: Adonis Sfera, Jacob J Anton, Sabine Hazan. Mycoplasma and SARS-CoV-2 Virus: A Marriage of Convenience or a Binary Biological Weapon? A Psychiatrist’s Perspective. J Med Res Clin Rev. 2025; 1(1): 1-9.
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 1 of 9
Journal of Medical Research and Clinical Reviews
Review Article
Mycoplasma and SARS-CoV-2 Virus: A Marriage of Convenience or A Binary
Biological Weapon? A Psychiatrist’s Perspective
Adonis Sfera1,2,3*, Jacob J Anton4, and Sabine Hazan5
1Patton State Hospital,
2Loma Linda University,
3University of California Riverside
4California Baptist University,
5ProgenaBiome
*Correspondence: Adonis Sfera, Patton State Hospital, Patton, CA, USA
Citation: Adonis Sfera, Jacob J Anton, Sabine Hazan. Mycoplasma and SARS-CoV-2 Virus: A Marriage of Convenience
or a Binary Biological Weapon? A Psychiatrist’s Perspective. J Med Res Clin Rev. 2025; 1(1): 1-9.
Received Date: 18 February 2025;
Accepted Date: 24 February, 2025;
Published Date: 28 February, 2025.
ABSTRACT
Mycoplasma is the smallest, independently replicating microbe that lacks a cell wall and resembles a liposome because of its
sterol-rich cell membrane. Under pathological circumstances, Mycoplasmas cause respiratory and urogenital infections in
humans.
Human immunodeficiency virus (HIV) is known to be associated with Mycoplasma genitalium, suggesting that viruses may
commonly utilize Mycoplasmas to enhance infectivity. Along this line, COVID-19 critical illness was documented in individuals
with concomitant Mycoplasma infection, raising the possibility of a symbiotic relationship or binary biological weapon.
Binary biological weapons are comprised of two components that are safe to handle separately but, in combination, become
lethal. For example, concomitant infection with hepatitis D and B is deadly because the D virus takes advantage of the proteins
expressed by the B virus, turning this infection into a fatal disease.
Mycoplasmas have been known for their neuropsychiatric manifestations, including psychosis, anxiety, depressive disorders,
cognitive impairment, and schizophrenia. This is relevant as Mycoplasmas, like many antipsychotic drugs, enter host cells
via clathrin-dependent endocytic pathways, often remaining dormant in endosomes. Moreover, Mycoplasmas express aryl
hydrocarbon receptor, a transcription factor activated by many ligands relevant to neuropsychiatry, including dopamine, se-
rotonin, melatonin, clozapine, carbidopa, tryptophan, and microbial metabolites. Mycoplasma-expressed AhR, like its human
counterpart, senses environmental stimuli, including viruses, indicating that it may play a role in the Mycoplasma/SARS-CoV-2
symbiosis.
This perspective article examines Mycoplasma and its relationship with COVID-19, premature cellular senescence, and major
depressive disorder. We also discuss neuropathology potentially associated with designer pathogens and some therapeutic
strategies.
Key Words: Mycoplasma, Binary Biological Weapons, Neuropsychiatric Disorders, Cellular Senescence, Synthetic Biology
Introduction
Mycoplasma is the smallest, independently replicating microbe
discovered by Pasteur in the eighteenth century. It can be parasit-
ic or saprophytic and is found in plants, animals, insects, humus,
water, and sewage.
Detection of Mycoplasma in Golf War Illness (GWI) veter-
ans, patients with Human Immunodeficiency Virus (HIV), and
COVID-19 critical illness has brought this bacterium to the atten-
tion of researchers and clinicians as a possible bioweapon [1,2].
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This is further substantiated by the fact that Mycoplasma was first
synthesized in a US military laboratory in 1993.
The recent COVID-19 pandemic has highlighted the disastrous
impact a pathogen can have on the population and economy of
the entire planet. Non-kinetic means for waging wars, often called
fifth-generation warfare, involve information, economy, health-
care, education, and other aspects of life that form the tapestry
of human society. Since battles are often won before ever fought,
influencing the enemy may start years or even decades before the
open hostilities. For example, making drugs of abuse available to
the enemy population leads to addictions, chronic diseases, dis-
ability, depression, suicide, and plummeting birth rates. All these
deplete the military-age population, influencing the outcome of
present or future wars while providing plausible deniability of
planned interference in the internal affairs of other nations.
The chronology of artificial Mycoplasma: Shyh-Ching Lo, chief of
the Division of Molecular Pathology at the Armed Forces Institute
of Pathology in Washington, built the first synthetic microorgan-
ism, Mycoplasma fermentans incognitus (Lo’s Mycoplasma) in
1993 (patent number 5,242,820). Interestingly, this Mycoplasma
was detected in 45% of patients with GWI, linking this pathogen
to fatiguing disorders. Along this line, Myalgic Encephalomyeli-
tis/Chronic Fatigue Syndrome (ME/C FS) and Fibromyalgia (FM)
have been linked to Mycoplasma infection, indicating a predilec-
tion for chronic illnesses with muscle pain [3]. In addition, Myco-
plasma fermentans incognitus strain enhances tissue plasminogen
activator (tPA), which converts plasminogen into the biologically
active plasmin, a protein that cleaves the S antigen of the SARS-
CoV-2 virus at the S1/S2 site, indicating a symbiotic relationship
between this virus and Mycoplasma, cooperation reminiscent of
Mycoplasma genitalium and Human Immunodeficiency Virus
(HIV) [4,5].
The next step in Mycoplasma weaponization occurred in 1995,
when the Institute for Genome Research in Rockville, Maryland,
sequenced the genome of Mycoplasma genitalium, opening the
door for synthetic biology in warfare [6].
The story of artificial Mycoplasma continues. In 2010, a com-
pletely synthetic Mycoplasma mycoides JCVI-syn1.0 was created
in the laboratory, contributing further to the weaponization of this
pathogen. After this, Mycoplasma JCVI-syn2.0 and 3.0 strains
were developed by minimizing the genome to the smallest size
compatible with survival [7,8].
Mycoplasmas are members of the Mollicutes class of bacteria, the
most straightforward and smallest known self-replicating micro-
organisms [9]. They can be commensal or pathogenic, the former
dwelling on the skin or oral cavity, while the latter are usually
found in the intracellular compartment [10].
COVID-19 is characterized by variable clinical outcomes, ranging
from few or no symptoms to critical illness and death. Several
novel studies have found that coinfection with Mycoplasma could
be the primary driver of unfavorable COVID-19 outcomes [11,12].
Indeed, epidemiological studies found 47% comorbidity between
SARS-CoV-2 and Mycoplasma, further indicating a symbiotic re-
lationship. Mycoplasmas benefit viruses as they disrupt host im-
munity by blocking antiviral antibodies. Moreover, viruses may
also use Mycoplasma as a vehicle for entry into host cells [13].
