The basic structure of a virion consists of a piece of nucleic acid surrounded by a protein capsid [17]. Currently, the human virome is the most recently studied part of the human microbiome, but knowledge and research technology in this area are limited [18]. Distinctive viromes have been identified in the gastrointestinal tract, salivary glands, and respiratory tract. However, it is unclear which viruses have detrimental or beneficial effects on human health, and the molecular and physiological mechanisms of these effects are unknown. Whether a virus is harmful or harmless can depend on the immunological status and health of the host [19].

An analysis of the transcriptomic architecture of SARS-CoV-2, which analyzes how the genes of the coronavirus are translated from a single strand of ribonucleic acid (RNA), found that the shortened tails of the virus might represent aged and decay-prone RNA (as in disposable genetic waste products), similar to the type of RNA generated by the mitochondria [20]. Mitochondria organelles in cells contain their own disposable mitochondrial deoxyribonucleic acid (mtDNA), which is densely packed in nucleoids, separate from the genes in the cell nucleus [21]. The tight density of mtDNA packing is similar to the density of DNA tightly packed into the capsid of a papillomavirion [22]. The turnover of mtDNA has a relatively brief half-life, and degraded mtDNA may be abandoned without noticeable physiological harm to the mitochondria. Mammalian somatic cells can contain up to 2000 mitochondria per cell [23], with each mitochondria potentially contributing genetic waste products. Additionally, bacteria in the microbiome contain chromosomal DNA packed in a nucleoid [24], which can also contribute to genetic waste when the cell expires.

Cells have waste removal and recycling mechanisms that manage genetic waste products [25]. Proteins labelled with ubiquitin are targeted and broken down by proteasomes for reuse in synthesizing new proteins. Lysosomes contain digestive enzymes to breakdown organelles and viruses during the process of autophagy, and collected piles of unwanted cellular trash form aggregates, which might explain the formation of viral aggregates [26]. Extracellular vesicles (EVs) are also formed, and cargo is loaded and released by cells to function as a waste management mechanism that removes intracellular debris [27]. In pathological conditions, EVs may not clear promptly from circulation, contributing to the underlying pathology.

Some EVs may resemble the structure and function of viruses, carrying viral proteins and genome fragments that make these EVs indistinguishable from “noninfectious” or “defective” viruses, which do not fit the prevailing definition of infectious viral agents that multiply exclusively in living cells [28]. Genome fragments in EVs include discarded messenger RNA (mRNA), a genetic messenger molecule [29]. Importantly, both nuclear and mitochondria mRNA undergo degradation after having been translated during protein synthesis [30,31], and very small EVs called exosomes have been found to transport mostly mRNA fragments [32].

Evidence of the role played by noninfectious viruses in pathogenesis is considered “very limited” and “obscure” by textbook authors writing on virus replication [33]. However, the biological process of natural infection is much more complex than the oversimplified depiction in textbooks. For example, even though noninfectious viruses make up most of the viral population in influenza A infection, the range of biological activity attributed to noninfectious viruses, including self-aggregation, has been understudied and “does not necessarily imply a defect of any kind” [34]. Furthermore, nucleic acid detection of high viral loads in clinical specimens collected during a pandemic cannot distinguish between noninfectious viruses and viruses that are assumed to be proliferating, nor is detection of viral RNA in specimens always correlated with viral transmissibility [35].

An infectious virus is claimed to hijack a host cell’s DNA reproductive mechanisms in order to translate the virus genome and replicate the virus [38]. However, the genetic code in the mRNA, which is a transcribed message destined for delivery to the ribosomes, can only be used to translate the biogenesis of harmless proteins needed by the cell. Translation of the coded genetic message in mRNA fragments does not replicate the mRNA itself, making the fragments noninfectious. Similarly, RNA in SARS-CoV-2 contains 29,811 nucleotides that encode 29 proteins, most of which are unrelated to the structure of mRNA itself [39], implying that the virus, composed of noninfectious mRNA fragments, is itself noninfectious. If true, this further implies that SARS-CoV-2 cannot replicate within a host. The presence of noninfectious viruses could also explain why viral RNA is detected in a host even if a viral infection is not present [40]. In addition, mutations claimed to occur in influenza viruses are reassortments of RNA fragments, often packaged in groups of eight fragments, and more knowledge of the mechanisms in genome packaging is needed [41]. Furthermore, single virions are rarely sufficient to establish infections, and the dispersion of multi-virion structures in infection remain poorly understood, needing more study in this area of virology [42].

