Key words : Alloimmunity, Electromagnetic radiation, Exosome, Oxidative stress

Introduction

By the end of December 2019, an outbreak started in Wuhan, China, caused by a novel coronavirus. The Chinese Center for Disease Control and Prevention confirmed a report by the Wall Street Journal and announced identification of a novel coronavirus (SARS-CoV-2) on January 9, 2020.¹ The etiologic agent responsible for a cluster of pneumonia cases in Wuhan was identified as a novel betacoronavirus (in the same family as SARS-CoV and MERS-CoV) by next-generation sequencing from samples received from several pneumonia patients.^2-5 Shortly after, on January 21, 2020, an official announcement came from the World Health Organization (WHO), to what was a worldwide pandemic that resulted in considerable fatalities and global economic breakdown.^6-8 The rapid sequencing of SARS-CoV-2 or COVID-19 identified nearly 30 000 nucleotide bases that hold the genetic sequence of the virus.^2,5 When the whole genome is examined, the novel virus maintains ~80% nucleotide identity to the original SARS epidemic viruses.⁹ When compared across the many deposited COVID-2019 strains, a bat CoV sequence, RaTG3, was subsequently identified having >90% sequence similarity to the novel virus,¹⁰ which argued for bat origins for SARS-CoV-2. However, several reports later revealed that the COVID-19 pathogen has a genetic footprint that had never been observed in natural coronavirus, where the spike protein has a sequence known as “double CGG” (CGG-CGG) in a row that does not exist in nature for SARS-like viruses, suggesting that the “gain of function virus” might have been engineered in a laboratory.^5,11-13

A few months after the pandemic was declared, 10 vaccines entered phase 3 clinical trials in humans.^14-16 These vaccines employed different technologies, with the most innovative ones being from Pfizer-BioNTech’s BNT162b2 (US-Germany) and Moderna’s mRNA-1273 (US). They consisted of exosome-based technologies that include genetic materials such as messenger RNA (mRNA) encapsulated in lipid nanoparticles and delivered to a person through a regimen of 2 injections given 3 and 4 weeks apart, respectively. Other vaccines, such as AstraZeneca (UK-US), Johnson & Johnson (US), Gamaleya Research Institute of Epidemiology and Microbiology, Sputnik V (Russia), and CanSino Biologics (China) used different types of adeno-viruses as vectors to deliver the spike protein or used inactivated viruses (traditional vaccine) developed by several Chinese pharmaceutical companies like Sinovac Biotech or Sinopharm.^15,16

One year later, on December 31, 2020, Pfizer-BioNTech¹⁷ and Moderna¹⁸ published trial results of 2-month follow-up duration from nearly 44 000 and 30 000 volunteers, respectively. Participants were randomized by 1:1 ratio to receive 2 injections of either the mRNA vaccines or the placebo at 2- to 3-week intervals. The studies were only designed to test whether the vaccines were safe in the short-term and could trigger an immune response that may offer adequate protection against COVID-19. The vaccine’s effectiveness was defined mainly by the induction of neutralizing IgG antibodies against the SARS-CoV-2 spike protein, with considerable interindividual variations related to the distinct assays used by different investigators and the variable immune responses observed among different individuals. Interestingly, many vulnerable subgroups in the population, such as children, pregnant women, elderly individuals, and immunocompromised patients, were excluded from the trials. Later reports revealed waning immunity shortly after vaccination.^19-23

With the unknown origin of the SARS-CoV-2, the previously suspected and currently confirmed serious adverse events of the newly introduced mRNA vaccines,^16,24-29 their questionable effec-tiveness against the new variants,^30-34 their inability to stop viral transmission,^35,36 and most importantly the bypassing of the informed consent^16,24 despite their experimental nature, many questions have been raised about the scientific, ethical, and legal validity of the sanitary pass in public and private domains.^37,38 The analysis in this study represents a critical appraisal of the COVID-19 pandemic in most of its aspects discussed above. In the context of all the uncertainties, controversies, and many unanswered questions, this review attempts to uncover a different perspective on the origin of the outbreak.

