Could an obscure mechanism of cooperation with Prevotella bacteria be covid-19’s secret weapon?
Written by Igaal HANOUNA
Amid the mediatic frenzy and deafening lockdown silence, two scientists, thousands of miles apart and removed from the medical establishment, have built a groundbreaking theory on covid-19’s unique replication mechanism. They have done so independently, using different methodologies and largely online. Their approach is one of starting from factual observations, emitting a wide array of hypotheses unconstrained by prevailing dogma, and systematically searching for the best possible explanation.
Their theory is that covid-19 acts as a bacteriophage and uses a common type of bacteria present in human microbiome, Prevotella, as a Trojan horse to replicate silently in its human hosts. The result of their work seems to explain, to an astonishingly convincing degree, the peculiar epidemiology and symptoms of covid-19. It could prove crucial in controlling the current pandemic and avoiding the worst outcomes.
Yet their theory has been ignored if not derided by the scientific community. Is it because they challenge medical paradigms; or because the systematic repetition of mechanistic processes has deprived part of the scientific community of their ability for creative critical thinking? By all means, this may be a grave mistake costing time and lives amid the greatest epidemic of the past century.
We aim to tell their story and to give this theory a platform for due and prompt consideration by the scientific community.
Overview
The story starts with Sandeep Chakraborty, an India-born researcher in computational biology at University of California (UC Davis). Scanning medical studies data to identify patterns is his bread and butter. When covid-19 emerged, he naturally turned his attention to this new virus. As early as February [1] [2], he wrote about his suspicion that the high concentrations of Prevotella bacteria in covid-19 patients’ samples disclosed in Chinese studies were an important fact. Further reviewing the data he identified Prevotella’s genome associated with the early release of covid-19’s genome sampling [3].
In parallel, a yet anonymous French high-school science teacher using the online handle Bio Moon, decided to systematically review the description of covid-19 symptoms and epidemiology and develop potential explanations. Over time he focused on virus-microbiome cooperation and somewhat intuitively identified a candidate that seems to match a number of the peculiar symptoms: the Prevotella bacteria. Researching these hypotheses he found mentions of Prevotella in the tweets and blog posts of Sandeep Chakraborty.
Building on each other’s work, Chakraborty focused on data, genome analysis, and cellular biomechanisms, Bio Moon on epidemic and symptomatic manifestations, they cooperated to build the theory of a symbiotic relationship between covid-19 and the Prevotella bacteria.
The typical mechanism by which human viruses multiply is, schematically, by entering a human cell, hijacking it and causing it to create copies of the virus. Reviewing recent publication, Chakraborty has hypothesized that on top of this mechanism, covid-19 has the ability to enter bacteria, replicate alongside them and thus spread silently. Viruses that use bacteria to reproduce are called bacteriophage. In the case of covid-19, the virus’s host of choice would be the Prevotella bacteria, which is naturally occurring in humans and particularly in the intestinal tract, oral cavity, superior aerial tracts, vagina, and sometimes lower aerial tracts[4].
According to the theory it is the immune system’s overreaction to the spread of Prevotella, instrumentalized by the covid-19 virus, that causes the worst symptoms rather than the viral infection itself. Crucially, this theory explains virtually all of the peculiarities of covid-19 in terms of human symptoms: the contrast between mild or asymptomatic cases and grave ones; lesser severity of children’s cases; increased severity with age; increased gravity for individuals with co-morbidities such as diabetes, intestinal tract diseases; lesser severity for women on average; etc.
Yet, despite Bio Moon’s repeated, well-documented and intellectually intriguing online publications starting April 1st, the scientific community has largely ignored this theory. The fundamental reasons for this overlook appear to be four-fold. Firstly, bacteriophage viruses are well-known for being inoffensive to humans — they fundamentally infect bacteria [5]. Secondly, the otherwise rational axiom “antibiotics are not useful in viral infections” has prevented many scientists to even consider the virus-bacteria cooperation theory. Thirdly, certain bacteriophage viruses combine their genetic material with the host bacteria’s. While Prevotella’s genetic material seems to have been identifiable in the data from early Chinese scientific studies [6], when Chinese researchers published covid-19’s official genome sequence they published the standalone virus RNA and made no mention of the version recombined with Prevotella’s DNA[7]. Were Chinese researchers negligent, as Chakraborty believes in certain of his posts; did they rearrange reality for it to better match their preconception? Lastly, Bio Moon and Chakraborty’s findings published their work on scientific or personal blog platforms, outside of the formal channel of peer reviewed publications. Some form of condescension is undoubtedly at play.