Several Mycoplasmas have been known for their neuropsychiatric
manifestations, including psychosis, anxiety, depressive disorders,
cognitive impairment, and schizophrenia (SCZ) [14]. Interest-
ingly, Mycoplasmas express aryl hydrocarbon receptor (AhR), a
transcription factor activated by many ligands relevant to neuro-
psychiatry, including dopamine, serotonin, melatonin, clozapine,
carbidopa, tryptophan, and microbial metabolites. The Mycoplas-
ma AhR, like its human counterpart, senses environmental stimuli,
including viruses, indicating that it may play a role in the Myco-
plasma/SARS-CoV-2 symbiosis.
SARS-CoV-2 infection altered tryptophan catabolism, generating
excessive kynurenine, a primary AhR activator [15]. Conversely,
AhR inhibitors could block or disrupt Mycoplasma’s role in bi-
nary weapons by various actions, including altering the integrin
motif, which connects pathogens with the host extracellular matrix
(ECM) [16,17]. ECM disruption can lead to increased blood-brain
barrier (BBB) and gut barrier permeability, a characteristic of
neuropsychiatric illnesses and inflammatory bowel disease (IBD)
[18]. Furthermore, lipid-associated membrane proteins (LAMPs)
of Mycoplasma fermentans and Mycoplasma hominis have been
shown to upregulate cortisol secretion, connecting this bacterium
to dysfunctional biological barriers, post-traumatic stress disorder
(PTSD), and chronic fatigue [19].
Mycoplasmas destabilize the genome and exhibit carcinogenic po-
tential. Host cells respond by activating cellular senescence, an
established antitumor defense mechanism [20]. However, cellular
senescence has been associated with several neuropsychiatric con-
ditions, including MDD [21-24]. Virus-induced senescence (VIS)
refers to the capability of many viruses, including SARS-CoV-2,
to induce premature cellular/neuronal senescence and subsequent
depression. Indeed, the prevalence of depression and suicide in-
creased dramatically during the COVID-19 pandemic [25,26].
Biological warfare, synthetic microbiology, and
virology
Biological warfare involves pathogens such as bacteria, viruses,
and fungi that cause disease, death, or environmental damage [27].
As many of these agents enter the brain and trigger pathology, this
definition also includes neuropsychiatric illness.
Biological warfare was used for thousands of years by military
commanders throughout history, and civilizations realized that in-
dividuals who died of infectious diseases could be used as weap-
ons if their bodies were left to decompose in the enemy water or
food supply. Moreover, scarves from people with leprosy were of-
ten sold in enemy territory to ignite epidemics before wars.
Synthetic biology started with Lo’s Mycoplasma in 1993 and
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has developed rapidly. Whether synthetic microorganisms affect
the brain is currently unknown. Extinct bacteria or viruses were
brought back to life without considering their interaction with
modern microbes and humans and the possibility of triggering ep-
idemics.
In 1997, Taubenberger and coworkers recovered viral RNA from
the 1918 Spanish Flu in frozen tissues and bodies preserved in per-
mafrost and rebuilt the virus despite the risk of an outbreak [28].
In 2002, Cello’s team constructed a synthetic poliovirus using
original cDNA and RNA, officially establishing the discipline of
synthetic virology. Moreover, ancient viruses that infected our
ancestors, such as human endogenous retrovirus (HERVs) acti-
vation, were implemented in 2002-2003 regardless of the risks.
The same reasoning was given for building synthetic SARS-CoV
viruses using RNA from that year’s outbreak [29].
Binary bioweapons were unknown to the Western military estab-
lishment until 1992, when a Soviet Army biologist defected with
this information. He later published a chapter, “Next Generation
Bioweapons: Genetic Engineering and Biological Warfare,” in a
2004 book entitled “The Gathering Biological Warfare Storm.”
In this work, Temple 23 (defector’s code name) described several
Soviet binary bioweapon projects, including a nonvirulent plague
(Yersinia pestis) that could be handled safely. Still, it became dead-
ly and antibiotic-resistant in combination with a virus (classified).
Centers for Disease Control and Prevention (CDC) have catego-
rized pathogens and toxins into three groups based on their poten-
tial use in developing biological weapons. Group A includes sig-
nificant pathogens, such as Anthrax, Botulism, Plague, etc. Group
B (biological modulators) include binary partners, plasmids, and
microbial antigens. Group C consists of emerging pathogens, in-
cluding synthetic bacteria and viruses, with a high potential for
use in bioterrorism. It is noteworthy that both Mycoplasma and
SARS-CoV-2 are enumerated as potential bioweapons:
http://www.selectagents.gov/SelectAgentsandToxinsList.html
and
https://www.niaid.nih.gov/topics/biodefenserelated/biodefense/
pages/cata.aspx
Mycoplasmas, the ubiquitous and secretive slow killers
Mycoplasmas belong to the Mollicutes family, microbes without
a cell wall, surrounded by a sterol-rich plasma membrane, en-
gendering a liposome-like structure. Sterols and their principal
representative, cholesterol, are components of the lipid rafts and,
therefore, crucial for SARS-CoV-2 infectivity [30]. For example,
people with altered raft zymosterol, 24-dehydrolathosterol, or des-
mosterol have been associated with poor COVID-19 prognosis,
emphasizing the antiviral role of these lipids [31]. Indeed, im-
paired cholesterol synthesis enhances viral infection, suggesting
that the SARS-CoV-2 thrives by usurping host cholesterol metab-
olism.
The clinical picture of viruses and Mycoplasma infection over-
lap at many points, further complicating the differential diagnosis
[32,33]. Moreover, diagnostic tests, including Mycoplasma spe-
cies serology, culture, and even nucleic acid amplification, such
as PCR, are marred by numerous limitations [34]. In this regard,
false-positive and --negative COVID-19 serological test results
have been reported in many patients with Mycoplasma pneumoni-
ae, highlighting the limitation of these assays [35]. The next-gen-
eration sequencing by shotgun methodology appears promising
for differentiating Mycoplasma from SARS-CoV-2 and may help
diagnose long COVID [36]. However, leukopenia, lymphocytope-
nia, thrombocytopenia, and thromboembolism were documented
in SARS-CoV-2 and Mycoplasma infections, further highlight-
ing their intertwined etiopathogenesis [37]. Furthermore, specific
anti-microbial treatments, such as azithromycin or tetracyclines,
were beneficial for Mycoplasma and COVID-19, suggesting a
likely silent partnership between these quite different infections
[38]. Another enhancer of the Mycoplasma/SARS-CoV-2 sym-
biosis, the RGD integrin motif, is expressed by both pathogens,
suggesting that, independently of ACE-2, the integrin pathway en-
ables viral entry [39]. Other ECM proteins, including reelin and
AhR, have been implicated in severe mental illness, including
SCZ. In addition, as both Mycoplasma and SARS-CoV-2 express
fibronectin (FBN), these pathogens may fuse, engendering com-
bined pathology [40]. It was suggested that the SARS-CoV-2 virus
could be a bacteriophage “hiding” inside Mycoplasma, thus avert-
ing host immune defenses [41].
