BIOLOGY OF REPRODUCTION 79, 180–189 (2008)
Published online before print 14 May 2008.
Male Genital Tract Chlamydial Infection: Implications for Pathology and Infertility1
Kelly A. Cunningham and Kenneth W. Beagley2
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane,
Queensland 4059, Australia
Chlamydia trachomatis infections are prevalent worldwide,
but current research, screening, and treatment are focused on
females, with the burden of disease and infertility sequelae
considered to be a predominantly female problem. The
prevalence of chlamydial infection, however, is similar in males
and females. Furthermore, a role for this pathogen in the
development of male urethritis, epididymitis, and orchitis is
widely accepted. The role of Chlamydia in the development of
prostatitis is controversial, but we suggest that Chlamydia is an
etiological agent, with incidences of up to 39.5% reported in
patients with prostatitis. Infection of the testis and prostate is
implicated in a deterioration of sperm, possibly affecting
fertility. Chlamydia infections also may affect male fertility by
directly damaging the sperm, because sperm parameters,
proportion of DNA fragmentation, and acrosome reaction
capacity are impaired with chlamydial infection. Furthermore,
the proportion of male partners of infertile couples with
evidence of a Chlamydia infection is greater than that
documented in the general population. An effect of male
chlamydial infection on the fertility of the female partner also
has been reported. Thus, the need for a vaccine to protect both
males and females is proposed. The difficulty arises because the
male reproductive tract is an immune-privileged site that can be
disrupted, potentially affecting spermatogenesis, if inappropriate
inflammatory responses are provoked. Examination of responses
to infection in humans and in experimental animal models
suggest that an immunoglobulin A-inducing vaccine will be able
to target the male reproductive tract effectively while avoiding
harmful inflammatory responses that may impair fertility.
Chlamydia, male fertility, male reproductive tract, male sexual
function, prostate, prostatis, sperm
ARE CHLAMYDIA INFECTIONS A MALE PROBLEM?
Chlamydia trachomatis (CT) is the most prevalent bacterial
cause of sexually transmitted infections and can result in severe
genital and ocular disease. The World Health Organization
estimates that 92 million CT infections occurred worldwide in
1999 . Currently, World Health Organization guidelines
recommend that screening strategies be aimed at women. In
addition, research efforts are focused mainly on females, and
the burden of disease sequelae is considered to be primarily a
female problem. Thus, the importance of this pathogen in male
genital tract infection often is underrated. In the present review,
we aim to comprehensively examine the role of Chlamydia
infections in men, both in terms of disease sequelae and
potential to cause infertility, and look at current advances in
screening and vaccine development that may aid in the
eradication of this pathogen from both men and women.
The reported incidence rates of genital chlamydial infections
in the population likely are an underestimate because of the
highly asymptomatic nature of the pathogen. Furthermore, as
more cross-sectional population surveys are being conducted, it
is becoming increasingly apparent that the prevalence rates of
genital CT infection are very similar for heterosexual men and
women (for review, see [2, 3]). The results of recent large
surveys reiterate this trend and are presented in Table 1 [4–7];
Chlamydia positivity was determined by nucleic acid ampli-
fication techniques (NAAT) in those studies.
The reason for the higher prevalence of positivity in the
study by LaMontagne et al.  is uncertain. The prevalence in
females is greater in health care settings of any kind than in
population-based studies , however, and this also may be the
case with males. Before the reports presented in Table 1, a
systematic review of prevalence studies in the United Kingdom
was performed. Only 11% of the reported prevalence estimates
were from males, with estimates ranging from 0% to 4.8% (in
25- to 29-yr age group) . Clearly, there is paucity in the
literature of information regarding male prevalence, but
variation does exist among studies. The similar rates of
infection between males and females is consistent, however,
and highlights the importance of this pathogen in genital tract
infection of both men and women.
UNDERDIAGNOSIS AND TREATMENT OF CT
INFECTIONS IN MEN
Approximately 75% of CT infections in women and up to
50% of those in men are asymptomatic (for review, see [8, 9]).
In comparison to the high prevalence rates reported in Table 1
from screened populations, the most recent data from the
Centers for Disease Control and Prevention documented CT
infection rates of only 0.161% and 0.497% in the entire male
and female populations of the United States, respectively .
Thus, a large proportion of CT infections will go undetected
unless targeted screening programs are put in place.
Asymptomatic men who are infected with CT are younger
than their symptomatic counterparts . This also emphasizes
1Supported by the University of Newcastle Research Management
2Correspondence: Kenneth W. Beagley, Institute of Health and
Biomedical Innovation, Queensland University of Technology, Cnr
Musk Ave and Blamey Street, Kelvin Grove, QLD 4059, Australia.
