In the innate immune response to SARS-CoV-2 infection, the host cells' pattern recognition receptors (PRR) recognise evolutionarily conserved molecular structures on the virus, called pathogen associated molecular patterns (PAMPS). When PAMPs bind to PRRs, the inflammatory response begins. PRRs activate several transcription factors to regulate the expression of genes responsible for inflammatory cytokine, interferon, chemokine, and adhesion molecule production.

Onset of Inflammatory Response in COVID-19

- 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. 


University of Michigan - Ann Arbor

Smith College

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 innate immune response recognizes molecular patterns that are shared by foreign microbes and potential toxins and works via genes in an organism's germ line to eliminate these threats.  This is an organism's first line of immune response, and because a large number of cells in an organism express genes related to innate immunity, the response is very quick.  

Innate Immune Response

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.

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).

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

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 

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.

Impact of Enzymes on The Immune Response

All components of the innate immune response are the result of germ-line genes of the host organism.  Some of these defense structures are always active, such as barriers, mucus, and cilia, but the molecular responses become active when a host cell or protein comes into contact with the invading foreign entity.  Some of these elements work in tandem with the adaptive immune response by activating antigen-specific cells.

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