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COVID-19: Data and Hypotheses

By Pari Rapti, Endocrinologist

The unexpected appearance of the viral infection COVID-19, with tremendous global consequences, creates thoughts and concerns to doctors and researchers, regarding the possible impacts on other systems of the organism, such as the gastrointestinal, the nervous, the urinary and the endocrine systems,emphasizes Pari Rapti.

Various researches, conducted internationally, show that an interesting correlation seems to exist between the COVID-19 infection and particular endocrine and metabolic pathways.  Those pathways are related to the existence of the ACE2 receptor, which is present on the alveolar epithelial cells of the lungs and to the receptor’s expression.

Additionally, a correlation seems to exist between COVID-19 and the action of particular substances produced in the case of an inflammation, named proinflammatory factors or cytokines, which in some COVID-19 cases occur in the form of a “cytokine storm”.  We know that cytokines and especially Interleukin 6 (pleiotropic), are produced in various endocrine systems and glands throughout the organism, as well as in other organs, and regulate various biological procedures and responses, in each of the systems.

In the case of a coronavirus infection, those substances might contribute to the occurrence of a poly-systemic syndrome (in multiple organs), in potentially genetically predisposed patients.

A further examination of those endocrine and metabolic pathways might be important in examining the severity of the disease and in understanding, dealing and finding the disease severity markers, as well as in studying the genetic differences between the two sexes or between different populations.

We know that on the surface of the alveolar epithelial cells of the lung, which comprise the 15% of the lung cells, there are approximately 83% of the ACE2 (Angiotensin-converting enzyme 2) receptors, whereas the rest of them are located in other organs.  These receptors are important for the function of the Renin–Angiotensin–Aldosterone System (RAAS).

In the COVID-19 infection, the ACE2 receptor, as it is reported in the international scientific literature, seems to be connected to the Spike (S) glycoprotein of the coronavirus, through the presence of a particular protease, the serine protease TMPRSS2.

The protease TMPRSS2 cleaves the Spike (S) glycoprotein of the coronavirus.  This is a necessary condition, in order for the virus to enter the host cell, where the virus’ RNA uses the infected cell’s substances and pathways to replicate itself, creating a large number of viruses that will infect other cells.

Moreover, there is a need to highlight the fact that Type II lung cells produce a surface-active substance, (pulmonary surfactant), which has immunoregulatory properties and prevents the collapse of the cells.  The hypoxia created and its consequences in COVID-19 should be taken into consideration.

In genetic predisposition of patients, the possible important role of the following procedure should be emphasized:

As we mentioned earlier, ACE2 (Angiotensin-converting enzyme 2) receptors exist on the surface of the epithelial lung cells, which are related to the glycoprotein Spike (S) of the virus.

As a result, the virus enters the cytoplasm and the receptors on the lung cells’ surface are reduced.  The ACE2 receptor is also a converter of the immune response.  The role of ACE2 is to convert Angiotensin I to Angiotensin II and Angiotensin (1-7).

The Angiotensin-Converting Enzyme 2 (ACE2 / the equivalent of the known ACE, which converts Ang I to Ang II) is an aminopeptidase.  Normally, ACE2 cleaves Angiotensin II (Ang II) to Angiotensin (1-7) and consequently converts Ang I to Ang (1-9).  Thus, through ACE2, vasodilatation is induced and cardio-renal protection is accorded, through the reduction of Ang II levels and the parallel increase of the Ang (1-7) levels.  ACE2 receptors play a role in the pathogenesis of hypertension and diabetes mellitus, and they are expressed in the epithelial cells of many organs.

Angiotensin II is a peptide consisting eight amino acids, which is formed with the assistance of the Angiotensin-Converting Enzyme (ACE) through the conversion of Angiotensin I.  Angiotensin II is further metabolized to Angiotensin III.  The release of Angiotensin II is regulated by renin, blood pressure, blood volume, sodium balance and the concentration of aldosterone.  Angiotensin II stimulates the release of the antidiuretic hormone (ADH), the adrenocorticotropic hormone (ACTH), the prolactin, the luteinizing hormone (LH), the oxytocin, the aldosterone and others.  Moreover, it increases vasoconstriction and defers the sodium reabsorption by the renal tubules, and stimulates the development of the endothelial cells.

However, it is important that drugs, such as diuretics, mineralocorticoids, glucocorticoids, estrogens, oral contraceptives, adrenocorticotropic hormone, sodium, potassium, as well as the body posture during blood collection, influence Angiotensin II levels.  In COVID-19, the levels of Angiotensin II appear to increase.