EVs, including apoptotic bodies, exosomes, and microvesicles, are also responsible for the transmission of biomolecules in the development of sepsis [43]. Viral sepsis has been proposed as a critical immunopathological mechanism in COVID-19, based on findings of significantly elevated levels of cytokines, chemokines, and other immunological response agents in COVID-19 cases—part of a cytokine storm often seen in severe influenza infections [44]. Sepsis from infection is a complicated syndrome of pathophysiological mechanisms that are not yet fully understood. A little less than half of sepsis cases have non-bacterial causes, and viral sepsis is more often seen in immunosuppressed patients [45].

The above evidence raises the intriguing possibility that SARS-CoV-2 may be associated with endogenous genetic waste products. By contrast, no causal evidence supports a zoonotic transmission of exogenous viruses in COVID-19 [46]. About half of COVID-19 cases reported diarrhea and digestive symptoms in Wuhan, Hubei Provence, China, where SARS-CoV-2 was first detected in wet markets [47]. Gastrointestinal symptoms are highly unusual and inconsistent with the low amount of these symptoms in patients with severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) [48]. Although gastrointestinal symptoms are associated with the consumption of wild animal products [49], there is no causative evidence linking exposure to wild animal products and zoonotic transmission of SARS-CoV-2 from bat SARS-related coronavirus (bat SARSr-CoV) [50]. Of relevance, a study of Dietary Approaches to Stop Hypertension (DASH) found that a high dietary sodium intake was associated with a 27% increased risk of gastrointestinal bloating, compared with a 41% increased risk of bloating associated with a high dietary fiber intake [51]. Bloating from high dietary sodium was independent of dietary fiber intake in the study.

Briefly summarizing the reviewed evidence so far, there are many unknowns in the field of virology that require further investigation. Reviewed evidence in this article supports the mechanisms that excrete and transport endogenous waste products that have the potential to contribute to infectious disease pathophysiology. Of particular interest, viral infections are established by virion aggregates, not single virions, and viral aggregates may form from the undisposed waste products of cells. Furthermore, testing is insufficient to provide proof that the detection of viral RNA in specimens always correlates with viral transmissibility and viral proliferation in ILIs. The remaining sections of this article synthesize the transdisciplinary evidence from virological, immunological, pathophysiological, and epidemiological determinants, linking the molecular mechanisms of sodium toxicity with COVID-19.

Most viral infections are associated with other disease-causative agents, in addition to the viral infection itself [52]. Evidence suggests a somewhat independent relationship may exist between a viral infection and disease-causative agents. For example, a weak presence of disease-causative agents could explain why asymptomatic people with detected exposure to SARS-CoV-2 infections do not develop clinically significant disease symptoms. Conversely, a strong presence of disease-causative agents could explain why antibodies from SARS-CoV-2 infection alone may be insufficient to prevent severe disease symptoms in people who are reinfected with SARS-CoV-2 [53].

China and Italy were among the first countries to experience severe outbreaks during the COVID-19 pandemic. Hypertension was identified as a risk factor associated with severe cases of COVID-19 in China and Italy [54]. Of relevance, hypertension was found to be a risk factor associated with mortality in both the 2009 (H1N1) swine influenza pandemic [55] and the 2013 avian influenza A (H7N9) virus infection [56]. Hypertension risk is also associated with a high dietary sodium chloride intake [57], and China is among the highest consumers of sodium chloride in the world [58]. Almost half of the Chinese population between 35–75 years of age has hypertension, most of which is untreated and uncontrolled [59]. Italy also ranks high among consumers of sodium chloride [60], and hypertension prevalence in Italy affects up to 59% of the population over 18 years of age [61].