COVID-19 causative pathogen
News on patients with an unknown pneumonia related to a new unidentified pathogen were first reported on December 31, 2019, from Wuhan. Shortly after, the etiologic agent responsible for this cluster of pneumonia cases was identified as a novel betacoronavirus. The first sequence of the novel virus was posted online² 1 day after its confirmation by Chinese scientists in Shanghai. Subsequently, 5 additional novel coronavirus sequences were deposited on the Global Initiative on Sharing Avian Influenza Data database on January 11, 2020, from institutes across China.² On January 17, 2020, according to a WHO report, the novel coronavirus was isolated from a single patient and subsequently verified in 16 additional patients.³

The initial detection of the coronavirus in the first reported cases on January 24, 2020, was done through reverse transcriptase real time-polymerase chain reaction (PCR) performed in the plasma using 50 amplification cycles (Ct = 50) and was positive in some but not all reported patients. No test was performed to detect infectious virus in blood, with the authors stating, “We did not perform tests for detecting infectious virus in blood, we avoided the term viremia and used RNAemia instead.” The main limitations of the study included diagnosis confirmed with lower respiratory tract specimens not paired with nasopharyngeal swab, serological detection not done to look for COVID-19 antibody rises in 18 patients with undetectable viral RNA, and no availability of kinetics of viral load and antibody titers. Moreover, one-third of the patients had no history of exposure to the Huanan seafood market or had been in contact with any infectious case. Half of the patients were younger than 50 years old.³⁹

In a similar report published on the same day and updated several days later on January 29, 2020, RNA was extracted from bronchoalveolar lavage fluid samples that were collected from 3 affected patients and centrifuged. Supernatant was inoculated on human airway epithelial cells, obtained from patients undergoing surgery for lung cancer, and then purified and observed under transmission electron microscopy for 6 days. Cytopathic effects were observed at 96 hours after inoculation, and spherical particles with some pleomorphisms were identified by electron micrographs. These so-called “virus particles” had a diameter that varied from about 60 to 140 nm and had quite distinctive spikes, about 9 to 12 nm, giving virions the appearance of a solar corona. These identified nanoparticles were named SARS-CoV-2. The extracted RNA with amplification cycles higher than 34 was used as a template to clone and sequence a genome from lineage B of the betacoronavirus.⁴⁰ Notably, PCR tests with cycle thresholds so high (34-50) detect genetic leftover fragments of insignificant particular risk.

It is also important to note that there was no evidence that the RNA being used in the SARS-CoV-2 PCR test was found in those particles because one cannot identify the nature of the contents, which could be either protein, lipid, RNA, or DNA. Additionally, no autopsy was performed on patient 2, who expired, and no lung biopsies were performed on any of the patients to isolate viral pathogen. Therefore, there is no connection between the PCR test and the particles, and no proof that the particles are viral. These findings do not fulfill Koch’s postulates.⁴¹ Additional evidence is needed to confirm the etiologic significance of SARS-CoV-2 such as the identification of a SARS-CoV-2 antigen in the lung tissue of patients by immunohistochemistry, the detection of IgM and IgG antiviral antibodies to demonstrate seroconversion, and animal model (monkey) experiments to provide evidence of pathogenicity.

Many researchers continue to use these Koch’s postulates to robustly prove or disprove the existence of a pathogen and its exclusive relationship with a specific disease. Moreover, the so-called cytopathic effect is nonspecific and may be caused instead by the in vitro culture conditions. Indeed, cell exposure to low-dose antibiotics such as ciprofloxacin, an inducer of oxidative stress and mitochondrial dysfunction of mammalian cells, can lead to the release of new DNA sequences that had not been previously detected and that are associated with an extracellular nanoparticle called exosomes.⁴² Therefore, any cellular components such as proteins or fragments of nucleic acids identified in a cell culture may not be considered as virus antigens or genetic material belonging to a virus. Interestingly, several scientific reports have suggested structural, chemical, and functional similarities between exosomes and RNA viruses like retroviruses.^43-46 In fact, some investigators have suggested 2 decades ago the “Trojan exosome hypothesis” regarding an exosomal origin of retroviruses.⁴⁷

Exosomes and SARS-CoV-2
Exosomes are extracellular vesicles (nanoparticles) of intracellular origin having a diameter of 30 to 150 nm similar to the newly identified SARS-CoV-2. Exosomes may contain 1 or more than 1 cargo material such as nucleic acids (mRNAs, microRNAs, noncoding RNAs, DNA fragments), proteins, and lipids encapsulated by a phospholipid bilayer membrane that wraps the cargo before being released in the extracellular space.^43-46 Exosomes can be secreted by all types of cells and shuttle through biological fluids to different target cells. They transport and deliver their cargo containing the regulatory factors to adjacent or distant cells to induce systemic responses. Exosomes mediate intercellular communication and therefore are involved in different physiological and pathological processes.^47,48 Like SARS-CoV-2, exo-somes can strengthen innate and specific immune responses and are also capable of immunosup-pression. In fact, exosome-based therapeutic strategies are well established and may include drug delivery systems and vaccines such as the newly developed anti-SARS-CoV-2 mRNA vaccines.^16,44,47,48 Exosomes may be induced by several factors such as nutrients, drugs, cancer, infections, hypoxemia, different types of physical, chemical, mechanical injuries, immune response, many diseases, different types of radiation (ionizing, nonionizing, and electromagnetic), and psychological stress such as fear and anxiety.⁴⁹