All the implicated factors, which were mentioned above, are genetically defined and there is a high genetic diversity.

Two pathways are highly important inside the infected cell, JAK/STAT and NF-κB, and in the case of the coronavirus, the second pathway should be taken into consideration when dealing with the issues caused by the coronavirus.

The nuclear factor NF-κB consists of a protein complex, which controls the DNA transcription, the production of cytokines and the cell survival.  It is also involved in the cellular stress response, with the cytokines at the level of free radicals, with infrared radiation, in the acidosis of LDL and with bacterial and viral antigens.  It is a key factor of the immune response to infections.

Probably, a disturbance in the nuclear factor’s regulation is related to infections, autoimmune diseases, septic shock, viral infections, inadequate development of the immune system, synaptic plasticity, memory, etc.

The nuclear factor NF-κB is a protein (transcription factor) that controls the DNA transcription and controls over 500 gene products.

NF-κB has been identified as the major chemical mediator of inflammation.  The NF-κB inhibitors, probably, are very important in the evolution of a chronic inflammation.

The genes regulated by NF-κB include those which control the apoptosis, cell agglutination, cell multiplication, innate and adaptive immune responses, inflammation, cellular stress response and tissue regeneration.

The main classes of NF-κB cellular targets are chemokines (IL1α and IFNγ), apoptosis regulators (Bcl-xL, IAP), transcription factors (G-CSF, GM-CSF) and regulators of cellular life cycle (Cyclin D1, MDM2).

In case of coronavirus infection, due to the connection of Spike (S) of the coronavirus with the ACE2 receptor of the Angiotensin-Converting Enzyme found in the epithelial cells of the lungs and other organs, and due to the fact that the Renin – Angiotensin – Aldosterone system is highly important for the organism’s homeostasis, and not only, I consider that, in this case, it is imperative to further explore this pathway.

Furthermore, since researches mention the probable involvement of other organs and systems which are affected, (such as the hematopoietic system, the cardiovascular system, the central nervous system, the gastrointestinal system), the question is whether there is an involvement.

Ιf there is an involvement, the question is what is the importance of the neuroendocrine system and the endocrine glands, (e.g. thyroid, adrenal, hypothalamus, pituitary, fatty tissue of the pancreas), and hormones, (such as prolactin, estrogens, testosterone, pituitary hormones, thyroxin, insulin, various prohormones, etc.), and the genital systems of the two sexes, (ovaries, testes), as well as the involvement in the pathophysiology of various diseases (e.g. metabolic syndrome, type 2 diabetes mellitus, insulin resistance, thyroid disorders, Addison, hypertension, obesity, etc.)

The hypothesis that a cytokine storm occurs in severe cases and especially of Interleukin 6, which indicates that there is a hyperreactive immune response, raises the question whether all those mechanisms have any connection to the neuroendocrine immune axis of the organism and generally with the endocrine system.

Crucially important might be the role of the immune system, neuroendocrinology and hormones in the pathophysiology of various developments, due to the cytokine storm that seems to occur in a percentage of severe COVID-19 patients.  There is a plethora of researches in the recent years that refer to hypotheses of the interaction between the immune system, the neuroendocrine system and the cytokines, with the greatest interest in the pleiotropic cytokine Interleukin 6 (which has actions on many organism levels).

Further investigation is needed for the hypotheses, data and questions raised.

What is the connection between neuroendocrinology, immune system and proinflammatory factors, especially the Interleukin 6 (genes, Interleukin 1, TNF, ACE, and toll like receptors)?

From the data collected until today, we know that it is a complicated, but nevertheless fascinating matter.  Further exploration of “endocrine cytokines” could provide more answers and new information about the physiopathology in multiple acute and chronic diseases, such as diabetes mellitus, metabolic syndrome, endocrine system diseases, hypertension, immune system disorders, hematopoietic system disorders, obesity, and the influence of cytokines on the circadian rhythm and their production in physical exercise.


Data examination

The Hypothalamic – Pituitary – Adrenal axis is a particularly intricate complex, with their interaction as feedback.  This axis and the interaction of the three, compose the neuroendocrine system, defining and regulating the responses of many biological procedures of the organism, including stress mechanism, metabolism, defensive system, affect, emotions, sexuality and energy storage.