The reason why the covid-19-Prevotella cooperation theory is critical is because taking it into account could dramatically improve treatment effectiveness, especially of the most severe cases. Indeed if, as is postulated, it is the immune system’s excessive reaction to the bacterial spread that causes the worst cases, early antibiotic treatment targeting Prevotella could be the key to preventing the worst outcomes. Note that this may explain the apparent effectiveness of the hydroxychloroquine-azithromycin treatment promoted notably by the French virologist Dr. Raoult; because of the azithromycin’s antibiotic action against Prevotella rather than, or at least combined with, the hydroxychloroquine’s antiviral effect. Note that as soon as February 8, Sandeep Chakraborty stated his conviction that antibiotics could be an efficient emergency treatment for severe cases [8].
Additionally, the main last resort treatment currently applied of placing patients under ventilators could be highly counterproductive: it requires forcing a tube down the patient’s respiratory tract which is well-known for facilitating bacterial infections, including of all bacteria, Prevotella.
A theory near-perfectly matching observation
Like most viruses, covid-19 likely primarily reproduces by hijacking human cells, and causing them to produce a large number of copies of the virus, known as virions. In this case, covid-19 probably causes the same kind of rather mild, common cold-like symptoms as other coronaviruses. Bio Moon believes this is the mechanism at play in the vast majority of cases and notably the asymptomatic and mild cases.
According to Bio Moon and Chakraborty’s theory, covid-19 also has the ability to be a bacteriophage, using the Prevotella bacteria to spread. Bacteriophage viruses are well-known and overwhelmingly harmless to humans — although we note 2018 studies start to highlight such viruses’ potential pathogenic effects. They have two possible types of replication cycles: the lytic cycle and the lysogenic cycle. In the lytic cycle, the virus penetrates the bacteria cell and causes it to create virion, and the bacteria is destroyed after such replication. In the lysogenic cycle, the virus combines its RNA with the genetic material of the bacteria and replicates along with it — acting as a sort of parasite of the host bacteria. The virus thus remains dormant unless and until the conditions change possibly causing it to activate [9].
Prevotella are part of the natural oral, vaginal and intestinal human microbiome and are often found after respiratory tract infections (e.g. certain types of pneumonia, sinusitis, otitis). According to the theory covid-19 would cause a proliferation of Prevotella bacteria as it is spreading through a lysogenic cycle, and potentially increase the pathogenic effects of Prevotella.
Bio Moon and Chakraborty’s theory is that this lysogenic spread of covid-19 in certain of the human cases explains numerous of the oddities observed in symptoms and virus detection:
- Why typical PCR tests, which look for the virus’s RNA, produce many false negatives or take up to 3 weeks to reveal the presence of the virus. If and while the virus is replicating using a lysogenic cycle, its RNA is not in the open but buried in the DNA of the Prevotella population. It is only when this silent spread reaches its limit that the virus attacks human cells directly and its RNA is identifiable in the patient’s blood stream.
- Why certain specialists highlight a high concentration of the virus in fecal matter, and recommend testing accordingly. This could be due to the virus’s prior use of Prevotella, an intestinal bacteria, as a host during its lysogenic cycle replication.
- The numerous reports of diarrhea, parodontitis and angina for covid-19 patients [10]. The intestinal tract, mouth and throat are all body parts where Prevotella are naturally prevalent and where the virus-induced lysogenic cycle would cause it to proliferate to pathogenic levels.
- The pneumonia observed in many serious covid-19 cases. Prevotella are known for causing aspiration pneumonia, empyema and pulmonary abscess [11];
- Mild body members inflammation could also be explained by the immune response to Prevotella bacteria as is the case in certain chronic inflammatory disease [12];
- Crucially, the cytokine storms believed to be responsible for many of the worst patient outcomes. Indeed in dental care (reminder Prevotella are primarily an oral, intestinal and vaginal bacteria) a number of studies have highlighted Prevotella’s ability to cause cytokine storms [13].
The theory also explains the observed differences in gravity by type of population:
- The asymptomatic and mild cases would be due to a non-bacteriophage spread mode of the virus. Covid-19 would thus behave like a usual coronavirus triggering cold-like symptoms;
- Why gravity seems to increase with age and why in particular children seem less affected. Children’s initial microbiome is inherited in utero. It is over time that exogenous bacteria colonize their microbiome. In the case of Prevotella they are oral and intestinal tract bacteria primarily. It is believed that buccal infections help Prevotella spread to other parts of the body. The likelihood of such spread increases with age and is rare in children [14];
- The fact women seem less affected, on average than men, would be due to the fact Prevotella are common vaginal bacteria. Bio Moon postulates that women’s immune system is better equipped to limit their spread [15];
- Why patients with a comorbidity such as diabetes are at greater risk: Prevotella are unusually abundant in diabetic patients [16];
- Why differences in patients’ ecosystems (i.e. diet, lifestyle, and other environmental factors) could induce differences in covid-19’s apparent severity: due to difference in Prevotella’s prevalence in human hosts [17].
