheral organs.
- Research has found several afferent nerves capable of initiating coughs upon activation, with roles in the regulation of breathing patterns
- Nociceptors (peripheral afferents) detect noxious stimuli to mediate coughing and pain responses, with recent literature supporting their ability to cross-talk with pulmonary immune cells

PNS Innervation of the Lungs

Ray, P. R., Wangzhou, A., Ghneim, N., Yousuf, M. S., Paige, C., Tavares-Ferreira, D., ... & Neerukonda, S. V. (2020). A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction. Brain, Behavior, and Immunity.  doi:10.1016/j.bbi.2020.05.078. https://reader.elsevier.com/reader/sd/pii/S088915912030670X?token=47BD27DF03A0DC9F9945F6E90A2137EAFCB238A79393A82CA3917F589C6702E1240C841686F05BA6D96293A4B2699299

A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction

Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Support for indirect over direct causes of neurological symptoms:
- Cerebralspinal fluid (CSF) samples in some CoV-2 patients have shown the presence of SARS-CoV-2 antibodies (anti-S1 IgM) and increased multiple cytokines, suggesting a possible CoV-2 direct infection of the CNS (Benameur et. al). However, this coupled with low levels of CSF and plasma viral RNA in patients, suggests that the neurological symptoms present may be a result of autoimmune responses, rather than direct infection.

Support for autoimmunity:
- the anti-neuronal and anti-glial autoantibodies presence in CSF and serum lends support of a causal relationship between autoimmunity and neurological clinical symptoms (Franke et. al)
- transcriptomic data from COVID-19 patients, control samples, and mice studies, reveal evidence of virus-driven cell lysis (Ray et. al)

COVID-19 Neurological Effects as a Result of Autoimmunity in the PNS

- Direct infection injury detected in tissue samples 
- Blood circulation pathway, entering the CNS through BBB
- Neuronal pathway (e.g. olfactory neuron transport) infecting sensory or motor nerve endings
- Hypoxia injury, damages caused by lack of oxygen circulation
- Immune injury-- systemic inflammatory response syndrome(SIRS)
- Affecting the ability of ACE2 enzyme to regulate blood pressure, damaging the BBB

Mechanisms of CoV infections on the nervous system damage

Current research lends preliminary support for the hypothesis that sensory neurons innervating the lung have the capacity to modulate the lung's immune response to SARS-CoV-2 infection. 
- Pulmonary immune cell-derived receptors are upregulated following viral infection
- Sensory neurons (hDRGNs) express ligands for the receptors upregulated in lung immune cells

Limitations and caveats of the research are listed as follows:
- there is no transcriptomic data for sensory neurons of COVID-19 patients, and current research relies on an assumption that upregulated immune-cell receptors are responding to sensory-neuron ligands 
- there are no existing animal model studies on neuro-pertubation of immunity
- nociceptor (pain-receptor sensory neurons) directionality on lung immunity is unclear; these sensory afferents have been shown to provide either beneficial or detrimental effects, so neuron promotion or suppression of COVID-19 immunity is unknown
- research is limited to sympathetic nerves (DRGNs), and no conclusions can be drawn regarding parasympathetic nerves (nodose, jugular ganglia)

If lung-innervating sensory neurons signal to immune cells through the release of ligands, this establishes a positive feedback-loop/bidirectional interaction. This hypothesis opens up the possibility of neurogenic-mediated vasodilation, inflammation, pain, and immunity-recruitment.

Signaling: From Sensory Neurons to Pulmonary Immune Cells.

The immune response of the host to SARS-CoV-2 plays a key role in disease pathogenesis and clinical manifestations. SARS-CoV-2 activates antiviral immune responses and uncontrolled inflammatory responses. In order to manage the disease and develop treatments, we must first understand the mechanisms underlying this immune response. 

Immunopathogenesis and Immunotherapeutics 

- Inflammation in COVID-19

-Innate response process 
1. Virus enters through the nasal system by inhaling...it starts to replicate
2. Detected by nasal swabs 
3. It reaches the respiratory tract where it comes into contact with the innate immune response
4. Cytokine is part of the process by acting as chemical messengers. They regulate the immune response. 


Innate Immune Response to COVID-19

- B-Cell Immunity in COVID-19
- T-Cell Immunity in COVID-19
Adaptive response process
- Blood brings the cells throughout the body as normal where the B cells are working alongside t cells to go into the plasma where they produce antibodies specific to the antigen.  
- A neutralizing antibody is efficient in fully blocking the virus from entering the host cells. This helps limit the infection and relapse. 
- The overall adaptive immune response is directed by helper T cells, and cytotoxic T cells play a vital role in the clearance and cleaning of viral-infected cells
- Adaptive immune response against coronavirus requires stimulation of B cell and T cell epitopes


Adaptive Immune Response to COVID-19

Certain enzymes play a role in viral entry and can function similarly to the receptors involved in the COVID-19 immune response.

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