Commentary
Viruses May Be Redefined as Self-Replicating Entities: Expanding the Definition of Life
by George B. Stefano1, Pascal Büttiker1, Simon Weissenberger2, Martin Anders1, Jiri Raboch1 and Richard M. Kream1
1Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague, Czech Republic
2Department of Psychology, University of New York in Prague, Prague, Czech Republic
Cite as: Stefano, G. B. et al. (2024). Viruses May Be Redefined as Self-Replicating Entities: Expanding the Definition of Lifes. THE MIND Bulletin on Mind-Body Medicine Research, 3, 2-8. https://doi.org/10.61936/themind/202412122
Viruses have traditionally been classified as non-living because they require a host cell for replication (reviewed in (Harris & Hill, 2020; Stefano & Kream, 2022b). However, extensive research has greatly advanced our understanding of how viruses hijack and manipulate host regulatory and metabolic processes to produce infectious progeny. The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has prompted a reconsideration of viruses as potentially living entities (Harris & Hill, 2020; Stefano & Kream, 2022b). SARS-CoV-2 comprehensively controls cellular processes; this suggests that its linear single-stranded (ss)RNA genome encodes a dynamic informational system that is capable of responding to evolutionary constraints (G. Stefano et al., 2023).
While some individuals can host viruses with no noticeable effects, the same virus may trigger an immune and neural responses in others (Zheng & Savitz, 2023; Zheng et al., 2023). We speculate that this variability is based largely on the virus' molecular structure, which can take on different conformations to adapt to a target molecule. These conformations may align well with the host's molecular system and thus result in no or few specific effects; others may induce harmful outcomes. A virus frequently interacts partially with a host and may not influence an entire molecular pathway (G. Stefano et al., 2023; Zheng et al., 2023). This limitation might explain why a virus might only be able to take over a host system when it finds the compatible "fit" needed to achieve the desired outcome, e.g., reproduction. This process must proceed rapidly and target the genetic processes of the host that are involved in reproduction and energy metabolism (e.g., mitochondria) in order to escape a defensive immune response (Trubetskoy et al., 2022), most notably early in the infection process, thereby facilitating viral targeting and immune neutralization. Additionally, the microenvironment, including thermodynamic influences, may also elicit conformational changes in the virus, thereby facilitating dynamic communication between molecules involved (Bitra et al., 2019; Stefano & Kream, 2022b).
The evolutionary constraints that favor viral host hijacking have shaped the ssRNA genome of SARS-CoV-2 into a three-dimensional structure defined by conserved base-pairing and complex secondary and tertiary configurations (Stefano & Kream, 2022b). Regulatory control of the virus's infectious processes relies heavily on extensive protein-protein interactions that direct conformational matching and shape recognition of viral and host nucleic acids and proteins. The seamless integration of complex replicative processes depends on the precise nature of the complementary nucleotide sequences and their corresponding structural and non-structural viral proteins. Interestingly, the virus's ability to commandeer transcriptional and translational activities within specific cellular domains resembles artificial intelligence strategies, as both are fluid, self-correcting, and adaptive to change (Stefano & Kream, 2022b; Stefano et al., 2024).
Moreover, both intracellular bacterial pathogens and mitochondria, which originated from ancient bacterial species can reproduce in a eukaryotic cell; a virus pathogen is thus not unique in this regard (McClure et al., 2017; Murphy & O’Neill, 2024). Multifaceted mitochondrial disorders have also been associated with human disease (Angrand et al., 2021; Marques et al., 2024). Thus, we sought to examine the sequences of introns, which are currently emerging as biologically important reservoirs of genetic information similar to what has been described for mitochondrial heteroplasmy (Stefano & Kream, 2022a; Stewart & Chinnery, 2015). Though introns do not encode amino acid sequences, they play several critical roles in gene expression and its regulation (Birkholz et al., 2024; Girardini et al., 2023; LaRoche-Johnston et al., 2018; LaRoche-Johnston et al., 2023; Shaul, 2017). As a group, these reports highlight the functional significance of introns based on several of their important properties. Among these, introns contain regulatory elements, including enhancers and silencers, that control the timing, location, and level of gene expression. Introns also facilitate alternative splicing of mRNA and allow different combinations of exons to produce multiple protein variants from a single gene. Overall, this serves to increase protein diversity and facilitate complex regulation of cellular functions. Furthermore, intron splicing is essential for the proper export of mRNA from the nucleus to the cytoplasm, where translation into proteins occurs. Some introns have an impact on mRNA stability and lifespan, thereby altering its availability for translation. Introns also provide evolutionary flexibility by acting as buffers against mutations and allowing new gene functions to evolve without disrupting original protein function. Finally, introns contribute to the genomic organization and have a significant impact on the architecture and accessibility of chromatin (Birkholz et al., 2024; Girardini et al., 2023; LaRoche-Johnston et al., 2018; LaRoche-Johnston et al., 2023; Shaul, 2017).
