1. Review
Potential Therapy for Neisseria
Gonorrhoeae Infections With
Human Chorionic Gonadotropin
C.V. Rao, PhD1
Abstract
The scientific evidence suggests that Neisseria gonorrhoeae (NG) infects human fallopian tubes by molecular mimicry in which
pathogens act like a ligand to bind to epithelial cell surface human chorionic gonadotrophin (hCG)/luteinizing hormone (LH)
receptors. The hCG-like molecule has been identified as ribosomal protein L12 in NG coat surface. Human fallopian tube epi-
thelial cells have been shown to contain functional hCG/LH receptors. As previously shown in human fallopian tube organ and cell
culture studies, cellular invasion and infection can be prevented by exposing the cells to excess hCG, which would outnumber and
outcompete NG for receptor binding. Based on these data, we suggest testing hCG in clinical trials on infected women.
Keywords
human chorionic gonadotropin, Neisseria gonorrhoeae, fallopian tubes, hCG/LH receptors
Introduction
Neisseria gonorrhoeae (NG) is 1 among the 7 other pathogens
that cause sexually transmitted diseases (STDs), also popularly
known as venereal diseases. These infections are contagious
and can be treated with antibiotics. The prevalence of NG
infections is higher among women than in men, high among
sexually active adolescents, and closely associated with an
onset of menses.1,2
According to the US Center for Disease
Control and Prevention estimates, 334 826 cases of NG infec-
tions were reported in 2012, and the infection rate has increased
by 4.1% since 2011. These numbers will be much higher world-
wide, and all the numbers are likely to be underestimates.
These infections have a high economic and human cost, in
terms of medical treatments, productivity loss in the work
place, pain, suffering, and social stigma. Left untreated, these
infections can progress into salpingitis, pelvic inflammatory
disease, increased risk of infertility, ectopic pregnancy, and
so forth. Hematogenous disseminated infection can lead to sev-
eral systemic illnesses and even death in some cases.
Fallopian tubes are commonly involved in the infections by
molecular mimicry, in which NG acts like a ligand to bind to
epithelial cell surface receptors.3
Supporting this possibility,
NG has been found to express human chorionic gonadotrophin
(hCG)-like molecule in their coat surface and human fallopian
tube epithelial cells have been shown to contain functional
hCG/luteinizing hormone (LH) receptors.4,5
The hCG-like
molecules have been identified as ribosomal protein L12
(RPL12) in NG.6,7
It is not an ortholog of hCG. It is simply a
prokaryotic single polypeptide chain of 123 amino acids with
a molecular mass of about 13 kDa. It is not glycosylated. It
is constitutively expressed, membrane associated, surface
exposed, and immunologically similar to hCG and its binding
can be blocked by hCG.6,7
It serves as a receptor sensor.6
The
RPL12 is present in both noninvasive and invasive NG pheno-
types, which suggests that RPL12 may only facilitate NG bind-
ing to hCG/LH receptors, regardless of their virulence. It is the
first structurally unrelated protein, to the author’s knowledge,
which seems to bind hCG/LH receptors in a reversible manner.
It should be interesting to determine how exactly RPL12 can
bind to hCG/LH receptors, its binding characteristics, and
whether it can activate signaling systems and cellular responses
as hCG and LH.
Binding of NG may induce other molecules such as adhesin
that seem to be required for invasion of NG into the cells.
Adhesin is not present in NG grown in culture media alone,
thus exposure to receptor-positive cells is required.6
In addition
1
Departments of Cellular Biology and Pharmacology, Molecular and Human
Genetics and Obstetrics and Gynecology, Reproduction and Development
Program, Herbert Wertheim College of Medicine, Florida International
University, Miami, FL, USA
Corresponding Author:
C.V. Rao, Departments of Cellular Biology and Pharmacology, Molecular and
Human Genetics and Obstetrics and Gynecology, Reproduction and Devel-
opment Program, Herbert Wertheim College of Medicine, Florida Interna-
tional University, 11200 SW 8th Street, GL 495 C, Miami, FL 33199, USA.
Email: crao@fiu.edu
Reproductive Sciences
2015, Vol. 22(12) 1484-1487
ª The Author(s) 2015
Reprints and permission:
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DOI: 10.1177/1933719115580998
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2. to adhesin, there maybe other molecules that determine the
route of some of the internalized NG.
