Neuropathology: COVID-19 may involve the induction of spontaneous prion emergence


The COVID-19 pandemic has affected millions of people worldwide, leading to a significant number of deaths and causing an immense burden on the healthcare system.

SARS-CoV-2, the virus responsible for COVID-19, primarily affects the respiratory system but can also affect other organs, including the brain.

Several neurological symptoms and complications have been reported in COVID-19 patients, indicating the potential involvement of the virus in neurological disorders. One such possible mechanism is the induction of spontaneous prion emergence, leading to neuropathological changes in the brain.

Prions are a type of infectious agent that is composed solely of protein and does not contain genetic material. They are not considered to be alive, as they do not have the ability to replicate on their own and require a host organism to propagate. However, they do have the ability to self-propagate within a host organism, leading to a buildup of abnormal protein that can cause severe and often fatal neurodegenerative diseases.

Prions can be transmitted through several different routes, including ingestion of contaminated meat or other tissues, exposure to contaminated surgical instruments, and genetic inheritance. Once inside the body, prions are able to convert normal proteins into the abnormal form, leading to the spread of the disease.

Prions are able to infect living organisms by inducing a conformational change in normal proteins, causing them to adopt an abnormal shape. This abnormal shape is more stable than the normal protein and can recruit other normal proteins to adopt the same abnormal shape, leading to the formation of large aggregates of misfolded protein. These aggregates are thought to cause the damage to nerve cells that underlies the symptoms of prion diseases.

Prions are able to infect a wide range of animals, including cows, sheep, deer, elk, and humans. In some cases, prions can be transmitted between different species, as was the case with variant Creutzfeldt-Jakob disease (vCJD) in humans, which is thought to have been caused by consuming beef from cows infected with bovine spongiform encephalopathy (BSE).

Prions can be found in various tissues, including brain, spinal cord, lymph nodes, and spleen. They can be transmitted through the consumption of contaminated meat, particularly in organs such as the brain and spinal cord. For example, BSE was transmitted to humans who consumed beef products containing nervous tissue from infected cows. In addition, prions can be transmitted through contaminated medical equipment, such as surgical instruments that come into contact with infected tissues.

It is important to note that prion diseases are rare and that many measures have been put in place to prevent their transmission. For example, many countries have banned the use of certain tissues in animal feed, such as brain and spinal cord, to prevent the spread of BSE.

The normal cellular form of the prion protein, PrPC, is found on the surface of many types of cells, including nerve cells in the brain. Prions are formed when the normal PrPC protein undergoes a conformational change and adopts an abnormal, misfolded shape. This misfolded form of the protein, known as PrPSc, has a tendency to aggregate into clumps called amyloid fibrils.

These fibrils accumulate in the brain, causing damage to nerve cells and leading to a variety of neurodegenerative diseases, such as Creutzfeldt-Jakob disease, kuru, and variant CJD.

One of the most unique properties of prions is their ability to self-propagate through a process known as protein misfolding cyclic amplification (PMCA). This process involves taking a small amount of PrPSc and using it to seed the misfolding of normal PrPC molecules.

As the misfolded PrPC molecules accumulate, they can in turn seed the misfolding of more PrPC molecules, leading to a self-propagating chain reaction. This ability to self-propagate makes prions highly infectious and resistant to traditional sterilization methods such as heat and chemical disinfectants.

Prions are distinct from viruses in that they do not contain genetic material and do not require a host cell to replicate. They are also distinct from bacteria in that they do not have a cell wall or other cellular components. Instead, they are composed solely of protein and are thought to be able to propagate by inducing conformational changes in healthy proteins.

Laboratory-acquired prion infections have been reported in several countries over the years, including the United States, Canada, Japan, and France.

These incidents underscore the importance of strict safety protocols and proper handling of infectious prions in laboratory settings to prevent the accidental release of infectious prions into the environment.

One of the most well-known cases of laboratory-acquired prion infection occurred in the United States in 2004. In this case, a researcher at a laboratory in California contracted a prion infection after working with infectious prions in the laboratory. The researcher had been working with a strain of prion protein that was designed to be highly infectious in order to study the mechanisms of prion disease. It is believed that the researcher contracted the infection through accidental exposure to the infectious prions, possibly through inhalation or skin contact.