Integrin originates in the cytoskeleton, exits the cell through the
cholesterol-rich lipid rafts, and changes length as it connects to
intra and extracellular proteins. The dimensional shift of the integ-
rin molecule acts as a switch, initiating or terminating the contact
with other ECM proteins. Depending on the location of the ligand
attachment, contact between intra and extracellular proteins may
be activated or inhibited [42]. For example, when a ligand binds
to the cytoplasmic domain of the integrin molecule, the extracellu-
lar integrin portion elongates, establishing contact with the ECM
components [43,44]. Conversely, when a ligand binds to the extra-
cellular portion, the integrin shortens, terminating the interaction
with ECM proteins [45]. Integrins’ ability to influence signaling
between intra and extracellular molecular assemblies, especially
in neurons, highlights integrin’s transistor-like qualities, including
access to Boolean logic gates, the building blocks of computation.
This indicates that the SARS-CoV-2/Mycoplasma complex affects
information processing by targeting integrins, probably account-
ing for cognitive changes or “brain fog” experienced by many
COVID-19 patients [45,46]. This may also explain the role of
ECM proteins, including integrin, reelin, and AhR, in psychosis,
including SCZ. Interestingly, new-onset psychosis has been asso-
ciated with integrins, AhR, and reelin.
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Figure 1. Integrins originate in the actin filaments of the cellu-
lar cytoskeleton, cross the cell membrane, and interact with the
extracellular matrix (ECM) molecules. Uniting intra- and extra-
cellular molecular assemblies supports cognition and perhaps
awareness. Ligand-binding to integrins lengthens or shortens
the molecule, connecting and disconnecting intra- and extracel-
lular molecular assemblies. This may explain the difference in
information processing during wakefulness vs. sleep [47].
Putting it all together, Mycoplasma and SARS-CoV-2 bind to
ECM proteins, disrupting the function of integrins in somatic cells
and neurons and information processing. Due to its liposome re-
semblance, Mycoplasma can be utilized as a virus-transporting
vehicle, facilitating the development of binary bioweapons.
SARS-CoV-2 and Mycoplasma-induced premature en-
dothelial senescence
In 1961, Leonard Hayflick discovered that human cells undergo
40-60 division cycles, after which they enter a state of proliferative
arrest marked by an active and re-wired metabolism that generates
toxic molecules, known generically as senescence-associated se-
cretory phenotype (SASP) [48]. Due to their intimate contact with
the circulatory system, senescent endothelial cells (EC) release
SASP directly into the systemic circulation, spreading senescence
throughout the body. For this reason, many viruses, including
SARS-CoV-2, usurp ECs, facilitating viral infection by activating
VIS. Depression and other neuropsychiatric disorders are associ-
ated with upregulated senescent markers such as p16, p53, SASP,
and major depressive disorder (MDD)[21,49,50].
Senescent cells provide a hospitable environment for viral proge-
ny due to the abundance of intracellular iron, which can be up to
40 times higher in old than in young cells [51]. In this regard, both
the SARS-CoV-2 virus and Mycoplasma possess the capability of
inducing premature cellular senescence, a feature exploited by the
manufacturers of biological weapons. Indeed, the accelerated ag-
ing of the enemy population, affecting combat readiness, is highly
desirable for population reduction and disseminating depression,
docility, and reluctance for combat. Furthermore, depression treat-
ment, especially SSRIs (selective serotonin reuptake inhibitors),
may cause judgment errors, such as accepting unfair outcomes to
avoid confrontation [52].
Angiotensin II (ANG II,) upregulated by the SARS-CoV-2 vi-
rus, induces cellular senescence, further contributing to organis-
mal aging [53]. Indeed, combining VIS with other lethal means,
such as drugs, makes much sense from foreign military planners’
standpoint because it reduces the number of combat-ready troops.
Therefore, releasing a virus before a military conflict can be part
of the overall planning.
At the cellular level, the accumulation of aging cells can over-
whelm efferocytosis (elimination of damaged cells), exacerbating
inflammation and promoting chronic diseases [54].
Disturbances of cholesterol metabolism and the renin-angiotensin
system (RAS) are the key drivers of senescence-associated with
SARS-CoV-2 and Mycoplasma.
Under normal circumstances, cholesterol synthesis in the liver reg-
ulates cellular senescence, while oxidated cholesterol likely dis-
rupts this process, leading to premature senescence, as observed
in COVID-19 and HIV [55,56]. Oxidized cholesterol affects the
renin-angiotensin system (RAS) by increasing the activity of an-
giotensin II (ANG II), an endogenous toxin hydrolyzed by angio-
tensin-converting enzyme-2 (ACE-2) (Singh BM). Mycoplasma
infection can increase ANG II levels, while some Mycoplasma
strains possess specific ANG II binding sites, suggesting a direct
interaction between this bacterium and RAS [57,58].
COVID-19 has been associated with dysfunctional RAS, as the
SARS-CoV-2 virus attaching to ACE-2 turns off this enzyme,
leading to unopposed accumulation of ANG II and incapacitation
of the entire protective RAS branch (Fig.2 ). The MasR axis has
been implicated in the pathophysiology of depression and anxiety.
At the same time, high levels of Ang-(1–7) exert antidepressant
properties [59].
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Figure 2. The vertical and horizontal RAS branches. The ACE-
2/SARS-CoV-2 binding turns off the horizontal (protective)
branch, deleting NO and upregulating the toxic peroxynitrite.
As angiotensin-converting two enzyme (ACE-2) is “occupied”
by the virus, Angiotensin II (ANG II) levels increase, inducing
premature cellular senescence.
ANG II was associated with premature cellular senescence marked
by telomere attrition, a common finding in severe COVID-19 and
children with Hutchinson-Gilford progeria, a congenital syndrome
of accelerated aging [60,61].
Putting it all in perspective, accelerated aging may have been
the aim of the COVID/Mycoplasma binary complex. Premature
cellular senescence and accelerated aging are a strategy to lower
military combat readiness. Cellular senescence and subsequent
depression and other neuropsychiatric conditions affect motiva-
tion, energy, and the level of alertness necessary for successful
combat. Fatigue added to these symptoms contributes to weakness
and lowers the combatants’ morale.
Potential interventions
Combating the effects of the SARS-CoV-2/Mycoplasma complex
requires reversing or preventing the onset of the senescent pheno-
type. Until recently, cellular senescence was considered permanent
and irreversible. Currently, there is growing evidence that cellular
senescence may be reversed [62]. Moreover, senolytic drugs se-
lectively eliminate senescent and damaged cells, while senomor-
phic compounds delete senescent markers, such as SASP, p16, or
p21. Interestingly, these markers are directly related to MDD. For
example, SASP is considered by some researchers as a biomarker
for mood disorders [24]. Moreover, as the integrin motif connects
Mycoplasma with the virus, anti-integrin drugs might be an option
to prevent Mycoplasma/SARS-CoV-2 interaction (Fig.3)
Figure 3. Mycoplasma lacks a cell wall but contains a mem-
brane comprised of lipoproteins and sterols. This bacterium
resembles a liposome or lipid nanoparticle with the SARS-
CoV-2 virus as a cargo. SARS-CoV-2 and Mycoplasma con-
nect via the integrin (RGD) motif that attaches on the viral
side to the viral receptor-binding site (RBS) and to lipoprotein
on the Mycoplasma site. Major Mycoplasma components, in-
cluding RNA, DNA, ribosomes, and proteins, are shown. The
Mycoplasma/SARS-CoV-2 complex attaches to host ECM
proteins via integrin αVβ3, which the virus exploits to induce
senescence. Anti-integrin drugs may dissociate the virus from
Mycoplasma, interfering with the symbiosis.