COVID-19 and electromagnetic radiofrequency
Recent reports have highlighted a serious connection between COVID-19 and exposure to radiofrequency from wireless communication radiation. Coinci-dentally, SARS-CoV-2 surfaced shortly after the implementation of city-wide fifth-generation (5G) wireless communications radiation in November 2019.^50,51 In an extensive review,⁵⁰ Rubik and Brown proposed a potential intersection between the pathophysiology of COVID-19 and adverse bioeffects induced by wireless communication radiation exposure. They claimed that such an exposure might have exacerbated the COVID-19 pandemic by weakening host immunity and increasing SARS-CoV-2 virulence. The authors postulate that (5G) wireless radiation possibly contributed to the early spread and severity of COVID-19. The 5G frequency ranging between 5 and 60 gigahertz introduced for the first time in the history of humanity a frequency exceeding by billions of times that of planet earth (Shuman resonance 7.83 Hz). Interestingly, after Wuhan, COVID-19 outbreaks followed shortly in areas like north Italy, many European cities, South Korea, and some areas in the United States like Southern California and New York where 5G technologies have been at least partially implemented.

Tsiang and associates reported that there were statistically higher attributed cases and death rates of COVID-19 in states and counties with 5G wireless telecommunications in the United States.⁵² The Bioinitiative Report,⁵³ updated in 2020, summarizes hundreds of peer-reviewed scientific papers documenting evidence of nonthermal bioeffects from exposure to electromagnetic radiations. An analysis of 97 studies by the European Union-funded review body EKLIPSE concluded that radiation from power lines and phone masts is a potential risk to bee and bird orientation and plant health.^54,55 According to recent reports by Lancet and other sources, environmental pollutions and COVID-19 share commonalities and their effects converge.⁵⁶

COVID-19 and environmental pollution
New observations from Italy,⁵⁷ Canada,⁵⁸ and the United States⁵⁹ demonstrated a strong correlation between exposure to particulate matter (PM10 and PM2.5) pollution and increased spread of COVID-19 infection, COVID-19 severity, and COVID-19 death rate. These atmospheric pollutants are the result of human activities that have led and are still leading to environmental damage. Longer durations of even relatively low average levels of exposure to these pollutants are associated with an exacerbated inflammatory response.^60,61 Interestingly, the poorest air quality status in Wuhan has been shown to extend between October and January, coinciding with the appearance of the COVID-19 outbreak in December 2019.⁶²

A recent review by the Forum of Respiratory Society highlighted the strong association between air pollution and noncommunicable diseases (NCDs),⁶³ such as advanced age, cardiovascular diseases, hypertension, lung diseases, chronic kidney diseases, obesity, diabetes mellitus, and malignancies. Particulate matter PM2.5 (PM <2.5 μm) in the air is associated with delayed psychomotor development, lower child intelligence, leukemia, and other pathologies such as allergic sensitization, autoimmunity, and increased intravascular coagulation.⁶³ The estimated contributions of all pollutions as risk factors to deaths caused by NCDs vary between 20% and 50%.⁶⁴ Overall, air pollution is associated with shortened life expectancy along with additive or multiplicative effects in vulnerable persons. The global estimated cumulative number of yearly deaths due to all types of pollution risk factors ranges between 8.5 and 9 million, with most deaths being linked to air pollution.⁶⁴