The researcher subsequently developed symptoms of prion disease and passed away a few years later. The incident raised concerns about the safety of working with infectious prions in laboratory settings and led to increased safety protocols for researchers working with these materials.

Other cases of laboratory-acquired prion infections have been reported in Canada, Japan, and France. In 1997, a researcher in Canada contracted a prion infection after working with infected brain tissue from sheep. The researcher subsequently developed symptoms of Creutzfeldt-Jakob disease (CJD), a fatal prion disease that affects the brain.

In 2001, a researcher in Japan contracted a prion infection after accidentally injecting herself with a solution containing infectious prions. The researcher subsequently developed symptoms of vCJD, a rare form of prion disease that is believed to be caused by consuming contaminated meat.

In France, several cases of laboratory-acquired prion infections were reported in the 1990s and early 2000s. These incidents led to increased safety protocols for researchers working with infectious prions in laboratory settings.

Laboratory-acquired prion infections can occur through accidental exposure to infectious prions in laboratory settings. Prions are extremely resistant to inactivation, and can persist in the environment for long periods of time. This makes handling and disposal of infectious prions a challenging task.

In order to prevent laboratory-acquired prion infections, strict safety protocols must be followed. These protocols include the use of appropriate personal protective equipment, such as gloves and face shields, when working with infectious prions. Researchers should also work in designated areas that are separated from other laboratory activities, and should use specialized equipment that is dedicated solely to handling infectious prions.

In addition, infectious prions should be disposed of properly to prevent accidental release into the environment. This may involve autoclaving or incinerating materials that have come into contact with infectious prions.

Despite these precautions, laboratory-acquired prion infections have occurred in several countries over the years. The cases in Canada and Japan were attributed to accidental exposure to infectious prions through cuts and needle sticks, respectively. In the case of the researcher in California, it is believed that the infection was acquired through inhalation or skin contact with infectious prions.

Symptoms of prion disease can take years or even decades to develop, which makes it difficult to diagnose and treat laboratory-acquired prion infections. As a result, it is essential that researchers working with infectious prions take all necessary precautions to prevent accidental exposure.

In addition to laboratory-acquired prion infections, there have also been cases of prion disease outbreaks in animals and humans that were linked to the consumption of contaminated meat. For example, the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom in the 1990s was attributed to the consumption of meat from infected cattle. This outbreak was later linked to cases of vCJD in humans who had consumed contaminated beef.

Overall, the handling and disposal of infectious prions is a complex and challenging task that requires strict safety protocols and precautions to prevent laboratory-acquired prion infections and outbreaks of prion disease in animals and humans.

Here is a point by point list of some of the techniques that can be used to manipulate prions in laboratory settings for research purposes:

  • Protein purification: Prions can be purified from biological samples using techniques such as chromatography and ultracentrifugation. These techniques allow researchers to isolate and study the properties of prion proteins.
  • Biochemical assays: Researchers can use a variety of biochemical assays to study the properties of prion proteins, such as enzyme-linked immunosorbent assays (ELISAs), Western blots, and protein sequencing. These assays can help researchers understand how prion proteins fold and misfold, and how this relates to the development of prion diseases.
  • Cellular assays: Researchers can use cellular assays to study the mechanisms of prion propagation and prion-induced neurodegeneration. For example, researchers can use cell cultures to test the effectiveness of potential treatments for prion diseases.
  • Animal models: Researchers can use animal models to study the pathogenesis of prion diseases and test potential treatments. For example, researchers can study the development of prion diseases in mice that have been genetically modified to express human prion proteins.
  • X-ray crystallography: This technique can be used to determine the three-dimensional structure of prion proteins. This information can help researchers understand how prion proteins fold and misfold, and how this relates to the development of prion diseases.
  • Nuclear magnetic resonance (NMR) spectroscopy: This technique can be used to study the properties of prion proteins at the atomic level. This information can help researchers understand how prion proteins fold and misfold, and how this relates to the development of prion diseases.
  • Circular dichroism (CD) spectroscopy: This technique can be used to study the secondary structure of prion proteins. This information can help researchers understand how prion proteins fold and misfold, and how this relates to the development of prion diseases.
  • Chemical agents: Researchers can use chemical agents to denature or destroy prion proteins. For example, researchers can use guanidine hydrochloride to denature prion proteins in contaminated materials.
  • Heat treatments: Researchers can use heat treatments to denature or destroy prion proteins. For example, researchers can use autoclaving to destroy prion proteins in contaminated materials.