FAX: 61 7 3138 6030; e-mail: firstname.lastname@example.org
Received: 17 January 2008.
First decision: 19 February 2008.
Accepted: 2 April 2008.
? 2008 by the Society for the Study of Reproduction, Inc.
ISSN: 0006-3363. http://www.biolreprod.org
the need for better screening or prevention practices, because
although up to 13.3% of young men may have a genital
chlamydial infection , only half of these will present with
any symptoms—and even fewer are likely to pursue treatment.
The deficiency in screening/treatment of men is further
highlighted by a U.K. study that found the testing rate for CT
infection in men reached a maximum of only 5% of the testing
rates in women. In 2004, only 5.1% of the diagnosed infections
in men were treated, compared with 25% in women . Thus,
a very high proportion of infections in men remain undetected
or untreated, enabling further spread of the bacterium within
the population. Screening of young men reduces cases of
inflammatory disease , and cost-effectiveness could be
improved by prescreening for Chlamydia-associated seminal
markers, such as antibodies, and then using NAAT .
The Centers for Disease Control and Prevention guidelines
for screening proposed in 2007 suggested that programs should
have a primary emphasis on screening women . We
believe, however, that because male infection is as prevalent as
female infection and likely plays a role in infertility, screening
should be focussed on both males and females. NAAT on first-
void urine with internal PCR controls should be used, because
it is more amenable than urethral swab collection and has
comparable sensitivity .
Following detection, standard treatment for genital infection
with Chlamydia consists of a single oral dose of 1 g of
azithromycin or 100 mg of doxycycline orally twice daily for 7
days (for review, see ). A recent study, however, has
shown that early identification and treatment of infected
patients within a population can actually interfere with long-
term immunity and result in eventual higher incidence rates
related to an increase in reinfections . Reinfection is a
significant problem, with a median probability of reinfection in
men of 11.3%, which is comparable to reinfection rates in
women . Hence, with the current deficiencies in detection,
uncertain long-term success of treatment when provided, and
high reinfection rates, a vaccine appears to be the only viable
option for eradication of Chlamydia-associated genital disease.
This will be discussed in greater detail later.
DURATION OF INFECTION AND BACTERIAL LOAD
Serious difficulties are involved in determining the duration
of infection in humans, because the onset of infection generally
is unknown, reexposure is common, and clearance is rarely
followed up . To a large degree, we have to rely on
information provided from animal studies for our information.
In male rodent models of Chlamydia muridarum infection, the
bacterium has been found to persist in upper reproductive tract
tissues beyond 7 wk [20, 21]. Primates, however, tend to
experience more prolonged infections than mice or guinea pigs
and, thus, are more likely to reflect the progression of disease
in humans. Persistence of CT infection has been observed for
up to 9 wk , and resultant chronic lymphocytic response
was seen for up to 3 mo in primate studies . It is interesting
to note also that animals often are antibody  and culture
negative but can still have chlamydial DNA in their tissues
A limited number of studies have demonstrated that
chlamydial positivity can, indeed, persist for a number of
weeks in humans (for review, see ), as it does in primates.
To our knowledge, however, no study has consistently
followed up infection in men for greater than 4 wk; thus, the
frequency of prolonged infections is unknown. For a
comparison, most evidence in women suggests that infection
persists for more than 60 days and even up to years in the upper
female reproductive tract [19, 25], and interestingly, it has been
suggested that a CT infection can maintain itself for up to 4 yr
within a couple . This may have implications for fertility,
which will be discussed later in this review.
Few studies have examined the infectious chlamydial load
in the reproductive tracts of males and females. The median
inclusion-forming unit count is 72 for urethral swabs from men
and 450 for cervical swabs from women , with other
investigators finding similar results . Organism load in
first-void urine samples and in urethral swabs correlates with
clinical signs or symptoms of disease in men [15, 28]. Urine is
a suitable alternative diagnostic specimen to urethral swabs,
because they both have similar infectious loads . One
obvious deficiency in the literature, however, is the organism
load in ejaculated semen. This information would be invaluable
in determining the transmission dose from men to women.
PATHOLOGY OF THE MALE REPRODUCTIVE TRACT
RESULTING FROM CHLAMYDIAL INFECTIONS
The role of CT infection in the development of urethritis and
epididymitis is now well accepted in the literature, but a role
for this pathogen in the development of prostatitis remains
controversial and will be discussed in detail. Another
complication arising from chlamydial infections in men can
include proctitis resulting from infection with the Lympho-
granuloma venereum (LGV) strain. Large clusters of LGV
infections in homosexual men have been found in Europe, the
United States, and Australia since 2003, making it an
increasing health problem (for review, see ).