COVID-19 and noncommunicable diseases
In 2015, an estimated 40.5 million worldwide deaths, representing 0.5% of the world population and 71% of total deaths, were attributed to NCDs. Of these deaths, 80% were due to malignancies, obesity, cardiovascular diseases, chronic respiratory diseases, and diabetes.⁶⁵ Patients with NCDs represent those within the world population who experienced the highest fatality rate from SARS-CoV-2, representing 80% of those who died during the COVID-19 pandemic.⁶⁶ The estimated mean global infectious fatality rate (the number of confirmed deaths divided by the estimated total number of infected people) from SARS-CoV-2 is estimated to be around 0.1%.³⁷ Nearly 80% of these fatalities had an average age of 85 years old, had 1 year life expectancy, and had many comorbidities. The estimated mean world case fatality rate as of February 14, 2023 (number of confirmed deaths divided by the number of individuals diagnosed with the disease) was 0.9% and varied according to country and age, ranging from 0.000% in children to 0.02% in people <50 years old, which increased with the number of associated comorbidities and age reaching 13% to 20% in those aged 80 years and greater.^8,37 The estimated total cumulative COVID-19 mortality over the last 3 years of the pandemic was around 6 780 000 deaths as of February 14, 2023. The average yearly mortality was ~ 2 260 000 (ie, 6 780 000/3), representing 8% of the global yearly fatalities from NCDs (2 260 000/[40 500 000 × 0.7]).

Excess mortality is defined as the increase in all-cause mortality relative to the expected mortality over historic trends. There has been no global, frequently updated statistics on the all-cause mortality data across countries.⁶⁷ There is no clear and robust evidence of increased deaths worldwide from all-cause mortality during the pandemic, suggesting COVID-19-related deaths may be part of the NCD mortality pool. Most of these cumulative COVID-19-related deaths occurred in the Americas, Europe, and Asia, excluding China (Figure 1).⁸ Nearly one-third to one-quarter of the population of the former 2 regions, respectively, is obese according to a recent report from the US government on global health policy.⁶⁸ Additionally, all 3 regions are responsible for the highest rate of CO₂ emission in the world from coal and fuel and have the highest number of deaths attributed to excess red meat consumption, which was responsible for almost 1 million fatalities globally in 2015.⁵⁶

According to a recent report from the Centers of Disease Control and Prevention (CDC)⁶⁹ involving more than 0.5 million individuals, COVID-19 was associated with several underlying medical conditions, with the majority being related to NCDs. Hypertension, old age, and disorders of lipid metabolism were the most frequently associated features, whereas obesity, diabetes with complications, anxiety disorders, and the combined conditions were the strongest risk factors for severe COVID-19 disease. For patients with NCDs and COVID-19 or any other infectious diseases, most of these comorbidity-related metabolic processes are associated with impaired tissue blood supply. These infectious and metabolic processes and the host defense response to the infection appear to be intimately connected to the mechanisms of disease, leading subsequently to excess inflammation, altered immunity, worsened tissue blood supply, and oxidative distress.^50,70

These findings imply a parallelism in the pathogenesis between COVID-19 and NCDs triggered and aggravated by the coexistence and/or the new introduction of different polluting factors of chemical, dietary, psychosocial, and electromagnetic origins in the surrounding environment. In a such polluted environment, the exposure of NCD patients to SARS-CoV-2 or any other infection, in a state of fear and panic, heightens their risk of death. This increased mortality risk is prompted by an alteration of their already impaired immunity through further exaggeration of the inflammatory state, suppression of the immune response, and additional reduction in blood supply with extra drop in tissue oxygenation, leading ultimately to increased disease severity and risk of death (Figure 2).

Origin of the pandemic
Clear conclusions about the outbreak’s origins are still lacking. The role of the Huanan seafood wholesale market in Wuhan in spreading SARS-CoV-2 remains murky.^2,5 Theories regarding most probable wildlife animal reservoirs for the SARS-CoV-2 such as snake, birds, pangolin, and camel have been scientifically shaky.⁵ Exactly how the virus jumped from a wild animal, presumably a bat, to another animal and then humans remains a mystery, and the precise sequence of events is unknown. Two competing theories regarding the outbreak are currently debated: laboratory escape scenario of a genetically engineered virus versus zoonotic emergence,^5,11-13,71 leading recently to many scientists to call for a transparent US and international investigation to answer many of the key COVID-19 origin questions.^72,73

What all of these potential animal reservoirs have in common is that they are all mammals sharing considerable biological similarity with humans. Therefore, any exposure of these mammals to a toxic environment of any kind, in particular electro-magnetic radiation of any radiofrequency, will result in several adverse nonthermal biological effects in both animal and human worlds.^53-55 A recent review highlighted the adverse effects of a wide range of electromagnetic fields (EMF) of variable frequencies on different cell types, tissues, and organisms.⁷⁴ These biological effects appear to be mediated through excessive intracellular calcium and exaggerated calcium signaling by disturbing voltage-gated calcium channels and worsening of intracellular oxidative stress, a biochemical condition defined by the imbalance between production of reactive oxygen species (ROS) and the antioxidative defense.^74-77 An increase in the generation of ROS associated with an impairment in the antioxidant enzyme activity induces the oxidative effects in all biological systems, manifested through a range of anomalies that include both cancer and noncancer pathologies.