Phosphoinositide-Dependent Kinase 1 (PDK-1) Inhibi-
tors
Novel data have shown that inhibitors of phosphoinositide-depen-
dent kinase 1 (PDK-1), such as kaempferol (also an AhR antag-
onist), may reverse the senescent phenotype [63]. On the other
hand, PDK1 activation of protein kinase B (Akt) and glycogen
synthase kinase three beta (GSK-3β) contribute to the pathogen-
esis of severe neuropsychiatric disorders [64]. In contrast, PDK-1
inhibitors may exert antipsychotic and antidepressant properties
by GSK-3β deactivation without the typical adverse effects of con-
ventional psychotropics.
AhR antagonists
The antipsychotic properties of AhR antagonists comprise the
proof of concept that excessive AhR activation triggers neuropa-
thology. The following natural and synthetic AhR inhibitors were
found therapeutic in severe mental illness, including affective dis-
orders.
Quercetin is a natural flavonoid, a plant pigment found in fruits,
that exhibits anti-inflammatory, antioxidant, and anticancer activi-
ties. It is a negative allosteric modulator of gamma-aminobutyric A
(GABA-A) receptors in the CNS and lowers gray matter loss [65].
Luteolin, a natural antipsychotic that reduces microglial inflamma-
tion, is currently in clinical trials for SCZ (NCT05204407) [66].
Alstonine is an indole alkaloid with antidepressant and antipsy-
chotic properties that does not affect dopaminergic pathways but
increases serotonergic transmission [67].
Apigenin is a plant-based remedy extract from Elsholtzia rugulosa
used by traditional African psychiatrists to treat mental illnesses.
In addition to antagonizing AhR, apigenin exhibits vasorelaxant
and antioxidant properties [68].
Synthetic AhR antagonists
Salicylamide is an analgesic drug that exerts a potent and long-last-
ing inhibition of the AhR-induced Cyp1a enzyme. In preclinical
studies, it has shown psychotropic properties [69].
IK-175, structure undisclosed, was shown by preclinical studies to
block lig-and-stimulated AhR activation of Cyp1a [70].
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HBU651 are novel synthetic AhR antagonists developed primarily
for cancer but appear to have a favorable profile for neuropsychi-
atric disorders [71].
Senotherapeutics
It is currently established that severe mental illness is associated
with cellular/neuronal senescence, indicating that endogenous or
exogenous toxins may play a key role in this pathology [72,73].
For example, viral or bacterial infections induce premature aging
in brain cells, which may trigger neuropsychiatric symptomatol-
ogy [74].
Senotherapeutics are natural or synthetic compounds that delay,
prevent, or reverse cellular/neuronal senescence. Senotherapeu-
tics comprise senolytics agents that facilitate the elimination of
senescent cells and senomorphic compounds capable of deleting
senescence markers, including SASP and Senescence-associated
beta-galactosidase (SA-β-gal) [75]. While it has been thought that
cellular senescence cannot be reversed in the past, newer studies
found that inhibiting 3–phosphoinositide-dependent protein ki-
nase 1 (PDK1) can revert cellular senescence in humans [63].
Senolytic antibiotics belong to a distinct class of agents, which in-
clude azithromycin, minocycline, and roxithromycin, and possess
neuroprotective, anti-inflammatory, and senolytic properties. For
example, it has been known for some time that minocycline may
be beneficial for neuropathology, suggesting that senolytics have a
place in psychiatry [76].
A senolytic vaccine, recently tested in progeroid mice, may ush-
er in a new era in neuropsychiatry, raising the possibility of vac-
cination or serum treatment for neuropsychiatric disorders [77].
Another immunological intervention, an antibody-drug conjugate
against a membrane senescence marker, was demonstrated to clear
senescent, damaged, or infected cells, emphasizing a new thera-
peutic strategy.
Mitochondrial transfer and transplantation
Mitochondria are former bacteria that retain the ability to “talk”
with microbes and influence their behavior. The endosymbiotic
theory proposes that mitochondria originated from bacteria and
archaea and formed intracellular organelles that benefit both part-
ners. Mitochondria generate energy in the form of ATP and coun-
teract the “low energy” symptoms of depression and fatiguing
disorders [78].
Cell-free mitochondrial DNA (cf-mtDNA) is a marker of IBD and
psychological stress [79,80]. For instance, loneliness and social-
ization deficit increased cf-mtDNA/TLR9 signaling, an inflam-
matory pathway. Furthermore, loneliness and isolation-upregu-
lated cf-mtDNA acts as a damage-associated molecular pattern
(DAMP), igniting “sterile” inflammation implicated in psycholog-
ical stress [81,82].
Mitochondrial transplantation experiments started in the 1980s
when naked organelles were co-incubated with various cell types
to facilitate mitochondrial internalization. Successful mitochon-
drial transplantation is currently possible on several cell types, in-
cluding cardiomyocytes [83].
Mitochondrial transplantation for rescuing neurons from apoptosis
has been performed successfully in animals and humans [84]. Nev-
ertheless, to the best of our knowledge, it has not been attempted
in mental illness.
Under physiological or pathological conditions, intercellular mi-
tochondrial transfer can occur via tunneling nanotubes (TNTs) or
extracellular vesicles (EVs).
Non-canonical mitochondrial transfer can occur through cell-cell
fusion, synaptosomes, or dendritic networks. Cell-cell fusion can
occur in senescent neurons that reenter the cell cycle but cannot
complete replication, remaining indefinitely in a fused state.
Besides its role in the intracellular compartment, a growing body
of evidence indicates that under physiological or pathological con-
ditions, mitochondria can be secreted into the extracellular space,
which plays a vital role in regulating metabolism and immunity
[85].
Preclinical research has shown that mitochondrial transplantation
decreases LPS-induced depression, emphasizing a possible thera-
peutic application for PTSD or MDD [86].
Conclusions
Approximately 47% of patients with COVID-19 have Mycoplas-
ma as a comorbidity. Mycoplasma is challenging to identify and a
frequent contaminant. Because of these characteristics, if detected
in a sample, Mycoplasma would be deemed contamination rather
than a clear sign of pathology.
Biological weapons target physical and mental readiness for com-
bat in enemy troops. Designer bacteria and viruses, unknown to
the human immune system, could trigger unpredictable respons-
es and cause unknown pathology and chronic illnesses. In other
words, the immune system may not recognize the acute phase of
diseases, allowing chronicity to settle in. Cellular senescence can
be attenuated by mitochondrial transplantation, senolytic, senom-
orphic drugs, PDK-1 Inhibitors, and AhR antagonists.