The primary site of infection in males is the penile urethra.
Undeniably, CT infection is a major cause of urethritis in men.
Estimates using NAAT for diagnosis attribute up to 30% of
urethritis cases to a CT infection, compared to only 4% in
healthy control subjects , whereas up to 42% of
nongonococcal urethritis cases may be caused by CT .
One study even suggested the presence of CT infection in as
many as 56.6% of male patients with urethritis using enzyme
TABLE 1. Incidence of genital CT infection in men and women.
Fenton et al. 
Miller et al. 
LaMontagne et al. 
Population-based survey in Britain aged 18–44 yr
Cross-section of young adults aged 18–26 yr in the US
UK national screening program of patients ,25yr of age
in non-genitourinary medical settings
Random selection of patients aged 16–24 yr from UK
general practice lists
Low et al. 
aPositive for infection by nucleic acid amplification techniques.
MALE GENITAL TRACT CHLAMYDIAL INFECTION
immunoassay on urethral swabs . CT infection appears to
be equally prevalent in symptomatic and asymptomatic urethral
disease [33, 34], again reiterating the highly asymptomatic
nature of this pathogen.
The role of CT as an etiological agent for the development
of epididymitis also is widely accepted (for review, see ).
There also are animal models in which this phenomenon can be
examined [21, 36, 37]. Direct immunofluorescence on urethral
swabs of patients with epididymitis found that 30.8% had a CT
infection, whereas 51.3% presented with serum immunoglob-
ulin (Ig) A antibodies against CT , indicating a past or
current infection. Chlamydial antigen also has been detected in
tissues from patients with acute or chronic epididymitis by
immunoperoxidase staining, indicating that the bacterium
ascends the male reproductive tract . The development of
CT epididymitis is most predominant in younger men, with a
number of studies demonstrating significantly higher rates in
men under the age of 35 yr [38, 40].
Ascending chlamydial infection to the testes has been
observed experimentally in rats , mice , and monkeys
. Furthermore, natural infection of bulls with Chlamydia
psittaci commonly results in the development of orchitis .
In humans, chlamydial antigen has been detected in urethral or
urine samples from 11% to 35% of men presenting with
epididymo-orchitis [42–45]. A causative link between CT
infection and epididymo-orchitis in men is now accepted .
Decreased sperm counts and decreased motility often are
demonstrated in cases of acute epididymo-orchitis of nonspe-
cific etiology , and this pathology also is consistently
associated with high rates of infertility . Ascending urethral
infection to the sites of spermatogenesis provides a plausible
means by which Chlamydia can interact with and impair sperm
function and, thus, affect fertility.
Ascending C. muridarum infection to the prostate has been
observed in experimental mouse models  (K.A. Cunning-
ham, unpublished data), and a male koala has been documented
that presented naturally with chlamydial organisms in the
prostate . Controversy exists in the literature, however, as
to whether CT is a cause of prostatitis in humans, despite a
large number of studies examining this relationship. This
largely is a result of the difficulties in accurately and
conclusively diagnosing prostatic infection with Chlamydia.
These can include variance in the method of detection and
difficulties in obtaining pure prostatic samples. Semen and
prostatic secretion samples may be contaminated via passage
through an infected urethra, making diagnosis of upper male
reproductive tract infection difficult . It has been suggested
that care also be taken in the interpretation of prostatic biopsy
findings when determining chlamydial presence, because some
biopsy samples may contain prostatic-urethral material .
The prevalence of CT infection in patients with chronic
prostatitis when detected by NAAT on secretions from the
upper male reproductive tract has ranged from 8.3% to 18.8%
in studies performed since 2000 (Table 2) [51–55]. A meta-
analysis to determine the magnitude of this association
conclusively could not be performed because of the great
differences among diagnostic methods, population demograph-
ics, and lack of control groups. One case-controlled study by
Weidner et al.  using culturing methods for detection found
that 14.9% of patients with prostatitis had positive cultures
from postprostatic massage urethral swabs; by comparison,
only 5% of healthy controls were positive.
