What Does SARS-CoV-2 Do to Our Body?

The motivation for this article sprouts not just from scientific curiosity, but also from a broader appreciation that we humans are more interconnected with our natural environment and our animal peers than we sometimes are aware of.

Therefore, a deeper understanding with respect to the impact SARS-CoV-2 is having on our body carries the potential to get us thinking more profoundly about those interconnections as well as galvanize us into embracing the concept of One Health.

A One Health approach basically handles health issues in a manner that is characterized by diversity: it incorporates a broad range of expertise and insights from its three core pillars — human health, animal health, and the environment — into one strategic action plan.

The usefulness of One Health in the particular context of the COVID-19 pandemic is for instance brought to the fore in a recent panel discussion by the Ontario Veterinary College (University of Guelph, Canada).

Let us now turn to the focus of this article, which is to reflect upon what science has been able to reveal so far in dealing with the virus’ behaviour when it enters and thrives within a human body.

SARS-CoV-2: Who Are You?

As part of the Coronaviridae family, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly discovered virus that causes the respiratory illness Coronavirus Disease 2019 (COVID-19).

Relying on bioinformatic approaches, such as genome sequencing, researchers suggest that SARS-CoV-2 has most likely been transmitted from a horseshoe bat. But whether there was an intermediate animal host that facilitated the viral transfer to humans is still up for debate.

Until December 2019, we were aware of six viruses of the coronaviridae family that nestle within human beings: SARS-CoV, Middle East Respiratory Syndrome (MERS) coronavirus, HCoV-OC43, HCoV-NL63, HCov-H229E, and HCoV-HKU1. SARS-CoV-2 has now taken up position number seven on that list.

In comparison with the coronaviruses SARS-CoV and MERS-CoV, SARS-CoV-2 shows a genomic similarity of 80% and 62%, respectively. It is this intimate genetic relationship that explains the resemblance in the name of the novel virus.

Fig. 1. (a) SARS-CoV-2 virus (Source: Scripps); (b) SARS-CoV virus (Source: JPMS); (c) MERS-Cov virus (Source: University of Minnesota).

In terms of size, SARS-CoV-2 is a spherically-shaped virus that is 80 times smaller than a red blood cell, and you could fit circa 1,000 of them side by side across the width of a human hair.

What is more, SARS-Cov-2 is an RNA (ribonucleic acid) virus, meaning that it transports RNA as genetic material instead of DNA (deoxyribonucleic acid). Other examples of RNA viruses include influenza virus, measles virus, Ebola virus, rabies virus, and MERS-CoV.

The problem with RNA viruses lies in the fact that, upon infection, the process of protein synthesis in our cells — which is based on RNA specifying which amino acids must link up to form proteins — is unable to distinguish between regular and viral RNA. That is to say, once infiltrated, the intruder hijacks these vital cell metabolic mechanisms so that it can get replicated and distributed within our body.

But how do we get infected in the first place?

In the outer shell of the virus — called the viral envelope — we find the spike glycoprotein S which the virus uses to bind to its target cell, e.g. a human lung cell. When SARS-CoV-2 enters our body, the spike protein seeks to fasten itself to an explicit kind of receptor sticking out of the target cell’s membrane, i.e. the angiotensin-converting enzyme 2 (ACE2) receptor. SARS-CoV operates similarly, only less efficiently than SARS-CoV-2.

Fig. 2. SARS-CoV-2 binding its S protein to an ACE2 receptor of a human lung cell. (Source: adapted from OpenHeart).

The S protein is split up in two subunits: S1 and S2. In a first step, S1, by means of a receptor-binding domain (RBD), couples S2 to a certain area of the ACE2 receptor (the peptidase domain).

Following that, subunit S2 gets activated to fulfill its role of fusing the host cell’s and the virus’ membrane — a process that is supported by the transmembrane protease serine-type 2 (TMPRSS2) protein. It is this merging process that enables the viral entry into the target cell.

After successful intrusion, SARS-CoV-2 can now release its viral RNA content into its host cell, thereby inducing RNA replication and reproduction of the virus.