The electromagnetic radiofrequency-mediated microthermal effects alter cellular structures, causing genotoxic, teratogenic, and carcinogenic effects through single- or double-stranded DNA damage and possible fracture with likely interaction with DNA repair mechanisms.^53,77,78,79 In fact, these DNA structural changes caused by microwave radiation have been long recognized since the mid-1980s.⁸⁰ Recently, a large body of evidence on radiofrequency radiation exposure containing over 30 000 research reports over the past 60 years was published. It shows a wide range of adverse effects from wireless radiation, even below current safety guidelines, applied in isolation or as part of a combination with other toxic stimuli.^50,81

These biological effects are mirrored through neurodegenerative diseases, neurobehavioral prob-lems like autism and attention deficit hyperactivity disorder, neuropsychiatric disturbances (such as irritability, fatigue, concentration difficulties, and depression), reproductive problems and pregnancy outcomes, cardiocirculatory and immune disorders, and different types of cancers, including lymphoma, leukemia, melanoma, breast, and central nervous system.⁸² Loss of sense of smell (anosmia) is a common feature of COVID-19 infection found in 30% to 60% of patients testing positive as their major presenting symptom. Interestingly, anosmia is a classic sign of the disease that was called radio wave sickness in the former Soviet Union.⁸³ Today, it is called electromagnetic sensitivity,^84,85 and it is often the only symptom of exposure to radio waves in otherwise healthy individuals.

Exposure to toxic insults of different nature may have additive or multiplicative harmful effects on organisms of animal or human origins with biological similarity such as mammals. These harmful effects may lead at the cellular functional level to either cell function suppression or cell excitation, necrosis, or apoptosis. These functional alterations are mediated by intracellular structural changes reflected by the formation of waste products that are induced by the toxic insults. This leads to the formation of exosomes with variable type of cargos, such as altered proteins, different types of fractured nucleic acids, lipids, and different classes of metabolites. The characterization of the exosomal cargo could be stress factor specific and may help explain their function in the cellular response.⁴⁹

Interestingly, in a recently published work, Valadi and colleagues elegantly demonstrated a novel mechanism of genetic exchange between cells of different species through an exosome-mediated transfer of mRNAs and microRNAs.⁸⁶ They showed that exosomes containing both mRNA and microRNA can be delivered to another cell and can be functional in this new location. The RNA from mouse mast cell exosomes was transferable to other mouse and human mast cells.⁸⁶ After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient human mast cells, indicating that transferred exosomal mRNA can be translated after entering another cell. These mechanisms of intercellular genetic exchange between and within species are the same ones utilized by retroviruses and by mRNA vaccines to induce their biological effects.^15,16,43-48 Moreover, with their proteinic cargo as well as the presence of antigenic structure on their phospholipid membranes, exosomes can facilitate processes such as antigen presentation.^44,86,87 Once excreted by the cells, exosomes are shuttled in the extracellular space through biological fluids to release their cargo to nearby or distant recipient or target cells and also to be ejected through bodily excretions such as blood products, feces, urines, saliva, milk, tears, and sweat in the external environment. Accordingly, exosomes may be immunogenic and could be involved in modulating immunity of host cells.

As a result of their antigen-presenting capacity, exosomes can activate immune cells and stimulate the release of inflammatory factors and the expression of immune molecules. Exosomes, SARS-CoV-2, and anti-COVID-19 mRNA vaccines seem to share commonalities through strengthening innate and specific adaptive T-cell immunity^87-91 and are also capable of immunosuppression.^87,91-93 Although asymptomatic and pediatric cases display preserved lymphocyte counts, adults with severe COVID-19 tend to have paradoxically elevated levels of inflammatory cytokines and chemokines (suggestive of a possible role for hyperinflammatory responses in COVID-19 pathogenesis) and lower total lymphocyte counts like T cells, T-helper cells and T-regulatory cells.^91,92 Alarmingly, Sahin and colleagues⁹³ showed a significant vaccine dose-dependent (BNT162b2-Pfizer) drop in the total lymphocyte count, a rough indicator of the immune state, in the first week after the first injection.