Introns can be influenced by intracellular pathogens through a variety of mechanisms, including viral integration and excision, which disrupts normal splicing; viral manipulation of splicing machinery to favor its own protein production; horizontal bacterial gene transfer, which facilitates the introduction of new genetic material into introns; modulation of the host's immune response by altering pre-mRNA splicing; bacteria-mediated introduction of insertion sequences or transposons, thereby disrupting splicing; and infection-induced epigenetic changes, such as DNA methylation or histone modification that also affect gene expression and splicing (Birkholz et al., 2024; Birkholz et al., 2023; Kurosawa et al., 2023; LaRoche-Johnston et al., 2018; LaRoche-Johnston et al., 2023). These interactions have a significant impact on host gene expression and cellular function, contribute to the pathogenesis of infection, and promote the evolution of host-pathogen interactions.
An examination of the presence and influence of introns may substantiate the concept of life as a simple process of self-replication. Intronic variants that lead to splice alterations have been identified as the underlying factors contributing to dystrophinopathy, neurofibromatosis type I, and inherited retinal diseases (Koczkowska et al., 2023; Kurosawa et al., 2023; Waldrop et al., 2022). These splice-altering variants lead to the formation of pathogenic pseudoexons and the extension of existing exons via disruption of the recognition process via the actions of splicing factors such as small nuclear ribonucleoproteins and RNA-binding proteins. These splicing alterations result in mRNA destabilization through nonsense-mediated decay or result in functional defects in the encoded proteins (Koczkowska et al., 2023; Kurosawa et al., 2023; Waldrop et al., 2022).
Group II introns are ancient genetic elements that have greatly influenced the development of modern eukaryotic genomes. These are self-splicing ribozymes that share a common ancestor with telomerase, the spliceosome, and many spliceosomal introns and non-long terminal repeat retroelements (LaRoche-Johnston et al., 2018). As a result, over half of the human genome includes elements that are derived from ancient group II introns which play crucial roles in promoting genetic function and diversity. Similarly, group II intron-related elements in bacteria, for example, abortive phage infection retroelements, diversity-generating retroelements, and some CRISPR-Cas systems have evolved to provide significant benefits to their hosts (LaRoche-Johnston et al., 2018).
By contrast, bacterial group II introns are rare, unevenly distributed, and often spread by lateral transfer. Thus, these are viewed mainly as “selfish” genetic elements that provide no benefits to the host (LaRoche-Johnston et al., 2018). However, new research has discovered that these introns can generate genetic diversity in bacteria at the RNA level (LaRoche-Johnston et al., 2018).
The results of this study revealed that the Lactococcus lactis Ll.LtrB intron can recognize and insert itself into specific sequences in cellular mRNAs by reverse splicing. This insertion and subsequent circularization collectively induce a novel trans-splicing pathway that creates chimeric RNA molecules. This finding identified new splicing mechanisms in bacteria that, similar to the spliceosome in eukaryotes, increase RNA-level genetic diversity and highlight further connections between group II introns, spliceosomal introns, and the spliceosome (LaRoche-Johnston et al., 2018).
Homing endonucleases, which can facilitate interference, are widely distributed across diverse families of phages, fungi, and archaea (Birkholz et al., 2023). A small subset of these endonucleases that are highly conserved with human glycoprotein gp210 can be found in jumbo phages that infect a wide variety of host cells, including both Gram-negative and Gram-positive bacterial species. Additionally, every mobile intron has the potential to evolve into a weapon given the differences in divergence rates observed between conserved target sites and the surrounding genome. This mechanism is particularly significant when considering the evolution of viruses, which are constantly competing with one another through co-infection and have rapid replication rates that allow even a small selective advantage to be amplified quickly (Birkholz et al., 2023). More broadly, a greater understanding of the fitness advantages provided by weaponized mobile introns could be relevant to any intracellular genetic competition, including those between plasmids, viruses, and their hosts, under the right circumstances.