The Human Body

The reason why multiple organs can be affected by SARS-CoV-2 is thought to be due to the omnipresence of ACE2 receptors in our body — the main entrance mechanism for this new virus. For example, researchers Aileen Pogue et al. recently identified their presence in the heart, lungs, liver, kidneys, eyes, blood vessels, the gastrointestinal tract, and the brain (specifically, in the amygdala, the cerebral cortex, and the brainstem).

Scientists Hao Xu et al. come forward with a similar picture of ACE2 scattered throughout the body, albeit slightly more pervasive (see Fig. 3).

Fig. 3. Expression of ACE2 in various organs throughout the human body. (Source: Paper Hau Xu et al.).

But regardless of the manifestation of ACE2 receptors, do we know whether SARS-CoV-2 has actually been detected in these organs? And if so, what havoc does it wreak on the respective organ?

At this point, it is worthwhile to heed the skeptical words of cardiologist Anish Koka: “[I]t’s vital to understand that it’s not unusual to find widespread organ dissemination of virus in very sick patients. This does not mean that the virus is causing dysfunction of the organ it happens to be found in”.

With that skepticism in mind, let us now explore the inner parts of our body in greater detail. As we already know that SARS-CoV-2 takes its toll on the lower respiratory tract of the lungs, this article retains its focus on less well-known facts about a number of other organs in our body, namely the heart, the brain, the kidneys, the gastrointestinal tract, and the liver.

Our Pumping Heart

Last month, two studies appeared, signaling that SARS-CoV-2 had been spotted in the heart’s muscle cells (cardiomyocytes) of six adults from Milan, Italy, and of one 11-year-old girl from Brazil.

In the case of the child, viral particles were additionally disclosed in other parts of the heart, notably in the walls of blood vessels and heart chambers (endothelial cells), in connective tissue (fibroblasts), and in white blood cells (inflammatory cells, including macrophages and neutrophils).

Concerning the adults in Milan, reported damage to the heart tissue involved the absence of cell death (apoptosis, the death of cells, is usually a natural process when they need to be replaced by new ones), growth in cell volume, and the build-up of fluid within cells (intracellular edema).

Only the girl passed away as a direct consequence of cardiac dysfunction, whereas the other six patients died from respiratory failure.

Fig. 4. The white arrows in (b) point to the presence of the actively transcribed virus (SARS-CoV-2 antisense RNA) in cardiomyocytes of a COVID-19 patient, versus (a) a healthy individual. (Source: adapted from news-medical.net).

According to Marisa Dolhnikoff et al., the inflammation of the child’s heart muscle — a condition called myocarditis — and the subsequent heart failure have probably been provoked by “the direct effect of SARS-CoV-2 infection on cardiac tissue” instead of being the secondary result of an overreactive immune system.

Notwithstanding the viral infection of the heart, some caution must be applied to causally connect SARS-CoV-2 to heart failure, as “[w]e do not know yet the relative contribution of the inflammatory cells invading the heart, the release of blood-borne inflammatory mediators, and the virus inside the heart muscle cells themselves to heart damage,” says Michael Gibson, MD.

Indeed, as Diana Lindner et al. point out in their autopsy study on 39 patients from Germany: “[T]he presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis.”

Still, research by Paola Songia et al. conveys that roughly 20% to 40% of hospitalized COVID-19 patients develop symptoms stemming from heart damage, such as chest discomfort, arrhythmias, palpitations, and cardiogenic shock.

Fig. 5. Grey text: human tissues that express ACE2 protein. Black text: clinical consequences of viral infection. (Source: Paper Paul MacDaragh and Noel Caplice).

Not only that, Qiurong Ruan et al. examined 68 deceased patients in Wuhan, China, and concluded that the cause of death could in 40% of the subjects be (partially) traced back to myocarditis. Other incidents of myocarditis-related deaths comprise a 16-year-old male from Italy, a 17-year-old male from the United States, a 35-year-old male from France, and a 63-year-old male from China.