As mentioned previously, exposure to EMF poses a potential biological health risk, with several scientific reports suggesting a serious connection between COVID-19 and exposure to radiofrequency from wireless communication radiation. According to recent reports,^94,95 by late 2019, China had installed 130 000 5G antennas throughout the country with at least 10 000 antennas installed in Wuhan alone, which made Wuhan one of the most 5G-electropolluted cities on the planet. In fact, Wuhan was one of the initial 16 cities selected to trial 5G back in 2018 and with plans to reach 20 000 antennas by end of 2020. South Korea was in second place with 75 000, followed by the United States with 10 000 antennas throughout the country, with lesser deployment in the 28 member states of the Europe Union, amounting to 181 trials during the same time period.⁹⁵ Most of the 5G deployments were in the following countries (by number of 5G-enabled major cities): Spain, France, Italy, United Kingdom, and Germany.

Interestingly, Chinese scientists have recently demonstrated relationships between the degree of exposure to extremely low-frequency electromag-netic radiation and the formation of serum exosomal microRNA in rats.⁴⁶ They identified by small RNA sequencing microRNAs that are common and dose specific for power frequency EMF (PFEMF). The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the downstream targets of different sets of microRNA markers suggested potential biological influences after PFEMF exposure.⁴⁶ They concluded that in vivo dysregulation of exosomal microRNAs upon PFEMF exposure, even at low frequency, may profoundly influence the homeostasis of tissues and organ targets and consequently potentiate the development of diseases.

In line with these findings, at the ultramicroscopic level, it has recently been shown that bats, known to be highly sensitive to EMF radiation, tend to significantly reduce their activity in habitats exposed to an EMF in the vicinity of radar stations compared with matched sites that register zero EMF levels. These behavioral changes in bats reflected by their avoidance of radar activity may be the result of proven thermal and nonthermal adverse biological effects of EMF radiation at different strength.⁹⁶

COVID-19 outbreak: different perspective
According to the scientific evidence discussed above, we propose a different perspective on the origin of the pandemic. The pathogenesis of any disease depends on 3 basic factors: (1) stressor, (2) environment, and (3) host nature in terms of health status and genetic background. The outcome is determined by the host response to the stressful environment, which depends on the complex interaction between all factors, where epigenetics plays a major role. The initial simultaneous occurrence of the COVID-19 pandemic in Wuhan and other major cities with similar polluted environment as Wuhan but outside China could be explained by the converging and cumulative effects of several stressors, in particular the most recent one, the 5G network of wireless communication, introduced shortly before the onset of the pandemic, as previously explained.

The resulting wide range of EMF-induced adverse effects may be observed when wireless radiations are applied, even below current safety guidelines, either in isolation or as part of a combination with other toxic stimuli.⁸¹ Millimetric high-frequency 5G EMF is vastly absorbed by oxygen, water, and plants and consequently has a highly suspected exposure risk, given its huge intensity compared with the Schuman resonance (Earth’s EMF). Concomitant exposure of mammals and plants to several toxic insults of different nature, mainly to the recently introduced 5G system,^{50,53-55,74-77} may have additive or multiplicative harmful biological effects.

In response to such stressful conditions, mammals and plants produce enormous amounts of different kind of exosomes with variable types of cargo, such as altered proteins, different types of fractured nucleic acids, lipids, and different classes of metabolites that are released through all types of biological fluids in the ambient environment.⁴⁹ Such exosomes share physical, structural, and functional similarities and are known to facilitate antigen presentation.^44,86,87 Moreover, exosomes carrying nucleic acid products and proteins and produced in massive numbers may be exchanged between mammals, as recently demonstrated.⁸⁶ Such molecular or antigenic exchanges between mammals, from humans to humans, animals to animals, human to animals, and animals to humans may explain the observed genetic similarities between the coro-naviruses or exosomes found in bats and humans and the variable degrees of alloimmune responses observed in SARS-CoV-2-infected patients.

In humans, these responses lead to a broad spectrum of disease severity, ranging from minimal reaction in asymptomatic healthy adults and children to severe cytokine storms. The hyperinflammatory state is observed mainly in either NCD patients known to have preexisting variable degrees of biological disturbances (host nature) as a result of oxidative stress, immune dysregulation, impaired tissue perfusion, and oxygenation or in healthy patients with certain prothrombotic genetic profiles and/or sensitivity to electromagnetic radiation.