Theory limitations
Three main observations seem to match imperfectly the Prevotella hypothesis and warrant further explanation.
- The greater risk covid-19 implies for obese patients. Indeed, contrary to what is the case for diabetic patients, Prevotella bacteria are less prevalent in obese individuals. Bio Moon did venture an hypothesis that did not seem particularly convincing.
- The fact that a large number of sudden drops in blood oxygenation and thrombosis are observed in covid-19 patients [18]. A recent Chinese study [19] has confirmed that covid-19 disturbs human hemoglobin’s ability to transport oxygen by preventing iron from attaching to part of the red blood cells. The impact of Prevotella in such mechanism is not immediately obvious, but I hereby venture a personal hypothesis: iron being a notoriously essential nutrient to bacteria growth, it is not entirely impossible, if speculative, that Prevotella’s own capture of blood iron is the mechanism underpinning covid-19’s apparent disruption of human hemoglobin.
- There may be an underlying inflammatory dimension to covid-19. Chakraborty himself, as early as Feb 10, 2020 [20], remarked that the virus seemed to cause an inflammatory reaction of epithelial cells. Among the consequences would be to prepare a fertile ground for the spread of bacteria. The observed Prevotella spread would thus be a consequence of the epithelial inflammation, rather than its cause. In this case there could be no need for Covid-19 to be a Prevotella bacteriophage to explain the bacterial effects. It could only be an additional factor to superimpose over the virus assumptions. But in that case, what about false negative tests?
Genome sequencing and Chinese disclosure controversy
As early as February 3, 2020 Chakraborty highlighted on Twitter the surprisingly high prevalence of significant Prevotella concentration in covid-19 patients. Further, on February 5 he indicated that covid-19 seems to have penetrated the Prevotella bacteria’s genome — a sign of likely bacteriophage behavior for the virus — and stressed on the fact it would be a first for a virus to be able to penetrate both human cells and bacteria.
On February 6, he noted that this suggests that when China published the official covid-19 genome, they published only the virus’s RNA and made no mention of Prevotella’s genetic material. When the WHO re-published the virus’s genome for the international scientific community, they reproduced China’s version and again did not hint at the association with Prevotella’s DNA.
This likely deprived the world of an essential clue in understanding the cooperation between the virus and bacteria. It may prove to have been a crucial omission from the Chinese scientific authorities.
Conclusion and potential treatment protocols
The hypothesis put forward by Sandeep Chakraborty and Bio Moon that covid-19 acts as a pathogenic bacteriophage using the common Prevotella bacteria as a host seems to explain most of the epidemic’s specificities in terms of symptoms and differences in severity by population group.
Odds are not good for this hypothesis to be confirmed. However the academic review Nature reported megaphages to infect Prevotella [21]. It is a rational reason not to purely dismiss the whole hypothesis.
Should it be confirmed, efficient and cost effective treatments would likely be promptly available and centered around (i) antibiotics treatment targeting the Prevotella bacteria, (ii) antiviral drugs, (iii) probiotics to promote healthy microbiome and outcompete Prevotella’s spread [22], (iv) blood balance monitoring, and (v) for the late-stage cases oxygen supply as well as anticoagulants against thromboses. Note that a similar treatment protocol has been implemented at the Medical University of Zhejiang in China [23].
We think it is great time for this exceedingly intriguing theory to be thoroughly tested by the scientific community. In the online collaborative work of two outsiders may lie the key to stopping the most disruptive pandemic the world has known in a century.
Sources
[1] https://twitter.com/sanchak74/status/1224348154700500995?s=20
[2] https://twitter.com/sanchak74/status/1224348761586974726?s=20
[3] https://twitter.com/sanchak74/status/1225017748310253568?s=20
[4] https://en.wikipedia.org/wiki/Prevotella
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027513/
[7] https://www.biorxiv.org/content/10.1101/2020.01.24.919183v1
[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027513/
[10] https://onlinelibrary.wiley.com/doi/full/10.1111/imm.12760
[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911379/
[12] https://onlinelibrary.wiley.com/doi/full/10.1111/imm.12760
[13] https://www.sciencedirect.com/science/article/pii/S2211124719309258
[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290626/
[15] https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-016-0160-7
[16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816710/
[17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881937/
[18] https://www.youtube.com/watch?v=jbKZFEhLk2M
[21] https://www.nature.com/articles/s41564-018-0338-9#Sec15
[22] https://www.ncbi.nlm.nih.gov/pubmed/7268409
[23] https://www.zju.edu.cn/english/2020/0323/c19573a1987520/page.htm