And even if infected individuals do recuperate, it might not be uncommon for cardiovascular irregularities to manifest over a longer period of time, argue Ahmed Goha et al., since the prospective outlook of COVID-19 could be similar to the SARS-CoV outbreak in 2002, whereby adverse long-term effects materialized in 40% of the recovered patients over a period of 12 years.

Our Electrified Brain

Although the experimental evidence of SARS-CoV-2 appearance in the brain remains rather scant, a couple of researchers have ventured into probing what sits beneath our cranium.

For one, scientists Maja Lindenmeyer et al. put forward some findings indicating that SARS-CoV-2 RNA has been detected in the brain of up to 38% of their autopsied COVID-19 patients. Further, a study by Shamik Bhattacharyya et al. has revealed low levels of the viral nucleocapsid protein — an RNA-binding protein initially located within the body of the virus — in brain tissue samples from the medulla oblongata (brainstem), the frontal lobe, and the olfactory nerve.

Regarding the frontal lobe, Clare Bryce et al. have gathered additional data, highlighting viral particles in endothelial cells.

Fig. 6. Schematic of the cerebral hemispheres. Parts encircled in red are places where SARS-CoV-2 have been identified, according to the mentioned studies. (Source: adapted from antranik).

More recent research by Akiko Iwasaki et al. directly observed the SARS-CoV-2 spike protein in the subcortical white matter — the brain tissue beneath the superficial layer of our cerebrum, i.e. cerebral cortex (see Fig. 6) — and in the blood-brain barrier (endothelial cells).

Even the cerebrospinal fluid, which surrounds the brain and spinal cord, is harbouring the virus. One piece of evidence comes from unpublished data of a patient in China, who was treated by Jingyuan Liu, and a second piece originates from a study by Takeshi Moriguchi et al.

Despite the evidence at hand, the available information is, by and large, scarce. Scientists, such as Yan-Chao Li et al., therefore continue to amass data on SARS-CoV-2’s ability to affect the brain as well as its potential role in the acute respiratory failure witnessed in COVID-19 patients.

In the meantime, several researchers conduct laboratory experiments to better understand the virus’ neurological impact. As a case in point, the work by Hin Chu et al. shows how lab-grown human neural progenitor cells — in the central nervous system, these cells perform similar duties to stem cells and transform into many of the glial and neuronal cell types — and brain tissue allow for SARS-CoV-2 infection and replication.

Fig. 7. Images of unaffected regions (left) and infected regions (right) demonstrating infection of neurons (top row) and microvasculature (bottom row). (Source: Paper Akiko Iwasaki et al.).

According to Silvia Natoli et al., 34% of hospitalized COVID-19 patients exhibit neurological manifestations, namely the loss of smell (anosmia), loss of taste (ageusia), or brain inflammation combined with internal bleedings and death of tissue (necro-hemorrhagic encephalitis).

In another study by Ling Mao et al. involving 214 patients, that number slightly rises to 36.4%. But when only considering the more advanced stages of infection, the fraction of patients displaying neurological implications reaches 45.5%. Some of the expressed symptoms of those patients consist of skeletal muscle injury (19.3%), impaired consciousness (14.8%), and acute cerebrovascular diseases, e.g. stroke, (5.7%).

To add to the list of neurological symptoms, Ross Paterson et al. have documented brain-related illnesses (encephalopathies) with psychosis (23.3%), inflammation of both the brain and the spinal cord (acute disseminated encephalomyelitis, 20.9%), and damage to the nerves in your shoulders (brachial plexopathy) in one of the 43 cases.

And Takeshi Moriguchi et al. tack on one more to the list: they describe the first event of a patient with inflammation of the membrane around the brain and spinal cord (aseptic meningitis).

Such studies illustrate that encephalopathies, albeit not widely reported, do arise in COVID-19 patients. What is more, even rare complications now start to make an appearance: one female airline worker in her late fifties contracted acute necrotizing encephalopathy, and a 61-year-old woman developed the Guillain-Barré syndrome. With regard to the latter disease, Ross Paterson et al. diagnosed six more individuals.

Be that as it may, what currently remains an open question is whether the neurological symptoms are the outcome of either a viral infection or an overstimulated immune system fighting off the virus.