Interestingly, in contrast to humans, bats, the world’s only flying mammals, do not develop sickness from coronaviruses and the other 130 viruses that they carry. In fact, during flight, their body temperature spikes to over 100 °F and their heart rates can surpass 1000 beats/min. For other mammals, such performance is incompatible with life. Consequently, bats have developed special immune systems to deal with the stress of flying. Their bodies make molecules that other mammals do not have, which help repair cell damage. In addition, their systems do not overreact to infections or to other foreign antigens, which protect them from developing diseases by the many viruses they carry.⁹⁷

These observations confirm that it is the environment and the genetically and epigenetically dependent host’s response (host nature) rather than the stressor itself that can cause the disease. In specific locations, like the wildlife markets in Wuhan, animals that would rarely mix in nature come together, and those animals are then mixed with humans who closely interact with each other. Such an overcrowded mammal environment can become conducive for the enhancement of antigenic exchanges among different mammals through bodily excretions and aerosol transmission.

Human exposure to foreign nonself antigens of human origin (solid-organ and bone marrow transplant, pregnancy, and blood products transfusion) or nonhuman origin (animal and plant) can trigger allosensitization, similar to what is observed in solid-organ transplant. The resulting innate and adaptive immune responses are of humoral and cellular nature. Responses vary from donor-specific immune tolerance to human-human or human-animal chimeric state or to acute cellular and/or humoral rejection,⁹⁸ leading ultimately to chronic graft dysfunction and graft loss if not controlled by immunosuppressive therapy, in parti-cular steroids as first-line treatment. Interestingly, steroids are the only scientifically-proven drug to improve survival in COVID-19.^99,100

Similarly, human exposure to pollen, a nonself antigen of plant origin containing proteinic and lipidic molecular structures, induces several types of immune responses.¹⁰¹ Scientific evidence has highlighted the role of innate and adaptive immunity in the pathogenesis of allergic airway inflammation induced by pollens, resulting into several clinical manifestations varying from allergic conjunctivitis to allergic rhinitis and finally to bronchial asthma.¹⁰² Likewise, steroids represent the conventional therapy against these allergic reactions.¹⁰³ Pollen grains are the largest bioaerosol particles, usually above 10 μm in size (from 10 to 150 μm). Pollen exposure occurs both via the intact pollen grains and via smaller-sized pollen allergens (<2 μm). Pollen allergens can bind to diesel exhaust particles and can act synergistically with these particles such as the PM2.5 and PM10, leading to enhanced pollen allergen-specific activation of the immune system in both animal and human studies.^104,105

Intriguingly, the size of polluting PM is directly linked to their potential for causing harmful biological effects translated into cardiovascular, pulmonary, and neurological diseases and malignancies. The smaller the particles the greater the harm, with those <10 μm in diameter posing the greatest problems because they can get deep into the lungs and possibly in the bloodstream. Most of these particles form in the atmosphere as a result of complex reactions of chemicals such as sulfur dioxide and nitrogen oxides, which are pollutants emitted from power plants, certain industries, and automobiles.¹⁰⁶ They can also bind to small-sized pollen particles. These are the same pollutants found in Wuhan and in major European and American cities. The PMs that are <2.5 μm in diameter pose the greatest risk to health.^57-64

Bioaerosols include viruses, bacteria, fungi, pollen, and their fragments as well as animal allergens.¹⁰⁵ It could be hypothesized that the outbreak of the pandemic in Wuhan was related to a massive production and release in the ambient environment of different types of immunogenic nanoparticles or exosomes representing small-sized bioaerosols of diverse animal, human, and plant origins. The enormous shedding of these immunogenic nano-particles was induced by the simultaneous and cumulative exposure of mammalian organisms to several types of toxic stressors that coexisted in Wuhan during the time of the COVID-19 outbreak and followed shortly after in certain countries and cities, as discussed above,^52,57-59 with similar scenario as Wuhan.^50,51 In cities with variable levels of
5G deployments,^51,94,95 a strong association was observed between exposure to particulate matter (PM10 and PM2.5) and COVID-19 infection spread, COVID-19 severity, and COVID-19 death rate. These observations imply a synergetic effect between the pollutant particulate matters (PM10 and PM2.5) and the exposure to 5G-induced radiations,^{53-55,78,79,107,108} resulting in the production and shedding of exosomes (smaller than PM10 and PM2.5) by different mammal species that carry comparable molecular cargos.