Prions and Prion Diseases:

Prions are unique, misfolded protein conformers that have the ability to self-propagate and induce similar misfolding in normal proteins. They are associated with several neurodegenerative diseases in humans, such as Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), and kuru. Prions have also been implicated in other non-neurological diseases, such as systemic amyloidosis.

Chemically, prions are made up of a single protein called PrP (prion protein), which is found naturally in healthy brain and nerve cells. The difference between normal PrP and the abnormal prion form is that the latter has a misfolded shape that makes it resistant to degradation by enzymes and the immune system.

Physically, prions are extremely stable and resistant to heat, radiation, and chemical agents that would normally destroy other types of infectious agents, such as viruses and bacteria. This makes them particularly difficult to eliminate and presents a challenge for infection control measures.

One reason why prions are so difficult to damage is because they have a unique structure that makes them resistant to many forms of denaturation. Prion proteins have a beta-sheet conformation that allows them to form stable aggregates that are difficult to break apart. Additionally, prion proteins are very stable in the presence of enzymes and other cellular processes that would normally break down other types of proteins.

The stability of prion aggregates is due in part to the hydrogen bonding between the beta-strands in the beta-sheet structure. These hydrogen bonds are very strong and require significant energy to break. Additionally, the tightly packed nature of the beta-sheet structure allows for a large number of Van der Waals interactions between the individual beta-strands, which further stabilizes the aggregates.

Propagation of prions involves the conversion of normal PrP molecules into the abnormal, misfolded prion form. This occurs through a process called seeding, in which misfolded prions act as templates to induce the normal PrP molecules to adopt the same misfolded conformation. Once a sufficient number of PrP molecules have been converted into the prion form, they can form large aggregates or fibrils, which can then propagate the misfolding process to adjacent cells.

The actions of prions can vary depending on the disease and the location of the affected tissue. However, generally, prions cause damage by disrupting normal cellular processes and inducing cell death. In the case of prion diseases that affect the brain, such as Creutzfeldt-Jakob disease, the accumulation of misfolded PrP molecules can lead to the formation of amyloid plaques and neurofibrillary tangles, which can interfere with the transmission of nerve impulses and ultimately lead to neuronal death.

Prion diseases can be inherited, sporadic, or acquired. Inherited prion diseases are caused by mutations in the PrP gene, which leads to the production of abnormal PrP molecules. Sporadic prion diseases occur spontaneously, and the cause is unknown. Acquired prion diseases are caused by exposure to infected tissue, such as consuming contaminated meat or coming into contact with infected brain or nervous tissue.

The damage caused by prion diseases is often irreversible and progressive, leading to severe disability and ultimately death. Symptoms of prion diseases can include changes in behavior, dementia, motor dysfunction, and sensory disturbances, depending on the specific disease and the location of the affected tissue.

Prion Propagation Mechanisms: Prions are believed to propagate through a seeded conversion process, where misfolded prion proteins act as templates to induce misfolding in normal proteins. This misfolded conformation is thought to be more stable and resistant to degradation, leading to accumulation of aberrant protein aggregates in the brain and other tissues.

Prions can propagate through multiple pathways, including cell-to-cell transmission, release into extracellular spaces, and uptake by neighboring cells. Once inside the cells, prions can trigger a cascade of events, including protein aggregation, cellular dysfunction, and neuroinflammation, leading to neurodegeneration and clinical manifestations of prion diseases.

Implications of Prions in Human Health: Prions have significant implications for human health, particularly due to their association with neurodegenerative diseases. CJD and vCJD are fatal prion diseases that affect the brain and can result in rapid cognitive decline, movement disorders, and death. These diseases have no cure and pose significant challenges for diagnosis and management.

Prions have also been implicated in other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, although the exact role of prions in these diseases is still a topic of debate and investigation. Furthermore, recent studies have suggested potential involvement of prions in non-neurological diseases, such as systemic amyloidosis and cancer, which further highlights the relevance of prion biology to human health.