Our Filtering Kidneys

In a study by Fabian Braun et al. — which links SARS-CoV-2 infection to disease severity — the presence of viral RNA in the kidneys of patients with acute kidney injury (AKI) was established in 72% of the subjects. Scientists Victor Puelles et al. furthermore identified in 62% of their patients both the spike protein S and contaminated RNA, predominately accumulated in the kidney’s glomeruli and tubules (see Fig. 8).

After carrying out an autopsy on six COVID-19 patients, researchers Huiming Wang et al. singled out virions — a virion is an entire virus particle — distributed across all of the examined kidney tissues, with nucleocapsid proteins (SARS-CoV-2 particles that play a part in viral replication through virion assembly) concentrated in the renal tubules (the part of the kidneys where the filtered fluid is either absorbed or secreted).

Fig. 8. Schematic of the renal tubules. It also shows the microvilli, which as a whole make up the brush border of the proximal tubule (3rd box from the top on the right). (Source: antranik).

In addition, in 78% of the executed autopsies, Hua Su et al. affirmed the existence of viral particles in both the proximal tubular epithelium (part of the renal tubules, see Fig. 8) and the outer cells of the glomerular capsule (podocytes, see Fig. 8 & 9).

The emergence of SARS-CoV-2 in the kidneys can result, among other pathologies, in acute tubular necrosis — the death of cells that make up the inside surface (epithelium) of the renal tubules — which eventually leads to AKI, in infiltration of white blood cells (lymphocytes and macrophages) into a certain region (tubulointerstitium), in luminal brush border sloughing — the degradation of microscopic fibers (microvilli) on the inside surface of the membrane of epithelial cells lining the proximal tubule (see Fig. 8 & 9) — in the swelling of cells (vacuolar degeneration), and in the fusion of multiple cells (syncytia).

Fig. 9. Schematic of possible mechanisms of kidney injury by SARS-CoV-2. Left image: the podocytes of the glomerular capsule. Right image: the proximal tubular epithelium. (Source: Paper Norma Bobadilla et al.).

Daniel Batlle et al. remind us that, within our kidneys, the ACE2 receptors of target cells — the main binding site for SARS-CoV-2 — chiefly spring up in the brush border of the proximal tubule, which could explain the brush border loss upon viral infection. Backed up by direct experimental evidence, researchers Leila Belkhir et al. as well as Evan Farkash et al. corroborate this specific viral targeting of the proximal tubular epithelium.

All the above findings underpin the hypothesis that the kidneys also qualify as a site of viral infection and replication.

Fig. 10. SARS-CoV-2 nucleocapsid protein (NP) antigen in kidney tissue. (A) Arrow indicates NP positive tubules, and arrowhead indicates viral inclusion body; (B) Arrow indicates viral NP positive cells dropped from normal tubule; (c) Arrow indicates NP positive cells, and circle indicates glomerulus. (Source: Paper Bo Diao et al.).

The figures relating to the occurrence of AKI vary from study to study. For instance, in the case of Fabian Braun et al., 82% of the 39 deceased COVID-19 patients with an established clinical kidney status were diagnosed with AKI, whereas the scientists Huiming Wang et al. uncovered a 27% prevalence of AKI among 85 patients.

Based on study reports and autopsy series, Bethany Lucas et al. point out that the principal explanations for AKI in the context of COVID-19 encompass loss of body fluids (hypovolemia), alterations in blood flow (hemodynamic changes; angiotensin II pathway activation), injury to the kidney tubular cells due to viral infection, multi-organ failure (cytokine storm), breakdown of the kidney filtering mechanisms (glomerulopathy), blood-clotting (thrombotic vascular processes), and the discharge of muscle fiber contents into the bloodstream (rhabdomyolysis).

In other words, even though direct viral infection by SARS-CoV-2 can lead to kidney injury, it is by no means the only cause thereof.

Fig. 11. Targeting of ACE2 by SARS-CoV-2 results in angiotensin dysregulation, innate and adaptive immune pathway activation, and hypercoagulation to result in organ injury and acute kidney injury (AKI) associated with COVID-19. Organ crosstalk between the injured lungs, the heart, and the kidney may further propagate injury. ATN: acute tubular necrosis. (Source: Paper Maria Jose Soler et al.).