The Hypothalamic – Pituitary – Adrenal (HPA) axis, the Hypothalamic – Pituitary – Gonadal (HPG) axis, the Hypothalamic – Pituitary – Thyroid (HPT) axis and the Hypothalamic – Neurohypophyseal system, form the four neuroendocrine systems, through which the hypothalamus and the pituitary,  guide and perform the neuroendocrine functions.

The endocrine system is formed by many glands, which are dispersed through the whole body, and produce and release hormones with diverse chemical structure, neuroamines, peptides and steroids.  Hormones are involved and regulate infinite physiological procedures, and have biological action in almost all the cells of the organism.  Potentially, these neuroendocrine axes are involved, through the cytokines and other proinflammatory factors, and play an important role in the pathophysiology and the development of a hyperreaction of the immune system and the evolution of the disease, triggered by coronavirus infection, and this should be further investigated.

Another axis, the immunoadrenal axis, might play a major role in the pathophysiology of the disease, as it is shown from the detailed analysis of the current international bibliography.

The immunoregulation and the immune response of the organism are extremely complicated procedures, in which many mechanisms, many systems and many biological, endocrine and metabolic pathways are involved.

We will try to explain, as plainly as possible, what is the contribution of the endocrine system, as well as the central nervous system, in the immune response and its modification.  We do not know exactly, whether and how the endocrine factors of the hypothalamus and the pituitary are involved in the development and the function of the immune system, and if this involvement is direct or through prohormones, and how this system functions in detail.  Though, we are aware from various researches that the hormones of the hypothalamus and the pituitary intervene in the multiplication and function of the immune system’s lymphocytes, which are located in the thymus, lymph nodes, spleen, tonsils and the hematopoietic system.

Various researches have shown that the multiplication of T-lymphocytes, e.g. the production of immunoglobulin by plasma cells, is hormone dependant.  Many disorders, hematological and immunological, seem to be influenced by and to influence the changes in endocrine homeostasis.

The question is whether there are receptors, in the lymphocytes or other cells of the immune system, on which there is a direct or indirect action of hormones, but mainly of prohormones, such as the growth factors.

Almost certain is the fact that the endocrine system regulates and modifies the immune response of the organism.  The cooperation of the nervous, endocrine and immune systems is extremely important in the investigation and treatment of many infections, as well as of other chronic diseases.

Probably, it is the action of not only one particular hormone, but also of a series of prohormones, which influence directly or indirectly the immune response cells’ function and the mechanisms used by the organism to deal with invaders and external factors (viruses, bacteria, various antigens), as well as with internal factors.  Various researches, in recent years, indicate and sustain that there is an important correlation and cooperation between the immune system and the neuroendocrine system.

The followed and used procedures, pathways and means of communication, are multiple and complicated.  Various researches demonstrate that the transmission of data from the immune system to the neuroendocrine system is performed through various substances, such as prohormonal factors and cytokines.

However, the transmission is performed through the afferent fibers of the vagus nerve, meaning that there is an involvement of the autonomous nervous system.

The immune and the neuroendocrine systems seem to have a common chemical and biochemical language and to use receptors, growth factors, connections, neuropeptides, neurotransmitters, neuroendocrine hormones and cytokines.

This means that various brain functions perform as immunoregulatory factors and are involved in the immune response.

It seems that many endocrine functions, as well as nervous system functions, perform as immunoregulatory agents and are involved in the responses of the immune system.

There is information about several hormones, such as the growth hormone IGF1, the thyroid-stimulating hormone, the prolactin, the ACTH, the cortisol.  Further exploration of the relations between the endocrine system and the immune system, seems to be extremely important.

New researches would provide more answers for both systems, mainly about their cooperation at the cellular level.  We should emphasize that this communication between the systems is also activated when inflammatory procedures are created or exacerbated by prohormonal cytokines, which antagonize the function of various hormones.  Additionally, it is known that homeostasis, during an infection, can occur from the balance between cytokines and endocrine hormones.

Regarding the over-secretion of Interleukin 6, which occurs as a storm in severe cases of COVID-19, no full explanation has been given yet.  A possible explanation is that part of the virus might function as a superantigen and as a result might stimulate a tremendous amount of macrophages and other cells of the immune system, such as T-lymphocytes, and cause over-secretion of cytokines, chemokines and growth factors, as well as a hyper-amplification of the whole biochemical communication between the cells and the immune response.

It seems that, in COVID-19, there is a massive over-secretion of cytokines, a massive cellular destruction and fibrosis.  The CD receptors of lymphocytes seem to play a main role, along with the histocompatibility system.  We will not mention, in this article, other potentially involved pathways.