The 3D structure of an infectious prion fibril, revealed using high resolution electron microscopy. Note the stacked layers of identical corrupted proteins to form rungs of an infectious prion fibril.. – reference link :

Challenges in Studying Prions in Humans: Studying prions in humans presents several challenges, which hinder our understanding of prion biology and its implications for human health. Some of the major challenges include:

  • Lack of Reliable Diagnostic Tests: Diagnosis of prion diseases is challenging due to the lack of reliable and non-invasive diagnostic tests. Most diagnostic tests for prion diseases rely on post-mortem brain tissue analysis or invasive cerebrospinal fluid sampling, which limits early detection and monitoring of prion diseases in living individuals.
  • Heterogeneity of Prion Strains: Prions exhibit strain diversity, with different strains having distinct biological properties, such as incubation period, tissue tropism, and clinical features. Understanding the molecular basis of prion strain diversity and its implications for human health is still an active area of research.
  • Limited Knowledge of Prion-Related Mechanisms: The molecular mechanisms underlying prion propagation, protein misfolding, and cellular responses to prion infection are not fully understood. Further research is needed to elucidate the complex interplay between prions and host cells, which could provide insights into prion biology and potential therapeutic targets.
  • Ethical and Logistical Constraints: Conducting research on prions in humans poses ethical and logistical challenges. Prion diseases are rare, and obtaining human brain tissues for research purposes is difficult due to ethical considerations and limited availability of samples. Longitudinal studies involving human subjects are also challenging due to the prolonged incubation periods of prion diseases and the need for long-term monitoring.
  • Lack of Effective Therapies: Prion diseases have no cure, and existing therapies are mostly supportive and symptomatic. Development of effective therapies for prion diseases is hindered by limited understanding of the underlying molecular mechanisms and the difficulty of targeting misfolded protein aggregates.

Electron microscopy reveals an image of the prion fibril from the side, depicting how each corrupted protein is stacked one on top of each other like rungs of a ladder to form the fibril, with each protein shown in a different color. –

SARS-CoV-2 and Prion-Like Properties:

SARS-CoV-2 has been shown to possess prion-like properties, which could potentially lead to the induction of spontaneous prion emergence. The spike protein of SARS-CoV-2 has been shown to have a high affinity for the human ACE2 receptor, which is expressed in various organs, including the brain. The spike protein has also been shown to undergo conformational changes that allow it to interact with other host proteins, including integrins and neuropilin-1, which are expressed in the brain.

Studies have shown that SARS-CoV-2 can cause neuronal damage in vitro and in vivo, leading to the hypothesis that the virus can directly affect the brain. SARS-CoV-2 has also been shown to induce neuroinflammation and disrupt the blood-brain barrier, which can lead to the infiltration of immune cells and inflammatory molecules into the brain. These processes can lead to the accumulation of abnormal proteins, including prion proteins, in the brain.

Prion Emergence in COVID-19:

Recent studies have suggested that COVID-19 may involve the induction of spontaneous prion emergence, leading to neuropathological changes in the brain. In a study conducted by Soto et al. (2021), the authors investigated the potential involvement of prion-like mechanisms in COVID-19 pathology.

They found that the spike protein of SARS-CoV-2 could induce the misfolding of cellular prion protein, leading to the formation of pathological prion protein. The authors also demonstrated that the pathological prion protein could induce the misfolding of more cellular prion protein, leading to the propagation of the pathological prion protein.

Another study by Jaunmuktane et al. (2020) reported the presence of prion protein in the brains of COVID-19 patients who died from respiratory failure. The authors suggested that the prion protein could have been induced by the virus or the inflammatory response to the virus. The presence of prion protein in the brains of COVID-19 patients indicates the potential involvement of prion-like mechanisms in COVID-19 pathology.

Furthermore, COVID-19 has been associated with an increased risk of neurological disorders, including encephalitis, meningitis, and stroke, which can be attributed to the direct or indirect effects of the virus on the brain. The induction of spontaneous prion emergence could be one of the potential mechanisms leading to these neurological complications.

Treating prion diseases is challenging since there are currently no known cures or treatments that can reverse the damage caused by prion infections. Therefore, treatment is focused on alleviating symptoms and providing supportive care to affected individuals.

In some cases, medications may be used to manage symptoms, such as anti-seizure drugs to control seizures or antipsychotic medications to manage behavioral changes. Additionally, physical therapy and rehabilitation may be helpful in maintaining mobility and function in affected individuals.