Doubt has been raised concerning the reliability of these
samples for accurate diagnosis, but a number of studies indicate
that seminal fluid/expressed prostatic secretion often is positive
for Chlamydia in patients with negative urethral swabs [54, 57,
58]. In fact, in one study, 39.5% of patients with chronic
prostatitis and negative urethral swabs were positive for CT
infection by McCoy cell culture on expressed prostatic
secretion/postprostatic massage urine . Antigen and DNA
detection techniques have indicated the presence of CT in
approximately 30% of biopsy specimens [60, 61], and pure
prostatic biopsy samples also can demonstrate chlamydial
positivity in the absence of urethral infection [52, 62]. These
examples warn against negative diagnosis of upper reproduc-
tive tract infection using specimens such as urethral swabs, and
they highlight the importance of relevant testing for determi-
nation of chlamydial etiology. They also suggest that
contamination of prostatic samples, be they fluid or biopsy,
via passage through the urethra may not be as much of a
problem for diagnosis of prostatic infection as has been
We believe that findings from studies employing sensitive
detection methods on suitable samples provide compelling
evidence of an association between CT infection and the
development of prostatitis. A recent comparative study
examining sperm parameters of patients with chronic pelvic
pain syndrome/prostatitis and healthy controls found that those
with prostatitis had poorer sperm morphology and concentra-
tion and a lower inducibility of the acrosome reaction .
Thus, Chlamydia-induced prostatic disease could have clinical
implications for male infertility. In the future, NAAT and direct
antigen detection should be conducted on transperineal/
transrectal biopsy specimens when possible to clinically prove
a role for CT in prostatitis. In terms of screening, when
symptoms are present or urine NAAT is positive for CT,
expressed prostatic secretion could be used as a supplementary
diagnostic sample to test for upper reproductive tract infection.
TABLE 2. CT as an etiological agent for prostatitis.
StudyN Positive (%) Samplea
Badalyan et al. 
Krieger and Riley b
Ostaszewska-Puchalska et al. 
PCR on semen
PCR on prostatic biopsy
LCR on urethral swabs
LCR on EPS
NAAT on semen
DFA/LCR on EPS
DFA/LCR on EPS/urethral swabs
Motrich et al. 
Zdrodowska-Stefanow et al. 
aDFA, direct fluorescent antibody; LCR, ligase chain reaction; EPS, expressed prostatic secretion.
bSample population excluded men who showed signs of urethritis or positive urethral culture for CT.
CUNNINGHAM AND BEAGLEY
DOES CHLAMYDIA PLAY A ROLE IN INFERTILITY?
The potential mechanisms for the effect of CT on fertility
may be a direct, negative effect of Chlamydia on spermatozoa
or indirect effect, via infection leading to inflammatory
obstruction of the tubules and/or epithelial damage that results
in impaired spermatogenesis. These possibilities will be
reviewed in detail in this section.
Does Chlamydia Interact with and Impair Sperm Function?
A number of electron microscopy studies have demonstrat-
ed an interaction of Chlamydia and sperm. This has been
shown both in biopsy samples of the testis and epididymis and
in semen samples [64, 65]. In fact, transmission-electron
microscopy has shown that CT serovars D, H, and I all attach
to human spermatozoa in vitro , and CT has been observed
attached to sperm in the peritoneal fluid of women with
salpingitis . An interaction, however, does not provide
indication of a negative effect of Chlamydia on sperm function.
Conclusive evidence for a direct effect of Chlamydia on
spermatozoa is shown by the tyrosine phosphorylation of
sperm proteins following interaction . Furthermore,
elementary bodies of CT serovar E and LGV can lead to
apoptosis of human sperm in vitro involving caspases [69–71].
This can be induced by chlamydial lipopolysaccharide, which
has a 550-fold greater spermicidal activity than that of
Escherichia coli lipopolysaccharide [72, 73]. Eley et al. 
proposed that chlamydial lipopolysaccharide interacts with
CD14 on the sperm surface (and, possibly, Toll-like receptors
if present), leading to increased production of reactive oxygen
species, resulting in caspase-mediated apoptosis. Excessive
generation of reactive oxygen species is related to an increase
in sperm defects both in vitro  and in infertile men . An
association of the bacterium with sperm has been demonstrat-
ed, and this potential for Chlamydia to affect sperm function
adversely has great implications for fertility.
The literature contains conflicting evidence concerning the
relationship between chlamydial infection and sperm function.
A large number of studies have suggested that positive markers
for CT infection are not associated with altered sperm
parameters [53, 77–83]. Others, however, have found that CT
infection correlates with reduced sperm motility [84–87];
increased proportion of sperm abnormalities ; significant
reductions in semen density, sperm morphology, and viability
; and increased likelihood of leukocytospermia [87, 90].