Fallopian Tube hCG/LH Receptors
Human fallopian tubes contain hCG/LH receptors in epithelial
and muscle cell layers as well as in blood vessels.5
However,
epithelial cells contain more than smooth muscle and blood
vessels, with no difference between ciliated and nonciliated
cells.5
The receptor levels are higher in ampulla than in isthmus
and higher in secretory phase than in the proliferative phase or
in postpartum tubes.5
The tubes from postmenopausal women
contain the least amount of receptors.5
The activation of fallopian tube receptors affects the
contractility as well as increases 5-lipoxygenase, cyclooxy-
genases (COXs) -1 and -2, and the products of their catalytic
activity, that is, 5-hydroxyeicosatetraenoic acid and prosta-
glandin E2 (PGE2).5,8-10
The increased PGE2 comes from
COX-2 rather than COX-1.5,10
Treatment with hCG upregu-
lates expression of COX-2 gene by increasing the stability of
its transcripts rather than by increasing the transcription rate
of the gene.10
Fallopian tubes play a central role in the events of gamete
transport, their maturation and fertilization, early embryonic
growth and development, and its timely transport for implanta-
tion in the uterus. These events are regulated by contractions,
ciliary beat, epithelial cell secretions, and blood flow changes
that are widely attributed to eicosanoids.11-16
Through increas-
ing their formation, hCG may regulate all the these tubal events
that are important for early pregnancy.
Oviductal glycoprotein (OGP), which also plays an impor-
tant role in gamete maturation, fertilization and early embryo-
nic growth, and development, is regulated by hCG/LH.17
As
expected, the hCG-induced increase in OGP synthesis
requires the presence of its receptors and cyclic adenosine
monophosphate/protein kinase A signaling.17
Treatment of
tubal epithelial cells with hCG increases OGP gene expres-
sion by increasing the stability of its transcripts rather than
by increasing the transcription rate of the gene.17
Cocultures
of early embryos with tubal epithelial cells increase their
growth and development, more than culturing in media
alone.18-20
The hCG treatment further enhances the benefit
of coculturing, and blocking the OGP synthesis reverses the
benefit.20
These findings may explain how embryos trans-
ferred from cocultures with autologous endometrial epithelial
cells can improve pregnancy chances in women who repeat-
edly fail after the transfer of embryos cultured in media alone,
in in vitro fertilization embryo transfer procedures.21-23
The
data also suggest that hCG treatment of cocultures may fur-
ther increase the chances of pregnancy.
Endogenous LH and hCG present during the periovulatory
period and early pregnancy, respectively, or exogenous hCG
administered for ovulation induction or for any therapeutic
reasons, may act on fallopian tubes to promote the early preg-
nancy events. It now appears that certain pathogens such
as NG and others, by virtue of the expression of hCG or
LH-like molecules in their coat surfaces, can hijack these
receptors to get themselves into the cells.4,24-31
Molecular Mimicry
The receptor binding per se, which eventually enables NG to
enter human fallopian tube epithelial cells, is not adequate for
infection. This is exemplified by the observations that animal
tubes, which also contain the receptors, are not prone to NG
infection.3,4,27
In addition, other parts of human reproductive
tract are not infected to the same extent as fallopian tubes,
although they also contain these receptors.32,33
This suggests
that the susceptibility of human fallopian tubes to infection,
compared with animal tubes, could be due to molecules that
human tubes can only produce upon coming in contact with
NG. These molecules remain to be discovered. The greater
involvement of fallopian tubes than the lower reproductive
tract could be partly anatomical and the rest could be due to
molecules that only fallopian tubes epithelial cells can pro-
duce at least in abundance as compared with the other repro-
ductive tract epithelial cells. These molecules are also yet to
be identified.