Our Digestive Gastrointestinal Tract

As per one study by Lei Mai et al., fecal samples of COVID-19 patients with and without gastrointestinal (GI) symptoms returned a positive test result for SARS-CoV-2 in 52% and 39% of the cases, respectively. In two severely ill individuals, viral RNA was found simultaneously in the esophagus, stomach, duodenum, and rectum — results that were equally confirmed by Hong Shan et al. for a larger number of patients.

Contaminated RNA was also detected in the stool specimen of the first reported instance of COVID-19 in the United States, and in that of 53% of hospitalized patients, as mentioned by the authors Hong Shan et al. In the latter study, 23% of the patients continued to test positive, even when the respiratory tissue samples came back negative.

Fig. 12. The gastrointestinal (GI) tract contains the oral cavity, the pharynx, the esophagus, the stomach, the small intestine, and the large intestine (colon). (Source: anatomyofthehumanbody).

These scientists furthermore observed that both the ACE2 and the viral nucleocapsid protein are present in the glandular cells of duodenal, rectal, and gastric epithelia, but almost nonexistent in the esophageal epithelium.

At the same time, Hao Zhang et al. discerned a relatively high expression of ACE2 in the esophageal upper epithelial and gland cells as well as in the final part of the small intestine (ileum).

As a side remark, although the enzyme ACE2 basically turns up in all organs, it is the pattern of ACE2 protein expression (the production of proteins) that is not fully understood, but nevertheless essential to viral infection. Fig. 13 depicts what science understands so far with reference to ACE2 expression in the human body.

Fig. 13. ACE2 expression in organs and systems most frequently implicated in COVID-19 complications. (Source: TheNewNeanderMedical).

In light of the high binding affinity of SARS-CoV-2 to ACE2, it is noteworthy to point out in the context of the intestines that, according to Wei Li et al., ACE2 expression occurs mostly in the epithelial cells of the small intestine (enterocytes) and in the vascular smooth muscle cells as well as in the endothelium of the large intestine (colon). Hao Zhang et al., in contrast, also find ACE2 expression in colonic enterocytes.

In addition, Qianming Chen et al. maintain that the inner lining of our mouth (oral mucosa) is another location in the GI tract where ACE2 expression is active. But ACE2, the authors assert, would be especially enriched in the tongue’s epithelium.

In any case, ACE2 expression levels throughout the GI tract are on average higher compared to the lungs, which is in line with the research done by Hao Xu et al. (see Fig. 3).

All in all, because viral particles have been identified in stool samples, this novel virus appears to possess the ability to replicate in the GI system, due to the ACE2 presence therein. In the words of Hao Zhang et al.: “[The above] observations suggest that SARS‐CoV‐2 actively infects and replicates within the GI tract, implying a possible role for a faecal–oral viral transmission route.”

Fig. 14. Immunohistochemical images of ACE2 expression in different tissues. (Source: Paper Hao Zhang et al.).

While Qin Yan Gao et al. claim that GI symptoms in COVID-19 patients, as for example diarrhea, nausea, and vomiting, are not very common (between 1% and 10%), one study stands out with a particularly high occurrence of diarrhea (24%), anorexia (17.9%), and nausea (17.9%).

The research by Jiabin Xu et al. provides us with an additional case of high incidence of GI symptoms (29%), more specifically pain in the pharynx (pharyngalgia, 50%), diarrhea (21.4%), anorexia (21.4%), and nausea (7.1%).

In fact, committed to pursuing a meta-analysis covering 60 studies and 4,243 infected patients, Ka Shing Cheung et al. noticed an overall prevalence of GI symptoms of 17.6%.

Again, to pinpoint the exact explication of these symptoms is subject of ongoing research, making it for now difficult to tell whether viral infection is the main culprit or whether a SARS-CoV-2-induced amalgamation of triggers is to blame.