In addition, Italy has a large ageing population with underlying health conditions, associated with an increased case fatality rate in COVID-19 [62]. Further studies are needed to investigate the population sodium intake associated with severity of COVID-19 outbreaks by country or region. Other large countries with a high sodium intake include India, the United States, Australia, Canada, and England [63].

Cases of COVID-19 in the research literature have been associated with stroke [64], thrombosis [65], cardiac arrhythmias [66,67], obesity [68], diabetes [69], kidney disease [70], hepatic disease [71], multiple sclerosis [72], systemic sclerosis [73], migraine [74], tinnitus [75], Bell’s palsy [76], polycystic ovary syndrome [77], and pneumonia [78]. Incidentally, the coronavirus discovered in Wuhan, China, in December 2019 was first detected in cases of novel coronavirus-infected pneumonia (NCIP) [79]. Likewise, high sodium chloride intake and sodium concentration levels are risk factors associated with stroke [80], thrombosis [81], cardiac arrhythmias [82,83], obesity [84], diabetes [85], kidney disease [86], hepatic disease [87], multiple sclerosis [88], systemic sclerosis [89], migraine [90], tinnitus [91], Bell’s palsy [92], polycystic ovary syndrome [93], and pneumonia [94], providing clinical evidence that these diseases form a transitive link between COVID-19 and a high sodium chloride intake. Transitive inference is a comparative analysis tool described in the present author’s previous work [16]. Inferred transitive links are not strong enough to prove causation, but these links are useful for exploring unknown areas and identifying related subjects for further research. In addition, pediatric Kawasaki-like symptoms associated with COVID-19 have been reported, known as multi-system inflammatory syndrome in children (MIS-C) [95]. As in COVID-19, MIS-C and Kawasaki-like symptoms have also been associated with hypertension [96], stroke [97], acute heart failure [98], and acute kidney injury [99], transitively linking sodium toxicity to pediatric disease pathophysiology. Although other dietary, environmental, and lifestyle factors are relevant to the pathophysiology of COVID-19, numerous transitive links with COVID-19 suggest that sodium toxicity may be among the leading factors potentially contributing to the disease.

Excessive sodium intake leading to sodium toxicity exceeds the human body’s minimum requirement of 500 mg sodium needed to function properly [100], which can be provided from natural foods without added sodium chloride. Sodium chloride contains about 40% sodium by weight, and Americans consume excessive sodium, averaging 3300 mg a day [101]. Although sodium chloride is an ionic compound that dissolves into separate sodium and chloride ions in an aqueous state, electrolysis is required to overcome the electrostatic force connecting sodium and chloride ions in a brine solution, producing poisonous chlorine gas [102]. No evidence exists that electrolysis naturally occurs within the human body to convert sodium chloride to free sodium ions and free chloride ions for physiological functions, such as ion passage through individual ion channels in cell membranes that select only one type of ion [103]. In addition, observational studies claiming increased mortality associated with a low sodium intake were challenged for having research design flaws, such as selection bias from not excluding seriously ill patients, and information bias from poor data collection of the daily sodium intake [104,105].

When the body content of water and sodium are excessively high in edematous conditions, hyponatremia (serum sodium levels <135 mEq/L) is caused by dilution from an osmotic shift of water out of cells [106,107,108]. Called hypervolemic hyponatremia, this type of hyponatremia is often treated with diuretics and the restriction of fluids and sodium. Hypervolemic hyponatremia should be differentiated from other types of hyponatremia where the body water content is low, as in hypovolemic hyponatremia, and the water content is normal, as in euvolemic hyponatremia. Disconcertingly, out of a dozen recent articles reporting adverse outcomes and increased mortality in COVID-19 patients with hyponatremia [109,110,111,112,113,114,115,116,117,118,119,120], only two of the articles mentioned hypervolemic hyponatremia [115,119]. Moreover, none of the studies in the 12 articles stratified patients by hyponatremia type. Further research is needed to clarify the prevalence of hypervolemic hyponatremia associated with high water and sodium levels in COVID-19 patients. Of relevance, hyponatremia that occurs in syndrome of inappropriate antidiuretic hormone secretion (SIADH), also reported in COVID-19 patients [115], results from excess water rather than sodium deficiency [121].