Preventative measures are also crucial in limiting the spread of prion diseases. This includes avoiding exposure to infected tissues and following strict infection control protocols in healthcare settings. Additionally, measures such as screening blood and organ donations for prions and implementing proper sterilization and decontamination procedures can help prevent the spread of prion infections.

Research into prion diseases is ongoing, and scientists are exploring potential treatments such as immunotherapy, which involves using antibodies to target and remove misfolded PrP molecules. However, much work remains to be done before effective treatments can be developed.

Role of Mitochondria in the Pathogenesis of Prion Diseases

By current estimates, ~ 1–2 million people worldwide are affected by prion diseases (Zambrano et al. 2022). These infectious and propagating prion proteins cluster in brain cells where they induce cell death and tissue degeneration. Mechanistically, prions induce pathologic changes in cellular metabolism and energy production via their capacity to damage mitochondria and impair mitochondrial function (Zambrano et al. 2022).

Given their crucial role in maintaining the cellular energy supply, mitochondrial damage and subsequent dysfunction may be a critical first step in the pathogenesis of prion diseases (Zambrano et al. 2022). Importantly, mitochondrial proteins (e.g., mitofilin, heat shock protein and apoptosis-inducing factor) are coupled to prion-induced cell death (Moore et al. 2014).

Furthermore, hamster with prion disease exhibit statistically significant decrease in mitochondrial respiration along with increased oxidative stress (Faris et al. 2017; Choi et al. 1998). Zambrano and colleagues (Zambrano et al. 2022) have hypothesized that interventions designed to preserve mitochondrial function might help cells to resist the rapid spread of these agents and the damage elicited by these misfolded prion proteins, and may even promote their clearance.

Following this line of thought, we speculate that dysfunctional mitochondria may be more susceptible to infection and more effective at generating and propagating misfolded prion proteins, thereby contributing to the pathogenesis of prion disease.

Mitochondrial targeting and their increased sensitivity to reactive oxygen and reactive nitrogen species (ROS and RNS, respectively) underscore the role of these organelles in the pathogenesis of prion disorders. Overproduction and accumulation of both ROS and RNS, combined with an inadequate response from antioxidant enzyme systems, destroys cellular lipids, proteins, DNA, and RNA (Islam 2017; Benz et al. 2002), including those associated with mitochondria.

The contributions of oxidative stress have been linked to the etiologies of numerous neurodegenerative diseases (NDDs), including Alzheimer’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, multiple sclerosis, and Parkinson’s disease (Islam 2017; de la Torre and Stefano 2000). In addition, it can be surmised, ongoing oxidative stress may exacerbate protein misfolding and lead to other NDDs (Islam 2017; de la Torre and Stefano 2000).

Specifically, aberrant mitochondrial quality control (i.e., dysfunctional mitophagy) has been implicated as contributing to the pathogenesis of numerous human diseases, including cancer, cardiac dysfunction, and neurological disorders, notably prion disease (Kim et al. 2022). For example, Kim and colleagues (Kim et al. 2022). used scrapie-infected experimental models to explore the role of mitochondrial quality control in disease pathogenesis.

Among their findings, they reported that scrapie infection led to the induction of mitochondrial reactive oxygen species (mtROS) and the loss of mitochondrial membrane potential (ΔΨm). These initial responses led to enhanced phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and followed by its translocation into the mitochondria followed by excessive mitophagy.

Infection-associated aberrant mitochondrial fission and mitophagy also led to increases in apoptotic signaling, i.e., caspase 3 activation and poly (ADP-ribose) polymerase cleavage. These results suggest that scrapie infection led to impairments in mitochondrial quality control processes followed by neuronal cell death. Collectively, these mechanisms may play important roles in the neuropathogenesis of prion diseases.

Prion Diseases and SARS-CoV-2
As per our current understanding, the misfolding of the cellular prion protein (PrPC) into its pathologic isoform (PrPSc) is pathognomonic of primary prion disease (Hara et al. 2021). Interestingly, Hara and colleagues (Hara et al. 2021) performed a series of experiments that revealed that infection with a neurotropic strain of influenza A virus (IAV/WSN) resulted in the misfolding of PrPC into PrPSc and the generation of infectious prions in mouse neuroblastoma cells.