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Volume 1| Issue 1 | 1 of 9
Journal of Medical Research and Clinical Reviews
Review Article
Mycoplasma and SARS-CoV-2 Virus: A Marriage of Convenience or A Binary
Biological Weapon? A Psychiatrist’s Perspective
Adonis Sfera1,2,3*, Jacob J Anton4, and Sabine Hazan5
1Patton State Hospital,
2Loma Linda University,
3University of California Riverside
4California Baptist University,
5ProgenaBiome
*Correspondence: Adonis Sfera, Patton State Hospital, Patton, CA, USA
Citation: Adonis Sfera, Jacob J Anton, Sabine Hazan. Mycoplasma and SARS-CoV-2 Virus: A Marriage of Convenience
or a Binary Biological Weapon? A Psychiatrist’s Perspective. J Med Res Clin Rev. 2025; 1(1): 1-9.
Received Date: 18 February 2025;
Accepted Date: 24 February, 2025;
Published Date: 28 February, 2025.
ABSTRACT
Mycoplasma is the smallest, independently replicating microbe that lacks a cell wall and resembles a liposome because of its
sterol-rich cell membrane. Under pathological circumstances, Mycoplasmas cause respiratory and urogenital infections in
humans.
Human immunodeficiency virus (HIV) is known to be associated with Mycoplasma genitalium, suggesting that viruses may
commonly utilize Mycoplasmas to enhance infectivity. Along this line, COVID-19 critical illness was documented in individuals
with concomitant Mycoplasma infection, raising the possibility of a symbiotic relationship or binary biological weapon.
Binary biological weapons are comprised of two components that are safe to handle separately but, in combination, become
lethal. For example, concomitant infection with hepatitis D and B is deadly because the D virus takes advantage of the proteins
expressed by the B virus, turning this infection into a fatal disease.
Mycoplasmas have been known for their neuropsychiatric manifestations, including psychosis, anxiety, depressive disorders,
cognitive impairment, and schizophrenia. This is relevant as Mycoplasmas, like many antipsychotic drugs, enter host cells
via clathrin-dependent endocytic pathways, often remaining dormant in endosomes. Moreover, Mycoplasmas express aryl
hydrocarbon receptor, a transcription factor activated by many ligands relevant to neuropsychiatry, including dopamine, se-
rotonin, melatonin, clozapine, carbidopa, tryptophan, and microbial metabolites. Mycoplasma-expressed AhR, like its human
counterpart, senses environmental stimuli, including viruses, indicating that it may play a role in the Mycoplasma/SARS-CoV-2
symbiosis.
This perspective article examines Mycoplasma and its relationship with COVID-19, premature cellular senescence, and major
depressive disorder. We also discuss neuropathology potentially associated with designer pathogens and some therapeutic
strategies.
Key Words: Mycoplasma, Binary Biological Weapons, Neuropsychiatric Disorders, Cellular Senescence, Synthetic Biology
Introduction
Mycoplasma is the smallest, independently replicating microbe
discovered by Pasteur in the eighteenth century. It can be parasit-
ic or saprophytic and is found in plants, animals, insects, humus,
water, and sewage.
Detection of Mycoplasma in Golf War Illness (GWI) veter-
ans, patients with Human Immunodeficiency Virus (HIV), and
COVID-19 critical illness has brought this bacterium to the atten-
tion of researchers and clinicians as a possible bioweapon [1,2].
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 2 of 9
This is further substantiated by the fact that Mycoplasma was first
synthesized in a US military laboratory in 1993.
The recent COVID-19 pandemic has highlighted the disastrous
impact a pathogen can have on the population and economy of
the entire planet. Non-kinetic means for waging wars, often called
fifth-generation warfare, involve information, economy, health-
care, education, and other aspects of life that form the tapestry
of human society. Since battles are often won before ever fought,
influencing the enemy may start years or even decades before the
open hostilities. For example, making drugs of abuse available to
the enemy population leads to addictions, chronic diseases, dis-
ability, depression, suicide, and plummeting birth rates. All these
deplete the military-age population, influencing the outcome of
present or future wars while providing plausible deniability of
planned interference in the internal affairs of other nations.
The chronology of artificial Mycoplasma: Shyh-Ching Lo, chief of
the Division of Molecular Pathology at the Armed Forces Institute
of Pathology in Washington, built the first synthetic microorgan-
ism, Mycoplasma fermentans incognitus (Lo’s Mycoplasma) in
1993 (patent number 5,242,820). Interestingly, this Mycoplasma
was detected in 45% of patients with GWI, linking this pathogen
to fatiguing disorders. Along this line, Myalgic Encephalomyeli-
tis/Chronic Fatigue Syndrome (ME/C FS) and Fibromyalgia (FM)
have been linked to Mycoplasma infection, indicating a predilec-
tion for chronic illnesses with muscle pain [3]. In addition, Myco-
plasma fermentans incognitus strain enhances tissue plasminogen
activator (tPA), which converts plasminogen into the biologically
active plasmin, a protein that cleaves the S antigen of the SARS-
CoV-2 virus at the S1/S2 site, indicating a symbiotic relationship
between this virus and Mycoplasma, cooperation reminiscent of
Mycoplasma genitalium and Human Immunodeficiency Virus
(HIV) [4,5].
The next step in Mycoplasma weaponization occurred in 1995,
when the Institute for Genome Research in Rockville, Maryland,
sequenced the genome of Mycoplasma genitalium, opening the
door for synthetic biology in warfare [6].
The story of artificial Mycoplasma continues. In 2010, a com-
pletely synthetic Mycoplasma mycoides JCVI-syn1.0 was created
in the laboratory, contributing further to the weaponization of this
pathogen. After this, Mycoplasma JCVI-syn2.0 and 3.0 strains
were developed by minimizing the genome to the smallest size
compatible with survival [7,8].
Mycoplasmas are members of the Mollicutes class of bacteria, the
most straightforward and smallest known self-replicating micro-
organisms [9]. They can be commensal or pathogenic, the former
dwelling on the skin or oral cavity, while the latter are usually
found in the intracellular compartment [10].
COVID-19 is characterized by variable clinical outcomes, ranging
from few or no symptoms to critical illness and death. Several
novel studies have found that coinfection with Mycoplasma could
be the primary driver of unfavorable COVID-19 outcomes [11,12].
Indeed, epidemiological studies found 47% comorbidity between
SARS-CoV-2 and Mycoplasma, further indicating a symbiotic re-
lationship. Mycoplasmas benefit viruses as they disrupt host im-
munity by blocking antiviral antibodies. Moreover, viruses may
also use Mycoplasma as a vehicle for entry into host cells [13].
Several Mycoplasmas have been known for their neuropsychiatric
manifestations, including psychosis, anxiety, depressive disorders,
cognitive impairment, and schizophrenia (SCZ) [14]. Interest-
ingly, Mycoplasmas express aryl hydrocarbon receptor (AhR), a
transcription factor activated by many ligands relevant to neuro-
psychiatry, including dopamine, serotonin, melatonin, clozapine,
carbidopa, tryptophan, and microbial metabolites. The Mycoplas-
ma AhR, like its human counterpart, senses environmental stimuli,
including viruses, indicating that it may play a role in the Myco-
plasma/SARS-CoV-2 symbiosis.
