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 

- 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.

Impact of Enzymes on The Immune Response

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.

University of Texas at Austin

Smith College

Grand Valley State University

- Affected organs and organ systems
- Circadian Physiology in relation to COVID-19
- Exercise/Physical Activity and COVID-19
- Immune response to COVID-19
- Laboratory methods
- Pathogenesis
- Patient comorbidities 
- Symptomology 
- Genetic mechanisms in COVID-19
- The body's response to stress hormones






Focuses of Human physiology studies on COVID-19

The mechanisms by which an organism eliminates pathogenic microbes and allergenic or toxic proteins, collectively known as antigens, in order to maintain normal function.  

Immune Response

Shi, Y., Wang, Y., Shao, C. et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 27, 1451–1454 (2020). https://doi.org/10.1038/s41418-020-0530-3

COVID-19 infection: the perspectives on immune responses

Wen, W., Su, W., Tang, H., Le, W., Zhang, X., Zheng, Y., ... & Dong, L. (2020). Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell discovery, 6(1), 1-18.

https://doi.org/10.1038/s41421-020-0168-9

Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing

(2020). What we know about the COVID-19 immune response: The latest on COVID-19 Immunity & the current global situation [PowerPoint slides]. Retrieved from https://www.who.int/docs/default-source/coronaviruse/risk-comms-updates/update-34-immunity-2nd.pdf?sfvrsn=8a488cb6_2. 

What we know about the COVID-19 immune response: The latest on COVID-19 Immunity & the current global situation

Retrospective epidemiological studies using clinical data and experimental molecular biologies studies have revealed biomarkers of COVID-19.  These elements not only reveal how COVID-19 mechanistically affects the body, but they may also be risk factors for developing severe symptoms and act as targets for pharmacological intervention.  They include:

- A1AT protection
- ACE2 expression and activity
- ADAM17 sheddase activity
- Furin protease activity
- Irregular respiratory function
- Pro-inflammatory cytokine concentration in the plasma
- TMPRSS2 serine protease genetic variation
- Variation in genetic susceptibility to SARS-CoV-2
- Viral interactions with glycosaminoglycans
- Nsp (Non-specific Protein) Activity
- Neuropilin-1 expression


Pathogenesis of COVID-19

Current studies show that many organs that are heavily affected by COVID-19 have a high expression level of ACE2.

- Cardiovascular system
- Central nervous system (CNS)
- Gastrointestinal tract (GI)
- Kidney
- Liver 
- Lungs (Respiratory System)
- Peripheral nervous system (PNS)
- Testis

Organs and Organ Systems Affected by COVID-19

- Animal models
- Cell lines
- Genetically engineered SARS-CoV-2

Laboratory Methods in COVID-19 Research

Immune Response to COVID-19 

Presence and severity of symptoms of COVID-19 depend largely on individual characteristics. COVID-19 produces both symptomatic and asymptomatic infection.

Symptomology of COVID-19 

- Pituitary gland: improper functioning of the hypothalamus in association with pituitary gland; changes the metabolism of ADH (regulates the amount of water in the kidneys); abnormal sodium levels
- Thyroid: sick euthyroid syndrome → decrease in size of thyroid gland; changes in TSH levels
- Adrenal gland: increased chance of COVID-19 infection if presented with Cushing’s syndrome (too much cortisol) or Addison’s disease (inadequate aldosterone and cortisol)
- Pancreas: those with diabetes are at higher risk of getting COVID-19
- Bone: low vitamin D and hypocalcemia

Dysfunctions/ diseases in endocrine glands/organs that could lead to greater susceptibility to COVID-19

Exercise and physical activity induce physiological changes on many levels, the effects of which are best understood using a biopsychosocial approach.  The bidirectional relationship between exercise and Covid-19 can be further broken down into different components:
- Exercise/PA and COVID-19 by geographical location
- Exercise/PA and COVID-19 by demographics


Exercise/Physical Activity (PA) and Covid-19

COVID-19 comorbidities are high risk conditions that put patients at greater risk for infection and negative outcomes. Some COVID-19 comorbidities have been found to be: 
- Cancer 
- Cardiovascular Disease
- Diabetes
- Digestive Diseases
- HIV
- Hypertension
- Immunological Disease
- Liver Injury
- Obesity
- Renal disease
- Respiratory System Disease

COVID-19 Patient Comorbidities

Circadian biology refers to any biological process that has a rhythmic component dependent on time of day.  Understanding the relation between COVID-19 and circadian rhythm could help improve clinical management in treating COVID-19.

Circadian Physiology in relation to COVID-19

ARTICLES RESEARCHED
- Genetic mechanisms of critical illness in Covid-19
- Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

Genetic mechanisms in COVID-19

Levels of stress may increase in those diagnosed with COVID-19, resulting in an alteration in stress hormone levels and the body's ability to cope with the stress.

The Body's Physiological Response to Stress Hormones In COVID-19 Patients

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

Adaptive immunity is defined by two important characteristics: specificity and memory. Specificity refers to the adaptive immune system’s ability to target specific pathogens, and memory refers to its ability to quickly respond to pathogens to which it has previously been exposed. These elements synergistically work with the innate response in order to completely control antigens.

Adaptive Immune Response

Regulators of Immune Responses

Many pediatric patients with MIS-C have had fever and mucocutaneous manifestations similar to those of Kawasaki Disease (KD), a rare childhood illness that causes inflammation in the walls of blood vessels and coronary-artery aneurysms. Although the cause of KD remains unknown, an active or preceding infection has been suspected. Some of the KD–like features of MIS-C are also seen in toxic shock syndrome, which has been associated with other viruses.


Relationship Between MIS-C, Kawasaki Disease (KD), and Toxic Shock Syndrome (TSS)

- RV Type 2
- RV Type 9
- RV Type 14 
- Respiratory syncytial virus
- Coronavirus type 229E


The Immune Response and Respiratory Viruses

Research suggests that stress affects immunology mainly through autonomic nerves innervating lymphoid tissue, hormone-mediated alteration of immune cells, or adoption of coping behaviors.

Stress and Immunology

Mindfulness mediation has been tied to a stronger immune system. A study found that participants who practiced mindfulness meditation exhibited a stronger response to flu vaccinations than participants who did not practice meditation. 

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