Normally, excess sodium is excreted by the kidneys, with additional losses through the skin and gastrointestinal tract, but a high sodium chloride intake may overload renal nephrons with excessive pressure and volume, causing a decline in the glomerular filtration rate [122]. Burdened renal function is associated with impaired sodium excretion, as in chronic kidney disease [123], which may gradually increase the development of sodium toxicity in the body tissues. No specific level of sodium intake has been associated with sodium toxicity. However, according to the U.S. Department of Agriculture and U.S. Department of Health and Human Services’ Dietary Guidelines for Americans 2020-2025, the daily sodium chronic disease risk reduction limit for adults is 2300 mg [124], implying that daily sodium intake above this level may increase risk of toxic or pathogenic effects. Lethal dietary sodium levels for some adults (just under four tablespoons of sodium chloride) are almost twice the upper range consumed by some people in China [125]. Although evidence has not previously linked sodium chloride as an associated risk factor for infectious respiratory diseases like COVID-19, a high sodium chloride intake has been associated with severe noninfectious chronic respiratory diseases such as asthma [126] and chronic bronchitis [127].

Evidence associating sodium toxicity with thrombosis and stroke in COVID-19 patients is grounded in research findings linking thrombosis to elevated serum sodium in mice, mediated by vascular endothelial cell secretion of the blood-clotting factor, the von Willebrand Factor (vWF) [81]. Researchers have also found that elevated sodium chloride increases vWF secretion in vascular endothelial cell cultures, and analysis of the data from the Atherosclerosis Risk in Communities Study revealed that serum sodium is associated with plasma vWF and stroke risk.

The cells of the respiratory system are susceptible to infection through exposure to viruses and other pathogens; however, a non-specific innate immune response and an adaptive immune response eliminates viruses and protects respiratory cells from infection [128]. As part of the mucosal immune system, the nasal mucosa provides physical protection against dehydration and injury from mechanical and chemical agents, and provides the clearance of particles and microorganisms [129].

However, sodium toxicity adversely affects the nasal mucosal immune system, which may lead to respiratory viral infection. For example, hypertonic concentrations of 2% sodium chloride were used in vitro to experimentally induce ciliostasis, paralyzing cilia beating in the nasal mucosa epithelial cells, which normally transport the mucous out of the airways. When the epithelial cells were infected with influenza A virus, the viral yield in the saline-treated cells increased two- to three-fold compared with the untreated cells, demonstrating that normally beating cilia impede viral infection [130]. Although 2% NaCl in these experiments is 2-fold and 20-fold higher than normal extracellular and intracellular concentrations, respectively, findings may be translated bench-to-bedside for more moderate clinical applications. Specifically, moderately impaired function of the cilia caused by sodium toxicity could inhibit mucociliary clearance, leading to increased accumulation of viruses in patients’ nasal passages, as detected in laboratory analyses of nasopharyngeal swab specimens collected during COVID-19 testing [131]. COVID-19 patients were found to have prolonged mucociliary clearance compared with healthy ear, nose, and throat outpatients with non-nasal symptoms [132]. Furthermore, the upper nasal passages are a potential portal allowing viruses and other particles to enter the bloodstream, eventually leading to viral sepsis [44]. Of relevance, other research has found that an increased concentration of plasma sodium in the hypernatremia was significantly associated with sepsis in elderly patients [133]. This evidence could explain sepsis in COVID-19 patients associated with sodium toxicity [44].