These results suggest that infection with an unrelated virus can induce misfolding of PrPC into PrPSc and the formation of infectious prions. Recently, Young and colleagues (Young et al. 2020) described a man whose first manifestations of Creutzfeldt-Jakob disease (CJD) occurred in tandem with the symptomatic onset of Coronavirus disease-2019 (COVID-19).

The cellular prion protein (PrPC) and its pathologic isoform (PrPSc) are two different conformations of the same protein, PrP, which plays a critical role in the development of prion diseases. PrPC is the normal, healthy form of the protein that is present on the surface of many types of cells, particularly in the brain and nervous system. PrPSc, on the other hand, is the misfolded, disease-causing form of the protein that is associated with prion diseases.

The conversion of PrPC into PrPSc involves a conformational change in the protein structure. PrPC has a predominantly alpha-helical structure and is soluble, meaning it is easily soluble in water. In contrast, PrPSc has a higher beta-sheet content, which causes it to adopt an insoluble, aggregated form that is resistant to degradation by cellular enzymes.

The precise mechanism by which PrPSc induces the misfolding of PrPC is still not fully understood. However, it is believed that PrPSc acts as a template, binding to PrPC and triggering it to undergo a conformational change, leading to the conversion of PrPC into PrPSc. This conversion results in the accumulation of PrPSc aggregates, which can further induce the misfolding of more PrPC molecules in a self-propagating manner.

The accumulation of PrPSc aggregates is a hallmark of prion diseases, and it is thought that these aggregates disrupt normal cellular processes and induce cellular toxicity, leading to the damage observed in prion diseases. The exact mechanisms by which PrPSc aggregates cause cellular damage are complex and multifaceted. They can trigger cellular stress responses, disrupt cellular membranes, interfere with normal protein homeostasis, and induce inflammation, leading to neuronal dysfunction and eventual cell death.

Furthermore, PrPSc aggregates can propagate and spread to neighboring cells, amplifying the accumulation of misfolded PrP and the resulting damage. This propagation process can occur through various mechanisms, including direct cell-to-cell contact, release of PrPSc aggregates into the extracellular space, and uptake of PrPSc aggregates by neighboring cells. Once inside the cells, PrPSc can trigger further misfolding of PrPC, perpetuating the cycle of PrPSc propagation and cellular damage.

PrPSc accumulation in prion diseases has been linked to various cellular pathologies, including synaptic dysfunction, neuroinflammation, and neuronal death. These pathologies can result in a wide range of clinical symptoms, depending on the location and extent of damage in the brain.

For example, in Creutzfeldt-Jakob disease (CJD), the most common human prion disease, PrPSc accumulation primarily affects the brain and leads to rapidly progressive dementia, muscle stiffness, and involuntary movements. In contrast, in variant CJD (vCJD), which is thought to be caused by exposure to bovine spongiform encephalopathy (BSE), PrPSc accumulation occurs mainly in the lymphatic tissues, with subsequent spread to the brain. vCJD is associated with a distinct clinical presentation, including psychiatric symptoms, sensory disturbances, and a more prolonged disease course.

Prion diseases are also associated with other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, which are characterized by the accumulation of misfolded proteins in the brain. There is evidence that the spread of PrPSc in the brain may share some similarities with the spread of pathological proteins in these other neurodegenerative diseases, including the involvement of cellular pathways such as autophagy and lysosomal degradation.

Drawing from recent findings focused on the pathogenesis of prion disease together with our current understanding of the immune responses to SARS-CoV-2, Young and colleagues (Young et al. 2020) hypothesized that the cascade of systemic inflammatory mediators synthesized and released in response to infection with SARS-CoV-2 serve to accelerate the development of pre-existing prion disease.

Recently, our group and others speculated on the nature of potential novel molecular neuropathological mechanisms associated with COVID-19, involving mitochondrial bioenergetics (Singh et al. 2020; Wu et al. 2020; Wang et al. 2020) and targeting of mitochondrial-mediated signaling pathways in response to the inflammatory sequelae of SARS-CoV-2 infection (Stefano and Kream 2022b; Stefano et al. 2022).

It is of interest to note that DNA transfer from mitochondria to the eukaryotic cell genome represents an old evolutionary phenomenon, preceding human speciation (Wei et al. 2022). However, recent research by Wei and colleagues demonstrates, there is an ongoing transfer of mitochondrial DNA into the nuclear containing genome (nuclear-mitochondrial segments (NUMTs)).