Specifically, a viruses' ability to infect the brain, as an example of their infectivity, is relevant to their potential to cause neuroinflammation and neurodegeneration. Several viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV), can enter brain tissue and lead to conditions like encephalitis, neurocognitive disorders, and long-term brain damage (see (Buttiker et al., 2022; de Almeida, 2021; Li et al., 2015; Limongi & Baldelli, 2016; Meyding-Lamadé et al., 2019; Tomonaga, 2004; Wongchitrat et al., 2024)). HSV-1 and VZV can reactivate and cause lasting harm, while CMV and HIV are particularly dangerous for immunocompromised individuals. Other viruses, such as rabies, West Nile, Zika, and Epstein-Barr virus (EBV), are linked to both acute and chronic neurological impairments, with some, like EBV, implicated in multiple sclerosis (see (Buttiker et al., 2022; de Almeida, 2021; Li et al., 2015; Limongi & Baldelli, 2016; Meyding-Lamadé et al., 2019; Tomonaga, 2004; Wongchitrat et al., 2024)). In this regard, viral targeting of bacteria, which includes mitochondria given their long evolutionary interaction/relationship, probably is the basis for targeting energy metabolism (Stefano et al., 2024). Research is ongoing into the role of viral infections in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
Furthermore, considering the novel concept that viruses are alive adds to their sphere of influence, including potential novel treatment modalities. Thus, their metabolic pathways, cellular machinery, and autonomous growth could be directly targeted by drugs, making it easier to disrupt their replication and survival. Additionally, their more complex structures would improve immune system recognition, enhancing vaccine effectiveness. Living viruses would also depend on specific environmental conditions, which may be manipulated to control infections. While they might develop resistance mechanisms, these could also be targeted, ultimately making viruses more vulnerable to various treatments, for example, limiting neurodegenerative actions.
Importantly, mitochondria organelles within eukaryotic cells are not classified as independent living entities, as they cannot survive outside the cell (Cutler, 1978; Malina et al., 2018). However, their unique features, such as possessing their own DNA, replicating through binary fission, and their critical role in cellular energy production reflect their evolutionary origins as once free-living prokaryotes. Notably, recent studies have demonstrated that mitochondria can function and exist in extracellular spaces ( see(G. B. Stefano et al., 2023; Zhou et al., 2024)). Furthermore, their genetic material can integrate into eukaryotic DNA, in a manner somewhat reminiscent of viral behavior (Wei et al., 2022). Additionally, the first pathogenic inversion in human mtDNA was documented by Musumeci et al., (Musumeci et al., 2000). More recently, Chanin and colleagues highlighted phase variation in bacteria, which is a mechanism enabling rapid genomic changes that enhance adaptability and survival (Chanin et al., 2024). This process, where recombinases flip a genomic region enhancing messaging, is notable because it occurs in bacteria, underscoring mitochondrial functionality as a conserved evolutionary mechanism, potentially unmasking their alive status. This mechanism supports survival through quick adaptation, influenced by microenvironmental factors. Thus, similar to viruses, mitochondria exhibit processes associated with self-replication, which raises questions about whether they too might warrant classification as living entities.
In summary, we propose that, contrary to conventional thinking, viruses are either alive or can become alive when found in an appropriate compatible environment, such as a eukaryotic cell. As with mitochondria, several characteristics of viruses support this conclusion: they can communicate with both prokaryotic and eukaryotic cells due to their shared chemical composition (e.g., nucleic acids), reproduce themselves, alter cellular energy metabolism to enhance their reproductive processes, survive and thrive in life-sustaining environments, and have optimized their replication process by adapting to host mechanisms that match their specific requirements, exhibiting molecular identity and diversity for the past two billion years. We speculate that during the course of evolution, early viral prototypes, similar to environmental DNA (Yang et al., 2022), eventually acquired the ability to self-replicate within a suitable coacervate-like droplet stage in environment (Agrawal et al., 2022; van Swaay et al., 2015), thus emerging as living entities. Additionally, achieving living status was facilitated by the virus’s capacity for spontaneous, high-frequency mutations, surpassing those of prokaryotes and eukaryotes. This significantly higher mutation rate likely enabled the development of a streamlined genetic code, allowing these entities to adapt to a wide range of compatible hosts. Therefore, an improved understanding of the self-supporting and self-reproducing behavior of viruses could open new pathways for biomedical research, e. g., neurodegeneration, that encompass both pathological and beneficial potential.
Acknowledgements
Pascal Büttiker is currently a Ph D candidate and awarded a stipend in the Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital Prague, Czech Republic. In part, it is acknowledged this document contains key elements that GBS presented as keynote speaker at the International Scientific Conference of Mind-Body Medicine (Nov. 4. 2024, Witten, Germany). During the preparation of this document Dr Radek Ptacek passed away. We honor his memory with this document.
Conflict of Interest
The authors declare that they have no competing interests.
Funding
This work, in part, was supported by Cooperatio Program, research area Neuroscience, and by the project MH CZ – DRO VFN64165.
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