SARS-CoV-2 infection altered tryptophan catabolism, generating
excessive kynurenine, a primary AhR activator [15]. Conversely,
AhR inhibitors could block or disrupt Mycoplasma’s role in bi-
nary weapons by various actions, including altering the integrin
motif, which connects pathogens with the host extracellular matrix
(ECM) [16,17]. ECM disruption can lead to increased blood-brain
barrier (BBB) and gut barrier permeability, a characteristic of
neuropsychiatric illnesses and inflammatory bowel disease (IBD)
[18]. Furthermore, lipid-associated membrane proteins (LAMPs)
of Mycoplasma fermentans and Mycoplasma hominis have been
shown to upregulate cortisol secretion, connecting this bacterium
to dysfunctional biological barriers, post-traumatic stress disorder
(PTSD), and chronic fatigue [19].
Mycoplasmas destabilize the genome and exhibit carcinogenic po-
tential. Host cells respond by activating cellular senescence, an
established antitumor defense mechanism [20]. However, cellular
senescence has been associated with several neuropsychiatric con-
ditions, including MDD [21-24]. Virus-induced senescence (VIS)
refers to the capability of many viruses, including SARS-CoV-2,
to induce premature cellular/neuronal senescence and subsequent
depression. Indeed, the prevalence of depression and suicide in-
creased dramatically during the COVID-19 pandemic [25,26].
Biological warfare, synthetic microbiology, and
virology
Biological warfare involves pathogens such as bacteria, viruses,
and fungi that cause disease, death, or environmental damage [27].
As many of these agents enter the brain and trigger pathology, this
definition also includes neuropsychiatric illness.
Biological warfare was used for thousands of years by military
commanders throughout history, and civilizations realized that in-
dividuals who died of infectious diseases could be used as weap-
ons if their bodies were left to decompose in the enemy water or
food supply. Moreover, scarves from people with leprosy were of-
ten sold in enemy territory to ignite epidemics before wars.
Synthetic biology started with Lo’s Mycoplasma in 1993 and
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 3 of 9
has developed rapidly. Whether synthetic microorganisms affect
the brain is currently unknown. Extinct bacteria or viruses were
brought back to life without considering their interaction with
modern microbes and humans and the possibility of triggering ep-
idemics.
In 1997, Taubenberger and coworkers recovered viral RNA from
the 1918 Spanish Flu in frozen tissues and bodies preserved in per-
mafrost and rebuilt the virus despite the risk of an outbreak [28].
In 2002, Cello’s team constructed a synthetic poliovirus using
original cDNA and RNA, officially establishing the discipline of
synthetic virology. Moreover, ancient viruses that infected our
ancestors, such as human endogenous retrovirus (HERVs) acti-
vation, were implemented in 2002-2003 regardless of the risks.
The same reasoning was given for building synthetic SARS-CoV
viruses using RNA from that year’s outbreak [29].
Binary bioweapons were unknown to the Western military estab-
lishment until 1992, when a Soviet Army biologist defected with
this information. He later published a chapter, “Next Generation
Bioweapons: Genetic Engineering and Biological Warfare,” in a
2004 book entitled “The Gathering Biological Warfare Storm.”
In this work, Temple 23 (defector’s code name) described several
Soviet binary bioweapon projects, including a nonvirulent plague
(Yersinia pestis) that could be handled safely. Still, it became dead-
ly and antibiotic-resistant in combination with a virus (classified).
Centers for Disease Control and Prevention (CDC) have catego-
rized pathogens and toxins into three groups based on their poten-
tial use in developing biological weapons. Group A includes sig-
nificant pathogens, such as Anthrax, Botulism, Plague, etc. Group
B (biological modulators) include binary partners, plasmids, and
microbial antigens. Group C consists of emerging pathogens, in-
cluding synthetic bacteria and viruses, with a high potential for
use in bioterrorism. It is noteworthy that both Mycoplasma and
SARS-CoV-2 are enumerated as potential bioweapons:
http://www.selectagents.gov/SelectAgentsandToxinsList.html
and
https://www.niaid.nih.gov/topics/biodefenserelated/biodefense/
pages/cata.aspx
Mycoplasmas, the ubiquitous and secretive slow killers
Mycoplasmas belong to the Mollicutes family, microbes without
a cell wall, surrounded by a sterol-rich plasma membrane, en-
gendering a liposome-like structure. Sterols and their principal
representative, cholesterol, are components of the lipid rafts and,
therefore, crucial for SARS-CoV-2 infectivity [30]. For example,
people with altered raft zymosterol, 24-dehydrolathosterol, or des-
mosterol have been associated with poor COVID-19 prognosis,
emphasizing the antiviral role of these lipids [31]. Indeed, im-
paired cholesterol synthesis enhances viral infection, suggesting
that the SARS-CoV-2 thrives by usurping host cholesterol metab-
olism.
The clinical picture of viruses and Mycoplasma infection over-
lap at many points, further complicating the differential diagnosis
[32,33]. Moreover, diagnostic tests, including Mycoplasma spe-
cies serology, culture, and even nucleic acid amplification, such
as PCR, are marred by numerous limitations [34]. In this regard,
false-positive and --negative COVID-19 serological test results
have been reported in many patients with Mycoplasma pneumoni-
ae, highlighting the limitation of these assays [35]. The next-gen-
eration sequencing by shotgun methodology appears promising
for differentiating Mycoplasma from SARS-CoV-2 and may help
diagnose long COVID [36]. However, leukopenia, lymphocytope-
nia, thrombocytopenia, and thromboembolism were documented
in SARS-CoV-2 and Mycoplasma infections, further highlight-
ing their intertwined etiopathogenesis [37]. Furthermore, specific
anti-microbial treatments, such as azithromycin or tetracyclines,
were beneficial for Mycoplasma and COVID-19, suggesting a
likely silent partnership between these quite different infections
[38]. Another enhancer of the Mycoplasma/SARS-CoV-2 sym-
biosis, the RGD integrin motif, is expressed by both pathogens,
suggesting that, independently of ACE-2, the integrin pathway en-
ables viral entry [39]. Other ECM proteins, including reelin and
AhR, have been implicated in severe mental illness, including
SCZ. In addition, as both Mycoplasma and SARS-CoV-2 express
fibronectin (FBN), these pathogens may fuse, engendering com-
bined pathology [40]. It was suggested that the SARS-CoV-2 virus
could be a bacteriophage “hiding” inside Mycoplasma, thus avert-
ing host immune defenses [41].