Our Detoxifying Liver

Within the liver, SARS-CoV-2 bears a high affinity with cholangiocytes — epithelial cells lining the bile duct (biliary cells) which contribute to liver regeneration, immune responses, and the secretion of bile (this fluid eventually passes through the pancreas into the duodenum of the small intestine to support digestion).

What lies at the basis of that targeted preference is the greater expression of ACE2 receptors in cholangiocytes relative to hepatocytes — these cells constitute 80% of the liver’s mass and are its key functional cells.

Xiaoqiang Chai et al. have demonstrated this inclination towards cholangiocytes by dissecting 4 healthy liver tissues: ACE2 expression was discovered in 59.7% of these biliary cells — approximately the same range as for the type II alveolar cells in the lungs — versus 2.6% of the hepatocytes.

Fig. 15. Left: the bile duct system. Right: hepatocytes and cholangiocytes within the liver. (Source: cancer.org and Paper Jesus Banales et al.).

Linking up the liver to the GI tract, Tobias Boettler et al. remark that viral infection of cholangiocytes may be the reason for finding SARS-CoV-2 particles in fecal samples (see the previous section “Our Digestive Gastrointestinal Tract”).

Though Lena Allweiss et al. indicate that traces of SARS-CoV-2 RNA can be spotted in up to 77% of COVID-19 patients, data disclosing direct evidence of viral liver infection seem to be slim at this point.

As regards contaminated RNA, Shu-Yuan Xiao et al. and Holly Harper et al. have distinguished low levels of the viral genetic material in biopsy specimens of liver tissues of just one deceased patient. And somewhat surprisingly — given the virus’ strong rapport with cholangiocytes — Yijin Wang et al. have tracked down plentiful viral particles in hepatocytes.

Fig. 16. Detection of SARS-CoV-2 particles in hepatocytes (black arrows). (Source: Paper Yijin Wang et al.).

On the whole, damage to the liver affects between 14.8% and 78% of COVID-19 patients and usually occurs at an advanced stage of the disease.

To determine the general health of our liver, liver function tests measure the level of a number of enzymes and proteins, such as alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP), as well as bilirubin — a chemical compound released during the death of red blood cells and transported to the liver.

For instance, in one study whereby 37.2% of the patients suffered liver injury, Jilin Cheng et al. noted that the fraction of the patients that unveiled elevated levels in the liver function tests stood at 21.6% (AST), 18.2% (ALT), 17.6% (GGT), 6.1% (bilirubin), and 4.1% (ALP). (For more clinical test results, see, e.g., Ying Huang et al., Li Zhang et al., Nan-shan Zhong et al., or Bo Hu et al.).

Fig. 17. Possible explanations for liver injury in COVID-19 patients. ALT: alanine transaminase; GGT: gamma-glutamyl transferase; MCP1: monocyte chemoattractant protein 1. (Source: Paper Katie Morgan et al.).

While “ACE2 expression in cholangiocytes may suggest a potential mechanism of infection and direct damage of bile ducts”, say Xiaoqiang Chai et al., liver injury is most likely the result of a combination of causes, including viral infection, drug-induced liver damage, diminished blood supply (hypoxia), and small blood clots (microthromboses).

Moreover, G.W. Guan et al. have proposed that liver injury by viral infection continues to manifest when cholangiocytes repair the liver — they do so by creating hepatocytes — since their feature of higher ACE2 expression is to some extent passed on to the hepatocytes. This could clarify why Yijin Wang et al., against all odds, came across an abundance of viral particles in hepatocytes.

The importance of the bile duct in COVID-19 is further endorsed by the research of Bing Zhao et al., in which they have shown that lab-produced human liver ductal organoids — simplified versions of the original organ — are susceptible to SARS-CoV-2 infection and replication.

A Balancing Act in the Making

The article started off with the assumption that a greater awareness of SARS-CoV-2’s role in the human body might excite our appreciation for the relevance of a One Health approach, in which animal health, human health, and our natural environment are all taken into account to address global health issues.

Whether or not that excitement is taking root in your brain, the fact remains that SARS-CoV-2 is teaching us how delicate the balance is between the habitats of people, animals, and nature in general.

What we do with that understanding from here on out is entirely up to us.

---

Back to Articles