Hypothesis Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior, 2023, Stefano et al

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Abstract

'Prion' is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria. Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation.

Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequenct production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manesfestions post-acute viral infection.

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Conclusion

Various viruses and virus infections can induce mitochondrial dysfunction. Thus, we hypothesize that the dysfunction of this bacterial-derived organelle is a critical component of many of these disorders. We proposed that this mechanism is directly related to the bacterial origin of this organelle at a time in evolutionary history that featured high rates of interaction between viruses and bacteria, with each serving as the primary target for one another.

Current work suggests that there is a link between the pathophysiologic sequelae of SARS-CoV-2 infection and the pathogenesis of prion diseases. Specifically, SARS-CoV-2 contributes to the long-term pathological outcome of prion disease, i.e., neurodegeneration. Here, we propose a mechanism in which SARS-CoV-2 targets mitochondria and promotes their dysfunction. Likewise, SARS-CoV-2-mediated overproduction of ROS can lead to the misfolding of prion proteins that can then propagate in this environment, thereby accelerating the development of long-term pathology (Zhou et al. 2022; Yardeni et al. 2019) (Fig. 1).

We note that certain tissues may be more susceptible to this mechanism, which may mask the true origin of the disease. In this regard, we hypothesize that illnesses that have been attributed to the syndrome known as long-term COVID-19 may actually originate, in part, from spontaneous prion production. We note that while fully developed prion disorders are universally fatal, misfolded proteins that accumulate in response to SARS-CoV-2 infection can most likely be cleared after a brief delay. By contrast, in the absence of another immunological challenge, the clearance mechanisms are severely overwhelmed in the setting of full-blown prion disease.

Put simply, virus infection alters the process via which prions reproduce. Although SARS-CoV-2 has not yet been widely localized in the CNS, its’ damage has been associated with the infection (Douaud et al. 2022; Stein et al. 2022). This phenomenon warrants additional attention given the clinical similarities exhibited by long-term COVID-19 and prion diseases.