Integrin originates in the cytoskeleton, exits the cell through the
cholesterol-rich lipid rafts, and changes length as it connects to
intra and extracellular proteins. The dimensional shift of the integ-
rin molecule acts as a switch, initiating or terminating the contact
with other ECM proteins. Depending on the location of the ligand
attachment, contact between intra and extracellular proteins may
be activated or inhibited [42]. For example, when a ligand binds
to the cytoplasmic domain of the integrin molecule, the extracellu-
lar integrin portion elongates, establishing contact with the ECM
components [43,44]. Conversely, when a ligand binds to the extra-
cellular portion, the integrin shortens, terminating the interaction
with ECM proteins [45]. Integrins’ ability to influence signaling
between intra and extracellular molecular assemblies, especially
in neurons, highlights integrin’s transistor-like qualities, including
access to Boolean logic gates, the building blocks of computation.
This indicates that the SARS-CoV-2/Mycoplasma complex affects
information processing by targeting integrins, probably account-
ing for cognitive changes or “brain fog” experienced by many
COVID-19 patients [45,46]. This may also explain the role of
ECM proteins, including integrin, reelin, and AhR, in psychosis,
including SCZ. Interestingly, new-onset psychosis has been asso-
ciated with integrins, AhR, and reelin.
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 4 of 9
Figure 1. Integrins originate in the actin filaments of the cellu-
lar cytoskeleton, cross the cell membrane, and interact with the
extracellular matrix (ECM) molecules. Uniting intra- and extra-
cellular molecular assemblies supports cognition and perhaps
awareness. Ligand-binding to integrins lengthens or shortens
the molecule, connecting and disconnecting intra- and extracel-
lular molecular assemblies. This may explain the difference in
information processing during wakefulness vs. sleep [47].
Putting it all together, Mycoplasma and SARS-CoV-2 bind to
ECM proteins, disrupting the function of integrins in somatic cells
and neurons and information processing. Due to its liposome re-
semblance, Mycoplasma can be utilized as a virus-transporting
vehicle, facilitating the development of binary bioweapons.
SARS-CoV-2 and Mycoplasma-induced premature en-
dothelial senescence
In 1961, Leonard Hayflick discovered that human cells undergo
40-60 division cycles, after which they enter a state of proliferative
arrest marked by an active and re-wired metabolism that generates
toxic molecules, known generically as senescence-associated se-
cretory phenotype (SASP) [48]. Due to their intimate contact with
the circulatory system, senescent endothelial cells (EC) release
SASP directly into the systemic circulation, spreading senescence
throughout the body. For this reason, many viruses, including
SARS-CoV-2, usurp ECs, facilitating viral infection by activating
VIS. Depression and other neuropsychiatric disorders are associ-
ated with upregulated senescent markers such as p16, p53, SASP,
and major depressive disorder (MDD)[21,49,50].
Senescent cells provide a hospitable environment for viral proge-
ny due to the abundance of intracellular iron, which can be up to
40 times higher in old than in young cells [51]. In this regard, both
the SARS-CoV-2 virus and Mycoplasma possess the capability of
inducing premature cellular senescence, a feature exploited by the
manufacturers of biological weapons. Indeed, the accelerated ag-
ing of the enemy population, affecting combat readiness, is highly
desirable for population reduction and disseminating depression,
docility, and reluctance for combat. Furthermore, depression treat-
ment, especially SSRIs (selective serotonin reuptake inhibitors),
may cause judgment errors, such as accepting unfair outcomes to
avoid confrontation [52].
Angiotensin II (ANG II,) upregulated by the SARS-CoV-2 vi-
rus, induces cellular senescence, further contributing to organis-
mal aging [53]. Indeed, combining VIS with other lethal means,
such as drugs, makes much sense from foreign military planners’
standpoint because it reduces the number of combat-ready troops.
Therefore, releasing a virus before a military conflict can be part
of the overall planning.
At the cellular level, the accumulation of aging cells can over-
whelm efferocytosis (elimination of damaged cells), exacerbating
inflammation and promoting chronic diseases [54].
Disturbances of cholesterol metabolism and the renin-angiotensin
system (RAS) are the key drivers of senescence-associated with
SARS-CoV-2 and Mycoplasma.
Under normal circumstances, cholesterol synthesis in the liver reg-
ulates cellular senescence, while oxidated cholesterol likely dis-
rupts this process, leading to premature senescence, as observed
in COVID-19 and HIV [55,56]. Oxidized cholesterol affects the
renin-angiotensin system (RAS) by increasing the activity of an-
giotensin II (ANG II), an endogenous toxin hydrolyzed by angio-
tensin-converting enzyme-2 (ACE-2) (Singh BM). Mycoplasma
infection can increase ANG II levels, while some Mycoplasma
strains possess specific ANG II binding sites, suggesting a direct
interaction between this bacterium and RAS [57,58].
COVID-19 has been associated with dysfunctional RAS, as the
SARS-CoV-2 virus attaching to ACE-2 turns off this enzyme,
leading to unopposed accumulation of ANG II and incapacitation
of the entire protective RAS branch (Fig.2 ). The MasR axis has
been implicated in the pathophysiology of depression and anxiety.
At the same time, high levels of Ang-(1–7) exert antidepressant
properties [59].
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 5 of 9
Figure 2. The vertical and horizontal RAS branches. The ACE-
2/SARS-CoV-2 binding turns off the horizontal (protective)
branch, deleting NO and upregulating the toxic peroxynitrite.
As angiotensin-converting two enzyme (ACE-2) is “occupied”
by the virus, Angiotensin II (ANG II) levels increase, inducing
premature cellular senescence.
ANG II was associated with premature cellular senescence marked
by telomere attrition, a common finding in severe COVID-19 and
children with Hutchinson-Gilford progeria, a congenital syndrome
of accelerated aging [60,61].
Putting it all in perspective, accelerated aging may have been
the aim of the COVID/Mycoplasma binary complex. Premature
cellular senescence and accelerated aging are a strategy to lower
military combat readiness. Cellular senescence and subsequent
depression and other neuropsychiatric conditions affect motiva-
tion, energy, and the level of alertness necessary for successful
combat. Fatigue added to these symptoms contributes to weakness
and lowers the combatants’ morale.
Potential interventions
Combating the effects of the SARS-CoV-2/Mycoplasma complex
requires reversing or preventing the onset of the senescent pheno-
type. Until recently, cellular senescence was considered permanent
and irreversible. Currently, there is growing evidence that cellular
senescence may be reversed [62]. Moreover, senolytic drugs se-
lectively eliminate senescent and damaged cells, while senomor-
phic compounds delete senescent markers, such as SASP, p16, or
p21. Interestingly, these markers are directly related to MDD. For
example, SASP is considered by some researchers as a biomarker
for mood disorders [24]. Moreover, as the integrin motif connects
Mycoplasma with the virus, anti-integrin drugs might be an option
to prevent Mycoplasma/SARS-CoV-2 interaction (Fig.3)
Figure 3. Mycoplasma lacks a cell wall but contains a mem-
brane comprised of lipoproteins and sterols. This bacterium
resembles a liposome or lipid nanoparticle with the SARS-
CoV-2 virus as a cargo. SARS-CoV-2 and Mycoplasma con-
nect via the integrin (RGD) motif that attaches on the viral
side to the viral receptor-binding site (RBS) and to lipoprotein
on the Mycoplasma site. Major Mycoplasma components, in-
cluding RNA, DNA, ribosomes, and proteins, are shown. The
Mycoplasma/SARS-CoV-2 complex attaches to host ECM
proteins via integrin αVβ3, which the virus exploits to induce
senescence. Anti-integrin drugs may dissociate the virus from
Mycoplasma, interfering with the symbiosis.