The following infection scenario can be drawn from the
published studies on the NG infections and hormone cell sur-
face receptor interactions.27,34,35
However, many knowledge
gaps remain. Initially NG comes in contact with fallopian tube
epithelial cell hCG/LH receptors to bind with a low affinity.27
RPL12 in NG surface may facilitate this low affinity bind-
ing.6,7
This binding induces the synthesis of a unique adhesin
molecules that increase the binding affinity.7
Once the bind-
ing affinity is increased, NG becomes invasive and the NG–
receptor complexes undergo receptor-mediated endocytosis,
just as it happens with hCG/LH. The difference is that while
internalized hormones are destroyed in lysosomes, NG avoid
this fate by dissociating from the receptors in the endocytosis
vesicles. There could be mechanisms inside the vesicles for
the selective release of NG from the receptors. The released
NG enters cytoplasm and induces the synthesis of tumor
necrosis factor (TNF) and expresses its own genes.36
The
increased TNF causes cell damage, as blocking its synthesis
diminishes it.36
The products of NG gene expression may
ensure the survival of intracellular NG.36
Some endocytosis vesicles may take the route of transcyto-
sis, in which case vesicles get across the cell to reach basolat-
eral plasma membrane to release NG into subepithelial
spaces. What directs these vesicles is not known. It is likely
that another set of induced proteins may facilitate this route.
This goes along with the notion that all endocytosis vesicles
do not have the same destination. The NG delivered into sub-
epithelial spaces may provoke proinflammatory changes. As a
result more cells in the vicinity will get infected and vascular
permeability increases. The latter may facilitate widespread
NG dissemination, which can lead to septic arthritis, tenosy-
novitis, bursitis, periostitis, meningitis, endo-, myo-, and peri-
carditis.37
These serious complications can not only reduce
the quality of life but also lead to death in some cases.
Rao 1485
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3. The STDs are also caused by Chlamydia trachomatis,
hepatitis B virus, herpes simplex virus type 2, HIV, human
papilloma virus, syphilis, and trachomonas. Neither a molecular
mimicry mechanism nor any single common mechanism is
likely to explain the infections by all these diverse organisms.
Blocking the Infection
Since the initial receptor binding of NG appears to be a prere-
quisite for infection, the vicious cycle of NG binding and cel-
lular entry into human fallopian tube epithelial cells can be
prevented by exposing the tubes to excess hCG.4,24,27
Since
the binding is reversible, excess hCG molecules will simply
outnumber and outcompete the pathogen for binding of recep-
tors. The studies on human fallopian tube organ and cell cul-
tures demonstrated that indeed hCG treatment prevents
endocytosis and transcytosis of NG and decreases the infec-
tion scores.4,24,27
The NG that remains outside the cells is
probably destroyed by immunoglobulins and immune cells
present in the tubal fluids.38
Therapeutic Implications
If hCG works in organ and cell cultures, it might also work in
infected women or even in high-risk patient populations as
a preventive measure. In light of the available scientific
evidence, the above-mentioned expectations are not too
farfetched. Obviously, hCG is a physiological hormone. It is
inexpensive and nontoxic. The commonly described side
effects of hCG administration by intramuscular route are pain
at the injection site, mild bloating, stomach or pelvic pain,
nausea, vomiting, and so on, which often do not require med-
ical attention. The hCG is likely better tolerated than antibio-
tics. There are many antibiotics-associated adverse events and
they vary with the person and the type of antibiotic used.39
Allergic reactions are the most common adverse events that
require visits to hospital emergency departments.39
The hCG
is already used for other clinical indications. It may be possi-
ble to combine hCG with lower antibiotic doses to reduce the
expense and to decrease the antibiotic-associated adverse
reactions. In addition, lower antibiotic doses may reduce the
chances of developing pathogens resistance.40
Because hCG
and antibiotics work by different mechanisms, one could
anticipate that combination treatment maybe even more effec-
tive than either treatment alone.
Questions will arise about the dose, frequency, and route of
administration. The answers can only be empirical from the
experience of using hCG for other clinical indications. A good
place to start is lower doses of hCG than the commonly used
ones for infertility treatments. For example, 500 to 1000 IU
hCG was administered into tubal lumen by laproscopy and
repeation, if a single treatment does not resolve the infection.
Intratubal hCG administration may not have any adverse
effects, as has been shown for intrauterine hCG administration
to increase implantation and clinical pregnancy rates, both of
which increased.41
So what is lost by testing hCG in a clinical
trials on infected women? After all, the use of antibiotics must
be curtailed, whenever possible, to avoid developing antibiotic-
resistant pathogenic strains.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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