Presently, there are no universally accepted safety standards for wireless communication radiation exposure, and proteomic data of plants irradiated with millimeter waves are limited.^50,109 Given their small size, these nanoparticles could have entered the lungs and probably the bloodstream and could have exacerbated the COVID-19 pandemic by weakening host immunity and increasing SARS-CoV-2 virulence, mainly in the elderly frail population, the electromagnetically sensitive and genetically predisposed individuals to thrombophilia.⁵⁰ Both RNA-carrying exosomal nanostructures and RNA viruses such as SARS-CoV-2 share multifaceted similarities. Moreover, the genetic resemblance between SARS-CoV viruses in different mammal species and their impact on the innate and adaptive immune system mainly in humans imply comparable biogenesis. Such findings suggest a possible exosomal origin of the COVID-19 virus (Figure 3), similar to what was proposed 2 decades ago for the exosomal origin of other RNA retroviruses (Trojan exosomes hypothesis).⁴⁷ Once the pathogen became established in Wuhan and then in major cities with similar environmental scenarios, its virulence increased¹¹⁰ with spread through air travel and further dissemination during the following waves to different regions with or without 5G.

Recent reports have indicated that aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces for up to several days.^111,112 Surprisingly, the SARS-CoV-2 RNA was found on surfaces of the Diamond Princess Cruise ship up to 17 days after passengers disembarked, and viral RNA was found on a variety of surfaces in cabins of both symptomatic and asymptomatic infected passengers and before disinfection procedures had been conducted.¹¹³ However, the CDC could not determine whether transmission occurred from contaminated surfaces. Nearly 20% of all passengers who were predominantly elderly tested positive, with half remaining asymptomatic during the quarantine period. Outbreaks extended easily on the vessel because of the close confines and high proportions of older people who tend to be more vulnerable to the disease.^113,114

The WHO followed with a report stating that SARS-CoV-2 airborne transmission may be possible in specific circumstances and settings in which procedures or support treatments that generate aerosols are performed.¹¹⁵ Airborne transmissions referred to the presence of microbes or exosomes within droplet nuclei, which are generally considered to be particles <5 μm in diameter, can remain in the air for long periods of time and can be transmitted to others over distances greater than 1 meter. In a later report released on July 9, 2020,¹¹⁶ and under pressure from many scientists around the world insisting on the possibility of the airborne spread of the novel coronavirus,^117-121 the WHO admitted according to some studies the presence of SARS-CoV-2 RNA in air in the absence of any aerosol-generating procedures. By October 2020, CDC followed and acknowledged that the coronavirus spreads through airborne transmission.¹²²

The updated guidance came after the agency had retracted 1 month before an erroneously post stating “coronavirus spreads through aerosols small droplets that could linger in the air,”¹²³ while the WHO was maintaining its position that COVID-19 virus primarily spreads through respiratory droplets that could be combined occasionally with aerosol transmission in indoor crowded spaces such as choir practices, restaurants, and fitness classes. Despite consistent evidence as to SARS-CoV-2 contamination of surfaces and the survival of the virus on certain surfaces, the agency maintained its position on the absence of any direct evidence demonstrating fomite transmission.

Conclusions

Our perspective reconciles at least in part with the zoonosis origin of the pandemic. It highlights the role of different mammal species in their contribution to the outbreak of the pandemic through their production of massive quantities of exosomes released in an overcrowded ambient environment under the influence of coexisting multiple different stressors. This shedding led to a considerable exosomal-mediated antigenic and nucleic acid exchange within and between different mammal species and the resulting host-dependent alloimmune response (Figure 3). Our perspective proposes what we label as “Mammalosis,” a mechanism responsible for an exosomal biogenesis of SARS-CoV-2 of animal and human origin. Mammalosis implies a probable chimeric nature of the SARS-CoV-2 induced by a bidirectional traffic and exchange of nanoparticles containing molecular material of different genetic origin,^{86,98,124-127} which could explain at least in part the observed wide variation in the immune response of COVID-19 patients. However, the immunological impact of such microchimerism is currently poorly understood.

Intense debate continues to evolve on the incrimination of a potential laboratory leak for the outbreak in Wuhan of a genetically engineered “gain of function virus” with a footprint that had never been observed in natural coronavirus.^5,11-13 Some scientists and government officials ascertain that the origins of the pandemic are most likely a potential laboratory leak.^128,129 However, other either support a zoonotic origin of the virus^129,130,131 or remain undecided, like the CIA and other US government agencies. The laboratory leak hypothesis as the origin of the outbreak is not universally accepted, has no scientific basis, and remains purely speculative. This has recently led many scientists to call for a transparent US and international investigation to answer many of the key COVID-19 origin questions.^72,73

Our next reviews represent a critical scientific appraisal of the validity of PCR testing in the diagnosis of COVID-19 cases, the usefulness of the nonpharmaceutical interventions to prevent SARS-CoV-2 infection, the efficacy and safety of anti-COVID-19 mRNA vaccines in immunocompetent and immunocompromised individuals and the validity of the vaccine mandate.

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