Phosphoinositide-Dependent Kinase 1 (PDK-1) Inhibi-
tors
Novel data have shown that inhibitors of phosphoinositide-depen-
dent kinase 1 (PDK-1), such as kaempferol (also an AhR antag-
onist), may reverse the senescent phenotype [63]. On the other
hand, PDK1 activation of protein kinase B (Akt) and glycogen
synthase kinase three beta (GSK-3β) contribute to the pathogen-
esis of severe neuropsychiatric disorders [64]. In contrast, PDK-1
inhibitors may exert antipsychotic and antidepressant properties
by GSK-3β deactivation without the typical adverse effects of con-
ventional psychotropics.
AhR antagonists
The antipsychotic properties of AhR antagonists comprise the
proof of concept that excessive AhR activation triggers neuropa-
thology. The following natural and synthetic AhR inhibitors were
found therapeutic in severe mental illness, including affective dis-
orders.
Quercetin is a natural flavonoid, a plant pigment found in fruits,
that exhibits anti-inflammatory, antioxidant, and anticancer activi-
ties. It is a negative allosteric modulator of gamma-aminobutyric A
(GABA-A) receptors in the CNS and lowers gray matter loss [65].
Luteolin, a natural antipsychotic that reduces microglial inflamma-
tion, is currently in clinical trials for SCZ (NCT05204407) [66].
Alstonine is an indole alkaloid with antidepressant and antipsy-
chotic properties that does not affect dopaminergic pathways but
increases serotonergic transmission [67].
Apigenin is a plant-based remedy extract from Elsholtzia rugulosa
used by traditional African psychiatrists to treat mental illnesses.
In addition to antagonizing AhR, apigenin exhibits vasorelaxant
and antioxidant properties [68].
Synthetic AhR antagonists
Salicylamide is an analgesic drug that exerts a potent and long-last-
ing inhibition of the AhR-induced Cyp1a enzyme. In preclinical
studies, it has shown psychotropic properties [69].
IK-175, structure undisclosed, was shown by preclinical studies to
block lig-and-stimulated AhR activation of Cyp1a [70].
J Med Res Clin Rev; 2025
Volume 1| Issue 1 | 6 of 9
HBU651 are novel synthetic AhR antagonists developed primarily
for cancer but appear to have a favorable profile for neuropsychi-
atric disorders [71].
Senotherapeutics
It is currently established that severe mental illness is associated
with cellular/neuronal senescence, indicating that endogenous or
exogenous toxins may play a key role in this pathology [72,73].
For example, viral or bacterial infections induce premature aging
in brain cells, which may trigger neuropsychiatric symptomatol-
ogy [74].
Senotherapeutics are natural or synthetic compounds that delay,
prevent, or reverse cellular/neuronal senescence. Senotherapeu-
tics comprise senolytics agents that facilitate the elimination of
senescent cells and senomorphic compounds capable of deleting
senescence markers, including SASP and Senescence-associated
beta-galactosidase (SA-β-gal) [75]. While it has been thought that
cellular senescence cannot be reversed in the past, newer studies
found that inhibiting 3–phosphoinositide-dependent protein ki-
nase 1 (PDK1) can revert cellular senescence in humans [63].
Senolytic antibiotics belong to a distinct class of agents, which in-
clude azithromycin, minocycline, and roxithromycin, and possess
neuroprotective, anti-inflammatory, and senolytic properties. For
example, it has been known for some time that minocycline may
be beneficial for neuropathology, suggesting that senolytics have a
place in psychiatry [76].
A senolytic vaccine, recently tested in progeroid mice, may ush-
er in a new era in neuropsychiatry, raising the possibility of vac-
cination or serum treatment for neuropsychiatric disorders [77].
Another immunological intervention, an antibody-drug conjugate
against a membrane senescence marker, was demonstrated to clear
senescent, damaged, or infected cells, emphasizing a new thera-
peutic strategy.
Mitochondrial transfer and transplantation
Mitochondria are former bacteria that retain the ability to “talk”
with microbes and influence their behavior. The endosymbiotic
theory proposes that mitochondria originated from bacteria and
archaea and formed intracellular organelles that benefit both part-
ners. Mitochondria generate energy in the form of ATP and coun-
teract the “low energy” symptoms of depression and fatiguing
disorders [78].
Cell-free mitochondrial DNA (cf-mtDNA) is a marker of IBD and
psychological stress [79,80]. For instance, loneliness and social-
ization deficit increased cf-mtDNA/TLR9 signaling, an inflam-
matory pathway. Furthermore, loneliness and isolation-upregu-
lated cf-mtDNA acts as a damage-associated molecular pattern
(DAMP), igniting “sterile” inflammation implicated in psycholog-
ical stress [81,82].
Mitochondrial transplantation experiments started in the 1980s
when naked organelles were co-incubated with various cell types
to facilitate mitochondrial internalization. Successful mitochon-
drial transplantation is currently possible on several cell types, in-
cluding cardiomyocytes [83].
Mitochondrial transplantation for rescuing neurons from apoptosis
has been performed successfully in animals and humans [84]. Nev-
ertheless, to the best of our knowledge, it has not been attempted
in mental illness.
Under physiological or pathological conditions, intercellular mi-
tochondrial transfer can occur via tunneling nanotubes (TNTs) or
extracellular vesicles (EVs).
Non-canonical mitochondrial transfer can occur through cell-cell
fusion, synaptosomes, or dendritic networks. Cell-cell fusion can
occur in senescent neurons that reenter the cell cycle but cannot
complete replication, remaining indefinitely in a fused state.
Besides its role in the intracellular compartment, a growing body
of evidence indicates that under physiological or pathological con-
ditions, mitochondria can be secreted into the extracellular space,
which plays a vital role in regulating metabolism and immunity
[85].
Preclinical research has shown that mitochondrial transplantation
decreases LPS-induced depression, emphasizing a possible thera-
peutic application for PTSD or MDD [86].
Conclusions
Approximately 47% of patients with COVID-19 have Mycoplas-
ma as a comorbidity. Mycoplasma is challenging to identify and a
frequent contaminant. Because of these characteristics, if detected
in a sample, Mycoplasma would be deemed contamination rather
than a clear sign of pathology.
Biological weapons target physical and mental readiness for com-
bat in enemy troops. Designer bacteria and viruses, unknown to
the human immune system, could trigger unpredictable respons-
es and cause unknown pathology and chronic illnesses. In other
words, the immune system may not recognize the acute phase of
diseases, allowing chronicity to settle in. Cellular senescence can
be attenuated by mitochondrial transplantation, senolytic, senom-
orphic drugs, PDK-1 Inhibitors, and AhR antagonists.
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