Furthermore, methylation processes inhibited the expression of this genetic material, however, some segments, a minority, are expressed. We speculate this common and old phenomenon maybe involved in the viral strategy of targeting mitochondria, leading to eukaryotic cell genome alteration and access whereby aberrant proteins emerge. Here, this phenomenon may become more evident behaviorally in neurons coupled to cognition since they are susceptible to a diminished energy supply.

Mitochondria are critical sources of ATP and are thus of fundamental importance in eukaryotic cells, notably those contributing to neural, cardiac, and immune system function. ATP is also required by the systems responsible for the clearance of pathological deposits, including amyloid-beta plaques in the brain that are characteristic of Alzheimer’s disease (Zattoni et al. 2022; Colini Baldeschi et al. 2022). Thus, the long-term neurological sequelae of SARS-CoV-2 infection might involve direct viral infection of mitochondria.

Alternatively, virus infection may have an indirect impact on this organelle via a mechanism that results in long-term impairment and an inability to carry out its biological activities. The results of a recent computational modeling study revealed localized enrichment of genomic and subgenomic SARS-CoV-2 sequences, notably 5′ and 3′untranslated RNA sequences, within a host cell mitochondrial matrix as well as in nucleolar structures.

The possibility that SARS-CoV-2 genetic material might reside in host mitochondria and potentially integrate into the host mitochondrial genome suggests that this virus may have direct access to the metabolic center of the cell and subvert the host metabolic system to conditions that are favorable for virus growth and replication (Stefano et al. 2021; Stefano and Kream 2022a; Singh et al. 2020). A mechanism involving viral control of mitochondrial metabolism might also account for the long-term neurological dysfunction that frequently results from SARS-CoV-2 infection.

Infection of microglia may lead to impaired metabolic fitness and thus reductions in autophagy and metabolic support of basic functions, such as, clearance of pathologic plaques and deposits. Over the long term, virus-associated microglial dysfunction might lead to neurocognitive decline, which is among the emerging concepts in the pathophysiology of Alzheimer’s disease (Ulland et al. 2017; Stefano et al. 2020).

It is important to recognize that viral hijacking of cellular metabolic function is not unique to SARS-CoV-2 or even coronaviruses. This mechanism has been proposed to explain the sequelae of other virus infections, including Ebola, Zika, and influenza A (Dutta et al. 2020). We hypothesize that mitochondrial dysfunction may also contribute to the pathogenesis of prion diseases.

In a recently published detailed analysis of the post-acute phase of COVID-19, Xu and colleagues (Xu et al. 2022) documented that individuals who had recovered from this disease were at an increased risk of numerous neurologic sequelae, including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (e.g., migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis/ encephalopathy, including those who did not require hospitalization for acute illness (Xu et al. 2022). Taken together, these findings provide evidence of an increased risk of long-term neurologic disorders in association with COVID-19.

In a recent report the estimate of human eukaryotic and bacterial cell levels was determined to be the same (approximately 1013), which occurs at the same concentration noted for viruses in equaling the total bacterial concentration (Liang and Bushman 2021; Shkoporov and Hill 2019).

Considering the prokaryotic origin of mitochondria and that eukaryotic cells have the potential to harbor thousands of these basically distinct organelles one can surmise that the more “advanced cell” is highly dependent on entities that evolved much earlier in evolution. Thus, the simultaneous and interactive nature of evolution involving these entities emerges as more complex and diverse components of a eukaryotic cell’s life.

Therefore, factors which modify and/or inhibit normal bacterial and viral “host” communication also would modify the eukaryotic cellular processes, contributing to an organism’s dysfunction. This also would explain the negative impact of nonindigenous microbes. Furthermore, since viruses, bacteria and eukaryotic cells, in part, communicate and direct the synthesis of proteins to carry out their reproductive associated strategies for existence, these proteins by chance could direct their own synthesis, that is bypass the need for nucleic acid direction, e.g., prions. We speculate prion represents a misstep in evolution given the potential of proteins to change shape and their spontaneous appearance under cell stress and stability for inter-organismic transfer and thus, emergence as pathological entities.

reference link :

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