No difference in viral load was found in asymptomatic infections of SARS-CoV-2 and infections with symptoms in Lombardy, Italy [134], and no viral load differences were found across patient gender, age, and disease severity in Guangzhou, China [135]. This evidence suggests laboratory confirmed viral infections of SARS-CoV-2 and clinical symptoms of COVID-19 may have separate causative pathways, which would explain why they do not always appear together. For example, asymptomatic infections occur without clinical symptoms [136], and clinical symptoms in post-acute COVID-19 syndrome persist after the acute infection stage subsides [137]. These facts support a hypothesis proposing that the association of COVID-19 and SARS-CoV-2 is mediated by a related disease determinant. On the other hand, compared with mild cases, the mean viral loads were 60 times higher in the nasal passages of cases associated with the most severe symptoms in Nanchang, China [138], which could be related to severely impaired viral clearance in the nasal mucosal immune system due to excessively strong sodium toxicity. Of relevance, the viral clearance was delayed and clinical outcomes did not improve when corticosteroids were used to treat SARS-1 patients [139], and corticosteroids cause retention of sodium [140]. Likewise, the French Health Ministry suggested that ibuprofen aggravates infection in COVID-19 [139], and non-steroid anti-inflammatory drugs (NSAIDs) like ibuprofen cause sodium and water retention [141].

Sodium chloride intake is associated with changes in immune responses that promote organ damage and inflammation, including increased release of inflammatory cytokines, like interleukin (IL)-6, macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor (TNF)-α [142]. Elevated sodium chloride concentrations also increase the proliferation of T-cells, while decreasing the anti-inflammatory responses—for example, anti-inflammatory M2 macrophages are suppressed while pro-inflammatory M1 macrophages are increased by high sodium chloride levels. Furthermore, sodium chloride was found to enhance the production of IL-4 and IL-13, and to suppress the production of interferon-γ (OFN-γ) in memory T cells [143]. Interleukin-17 (IL-17)-producing helper T cells (Th17) play a role in clearing the extracellular pathogens, and Th17 cell development is induced by a kinase signaling pathway activated by high sodium chloride concentrations [144].

Researchers have reported that a “high-salt diet promotes skin Na+ accumulation, which boosts macrophage activation”, leading researchers to “speculate” that cutaneous sodium storage provides a barrier against infection [145]. However, researchers have also noted “that skin Na+ deposition is linked with disease in humans”. Alternatively, macrophage activation suggests an inflammatory immune response to salt-induced tissue damage, as “high-salt diets result in interstitial hypertonic Na+ accumulation in the skin and muscle that activates tissue-resident macrophages” [146].

The secretion of cytokines in response to RNA viruses, like SARS-CoV-2, include TNF-α and IL-6, with a general imbalance toward pro-inflammatory responses in contrast with antiviral responses [147], similar to the responses to sodium toxicity. Resilient T cell immunity is necessary for the efficient control of viruses, and T cell counts in COVID-19 patients with mild symptoms were found to be normal or a bit higher—again, an immune response similar to sodium toxicity. However, T cell counts were reduced in moderate and severe cases, suggesting that the T cell response is dysregulated in severe cases, possibly because of exhaustion from over-activation. This reduction in T cell counts could be related to severe sodium toxicity, and more investigations are needed in this area. Of relevance, human receptor angiotensin-converting enzyme 2 (ACE2) is a binding site for SARS-CoV-2, and ACE2 is found in the membranes of alveolar macrophage cells in the respiratory tract and in other cells throughout the immune system [148], potentially providing a protective mechanism that facilitates endocytosis and the lysis of pathogens. However, this protection could be compromised, as ACE2 expression is reduced under conditions of high sodium chloride dietary intake, as was found to occur in the renal system in animal experiments [149]. In addition, based on the studies of other human coronaviruses, humoral responses to coronavirus infection are comparatively short-lived and provide only partial protection from reinfection. Considering the failure to find a cure for coronavirus infections in the common cold after many decades of research [150], the potential for newly developed vaccines to eliminate the virus and its variants does not portend well [151].