Understanding Viruses and Bacteria

Viruses are unique infectious agents that cannot survive independently; they require a host for replication. Their classification as non-living stems from their lack of essential life characteristics, such as:

1. Absence of energy metabolism
2. Inability to grow autonomously
3. No waste production
4. Lack of response to harmful stimuli

These entities are not cells but rather assemblies of genetic material (either DNA or RNA) encased in a protein coat known as a capsid. Some viruses are further protected by a lipid membrane called an envelope.

The diversity in viral biology is remarkable, varying widely in host selection, life cycle, and molecular structure. Retroviruses, for instance, are single-stranded RNA viruses that commandeer the host cell's machinery to convert their RNA into double-stranded DNA, which can then integrate into the host's genome. This integration enables the production of new viral particles, effectively using the host cell to propagate the virus. Later in this blog, we will discuss the implications of retroviruses in NDs.

In contrast, bacteria are living organisms classified as prokaryotes, making them one of Earth's earliest life forms. They are single-celled, lacking a nucleus or membrane-bound organelles, with their genetic material organized in a single loop of DNA. Some also possess plasmids, which provide advantages such as antibiotic resistance and can replicate independently.

Despite their minute size, bacteria play critical roles in human health through various symbiotic relationships, categorized into three types:

1. Commensalism: One species benefits without harming the other. For example, the skin hosts bacteria that thrive on dead skin cells without causing harm.
2. Mutualism: Both species benefit from the relationship. Rumen bacteria in cows help digest cellulose while receiving nutrients and shelter in return.
3. Parasitism: One organism benefits at the expense of the other. Ticks, for instance, feed on warm-blooded animals, causing harm while benefiting from the relationship.

Previous discussions have explored the relationship between the gut microbiome and NDs, but the influence of microbes extends beyond the gut. Microbiota inhabit various surfaces exposed to the environment, including the skin and respiratory tract. While viruses are not classified as microbes, they are considered part of the human microbiome.

Viruses are responsible for familiar illnesses like the common cold and flu, as well as more severe diseases such as HIV/AIDS and COVID-19. This raises the question: could they also play a role in initiating NDs?

The Complicated Relationship with Alzheimer's Disease

Traditionally, research on Alzheimer's Disease (AD) has focused on amyloid plaques and tau tangles as primary contributors to its pathology. The prevailing theory suggests that reducing amyloid-β peptide levels can alleviate or halt AD symptoms. However, numerous clinical trials targeting amyloid-β have failed to demonstrate effectiveness. For instance, a 2016 Phase 3 trial of Eli Lilly's solanezumab revealed no significant improvement in early-stage AD patients. Similarly, Merck halted its clinical trial of verubecestat, a drug designed to block the enzyme that produces amyloid-β.

In June 2021, Biogen's aducanumab was conditionally approved by the FDA despite mixed clinical trial outcomes, highlighting the ongoing debate about the efficacy of amyloid-targeting therapies. Critics argue that the quality of clinical trials has been subpar and question whether targeting amyloid-producing processes can truly halt disease progression.

In light of these setbacks, researchers are considering alternative avenues of investigation, including potential microbial connections. Harvard neurobiologist Rudolph Tanzi notes that any hypothesis regarding Alzheimer's must encompass amyloid plaques, tangles, inflammation, and potentially, infection.

Historically, infections have been implicated in NDs. In the 1990s, multiple laboratories studying different pathogens suggested a link to AD, but their findings were largely dismissed as unconventional. However, the persistence of these researchers has led to significant discoveries.

In 2011, Professor Herbert Allen observed spirochete bacteria in post-mortem brain samples of AD patients, a finding that suggested a microbial role in the disease's progression. This was supported by evidence of biofilms, which Allen hypothesized could provoke an immune response detrimental to brain tissue, thereby contributing to AD pathology. Neuroinflammation, an accepted factor in AD, is also triggered by both bacteria and viruses.

Additionally, research by Dominy et al. in 2019 identified Porphyromonas gingivalis, a bacterium associated with periodontal disease, in the brains of AD patients. This bacterium releases toxic proteases linked to tau and ubiquitin pathologies. Studies have shown that oral infection with P. gingivalis can lead to brain colonization and increased amyloid-β production, suggesting a connection between oral health and neurological conditions.

Similarly, Dourmashkin and colleagues discovered virus-like particles in the brains of Parkinson's disease (PD) patients, indicating that viral infections may also play a role in neurodegeneration. Three primary mechanisms have been proposed for viral entry into the central nervous system (CNS): retrograde transport, blood-brain barrier penetration, and 'Trojan-horse' invasion via infected immune cells.

In examining amyotrophic lateral sclerosis (ALS), there has been ongoing research into the role of neurotropic viruses. Human endogenous retroviruses (HERVs), remnants of ancient retroviruses embedded in human DNA, have been linked to ALS pathology. Studies suggest that certain retroviruses may contribute to the development of ALS by targeting motor neurons.

The Path Forward: Embracing the Microbial Link Hypothesis

As our understanding of NDs evolves, the potential roles of infectious agents in these diseases are gaining attention. Yet, questions remain: Does the presence of these pathogens indicate causation? Do individual immune responses influence disease progression? Could genetic factors modulate the impact of these infections?

Critics may still challenge the microbial link hypothesis, but an increasing number of researchers recognize its potential. Current treatments for NDs are largely ineffective, underscoring the need for fresh perspectives. While a definitive connection between infections and NDs has yet to be established, emerging evidence suggests a plausible association worth exploring.

At GenieUs, we remain committed to investigating these intriguing connections. We encourage further research and funding in this area, as identifying infections as a potential risk factor could lead to groundbreaking therapeutic interventions for neurodegenerative diseases.