It has been observed that many COVID-19 patients develop renal conditions, including acute kidney injury.  Older patients or those who have kidney conditions are more likely to die from COVID-19 while hospitalized.  Kidneys are known to have a greater level of ACE 2 expression than the lungs.  Kidney disease caused by COVID-19 is directly related to ACE2 expression: a study confirmed by electron microscopy that viral particles have been found in the glomerulus of COVID-19 patients. 

Effects of COVID-19 on the Kidney

Liver injury has been observed in a percentage of COVID-19 patients.  Cholangiocytes, the epithelial lining cells of the bile ducts of the liver, are known to have a high level of ACE 2 expression.  Overall, the liver has a greater expression level of ACE 2 than the lungs.  However, no studies have shown that SARS-CoV-2 can infect hepatic cells.  

Effects of COVID-19 on the Liver

Because as many as 10% of COVID-19 patients have the symptom of diarrhea, it is hypothesized that SARS-CoV-2 can infect gastrointestinal cells.  Symptoms such as loss of appetite and nausea have been commonly found with patients as well. It is known that the GI tract overall has a high expression level of ACE 2, with the duodenum and small intestine having an especially high level of expression. Viral RNA has been found in both the sputum and feces of COVID-19 patients.  

Effects of COVID-19 on the Gastrointestinal (GI) Tract

A main feature of symptomatic COVID-19 disease is respiratory infection. Severe damage to the lungs during respiratory distress may cause pulmonary fibrosis, necessitating lung transplants. Lasting damages to the lungs may occur even in recovering patients with mild infections. SARS-CoV-2 targets the following cell types:

- Type I pneumocytes (AT1) 
- Type II pneumocytes (AT2) 
- alveolar macrophages

ACE2 expression is primarily seen in AT2 cells which have been shown to be involved in the reproduction and transmission of the virus.  Viral targeting of alveolar macrophages is evidenced by N antigen expression.

Effects of COVID-19 on the Lungs

Patients with COVID-19 are likely to experience symptoms that can be attributed to  the virus affecting the cardiovascular system. Common complications to the system include arrhythmia, cardiac injury, fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation. Severe cases of COVID-19 may lead to lasting cardiac damage and those with pre-existing cardiac issues are likely to have worse prognoses. 

Effects of COVID-19 on the Cardiovascular System 

Impaired male fertility is a known symptom of COVID-19.  It is thought that the testes' high expression level of ACE2 and immunoactivity could contribute to this manifestation of the disease.  

Effects of COVID-19 on the Testis   

COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Effects of COVID-19 on the Central Nervous System

Some COVID-19 patients have presented with peripheral neurological symptoms. Although it is not a common complication of COVID-19, it is worth investigating all possible causes of the neurological symptoms that arise.

Effects of COVID-19 on the Peripheral Nervous System

- SARS-CoV-2 can be blocked by physical barriers in the placenta, such as densely branched microvilli and cytoskeletal network
- placenta can attack the virus with the following 3 molecular pathways: type III IFN signaling, secreted miRNAs triggering autophagy, and NF-κB pathway
- immunomodulation can be employed after viral infection to alleviate cytokin storm

Effects of COVID-19 on the Placenta

- There have been two reports of COVID-19 positive patients with conjunctivitis or conjunctival congestion
- Ocular secretions were seen in those with the SARS-CoV-2 positive serology
- This presents the possibility that the SARS-CoV-2 virus can cause conjunctivitis
- However, this relationship is not very clear at this point due to a lack of studies comparing the two
- It has also been suggested that the ocular system is a potential route of transmission of the virus

Effects of COVID-19 on the Ocular System

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

Michigan State University

University of Michigan - Ann Arbor

Smith College

- 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

ACE2 is known to be expressed in a variety of different tissues, including:

- Heart, kidneys, gastrointestinal (GI) tract, lungs, brain, testes, bladder, adipose tissue, vascular system, cholangiocytes (epithelial cells of the oral and nasal mucosa)

ACE2 expression may explain the SARS-CoV-2 organ localization.

Expression of ACE2 in Tissue and COVID-19

Tan, H. W., Xu, Y. M., & Lau, A. T. Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection. Reviews in Medical Virology, e2122. https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2122

Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection

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

Organs and Organ Systems Affected by COVID-19

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

Laboratory Methods in COVID-19 Research

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 

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

A majority of the COVID-19 symptoms are due to high or low ACE2 expression. Only 1 symptom can be seen when ACE2 protein expression is in the middle.

Tissue ACE2 Expression Levels as Related to COVID-19 Symptoms

- Inflammation of endothelial cells in the heart, lung, and small bowel
- A COVID-19 patient's kidneys were unable to filter blood and necrosis was present in the small intestine
- Another COVID-19 patient was found to have inflammation in the endothelial layer of the small intestine
- ACE2 receptors are used by the COVID-19 virus in the epithelial alveolar lining of the lungs, resulting in lung damage
- ACE2 receptors are located on endothelial cells, which are located in other organs and can negatively impact them
- Image shows an excess of mononuclear cells in the lung, resulting in the blockage of the small vessels in the lung


Effects of the ACE2 receptors on organ tissues of COVID-19 patients

Expression levels were determined using the HPA (https://www.proteinatlas.org).  Tissues that express ACE2 were broken down into five categories based off of the amount of ACE2 mRNA expression:

- (1, highest expression, score range: 122-10) small intestine, colon, duodenum, kidney, testis, gallbladder and heart muscle
- (2, medium high expression, score range: 5-1) adipose tissue, thyroid gland, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland and placenta
- (3, medium low expression, score range: 0.9-0.5) vagina, lung, appendix, skeletal muscle, fallopian tube, lymph node, tongue, stomach and prostate
- (4, low expression, score range: 0.4-0.1) remaining tissues
- (5, no expression, score range: 0) parathyroid gland, bone marrow, monocytes, B-cells, NK-cells, dendritic cells and total peripheral blood mononuclear cell

ACE2 Protein and mRNA Expression in Tissue

- increased ACE2 expression as a risk factor for COVID-19
- decreased ACE2 activity in comorbidities as a risk factor for COVID-19 symptom severity
- inconsistencies in ACE2 expression hypotheses

Hypotheses Regarding ACE2 Expression in Tissue and COVID-19

The HCCDB gene expression database (http://lifeome.net/database/hccdb/home.html) was used to determine ACE2 expression levels in both human adipose and lung tissue.  

- ACE2 gene expression was higher in both subcutaneous and visceral adipose tissue compared to lung tissue
- previous studies have shown that obesity alone does not affect ACE2 expression, but this study shows that obese individuals with more adipose tissue will consequently have more ACE2 receptors
- this study does not prove that SARS-CoV-2 can infect human adipose tissue or propose a possible mechanism of infection

ACE2 Expression in Adipose Tissue May Contribute to COVID-19 Morbidity and Mortality in Obese Patients

This graph displays the variance in the amount of ACE2 expression there is different types of tissues within the human body. 

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