In a large study of 627 semen samples, 136 of which had
evidence of CT infection, the presence of Chlamydia reduced
normal sperm morphology by 14.4%, volume by 6.4%,
concentration by 8.3%, motility by 7.8%, and velocity by
9.3% . In addition to these frequently examined sperm
parameters, a recent study has, to our knowledge, been the first
to demonstrate that coinfection with Chlamydia and Myco-
plasma results in 3.2-fold more sperm cells with fragmented
DNA than in uninfected controls . Chlamydia infection
affected DNA fragmentation more strongly than it did motility
or structural parameters . Antibiotic therapy was able to
reduce the number of patients with fragmented DNA and to
improve the pregnancy outcomes of their partners . Of
further relevance to fertilization, men with high levels of
antichlamydial antibodies in seminal plasma had a decreased
acrosome reaction capacity of spermatozoa  and a higher
level of sperm lipid peroxidation .
Almost all studies examining differences in sperm param-
eters between Chlamydia infected and noninfected males are
performed on male partners of infertile couples (MPIC). One
study, however, demonstrated that 45% of subfertile men can
have reduced semen quality , whereas another found that
74% of MPIC had reduced viability and 70% had reduced
sperm motility , making it potentially difficult to determine
an effect of chlamydial infection in the MPIC population. The
most reliable studies examining this phenomenon will be those
comparing sperm of Chlamydia-infected versus noninfected
men regardless of fertility status .
Chlamydia and Male Factor Infertility
A role for CT in male factor infertility is not yet proven [8,
94]. A direct interaction between sperm and Chlamydia has
been shown , however, as has a subsequent increase in
DNA damage , but whether this has a detrimental effect on
male fertility is uncertain. A number of studies have been
performed examining the rates of Chlamydia infection in men
from infertile couples. Proving an association between
infection and infertility, however, has been difficult because
of the variance among the studies, with differences in patient
demographics, method of Chlamydia diagnosis, and samples
Conclusively proving a link also is difficult because of the
scarcity of strong, case-controlled, prospective studies com-
paring chlamydial incidence rates in infertile men versus fertile
men using suitable diagnostic means. Mosli et al. 
examined chlamydial incidence by direct immunofluorescence
and culture on urethral swabs in age-matched MPIC and fertile
controls, and those authors found rates of 25% and 4%,
respectively, strongly supporting a role for Chlamydia infection
in male infertility.
To investigate the relationship between Chlamydia infection
and male infertility, we have compared reports of rates of
infection in MPIC to what is known about general prevalence
rates in males of similar demographics from population-based
studies. In virtually all studies concerning MPIC, the mean or
TABLE 3.Prevalence of CT infection in semen of male partners of infertile couples.
Study CountryAge range (yr)N Positive (%)
Gdoura et al. 
Bezold et al. 
Hosseinzadeh et al. 
de Barbeyrac et al. 
Hamdad-Daoudi et al. 
Eggert-Kruse et al. 
Pannekoek et al. 
Gdoura et al. 
Ochsendorf et al. 
Levy et al. 
MALE GENITAL TRACT CHLAMYDIAL INFECTION
median age is in the mid-thirties. Infection rates in males in the
general population aged 30–44 yr were reported as being 1.1%
, and rates in those aged 18–45 yr were reported as 1.9%
 as determined by NAAT on urine samples. A number of
studies examining the incidence from NAAT on semen of
asymptomatic MPIC are reported in Table 3 [58, 77, 78, 80, 83,
86, 90, 97–99]. Positive NAAT results are considered to be
indicative of a current active infection, and urine and semen
NAAT findings have high concordance .
No clear methodological explanations are available for the
wide variance in semen sample findings, with reported rates
ranging from 0.4%  to 42.3% . On the other hand,
documented rates of infection determined from urine samples
of MPIC range from 0.3% to 7.1% [100, 101]. Irrespective of
the varied findings, the majority of these studies report a higher
rate of incidence of chlamydial infection than that in the
Accurate determination of an active infection is important
for defining incidence rates, but it is plausible that determina-
tion of a previous infection (antibody presence) in men may be
more relevant for delineating a link to subsequent development
of sequelae, such as infertility. We have tabulated a number of
studies since 1995 that report levels of antichlamydial IgA in
samples from the reproductive tract of MPIC (Table 4) [80, 85,
With the exception of the study performed by Ochsendorf et
al. , the reported positivity rates are approximately 20%. In
infertile couples, a male factor is implicated only in
approximately 60% of cases . If the incidence of
Chlamydia infection had been examined in the approximately
60% subset of MPIC that were proven to be infertile, a link
between infection and infertility might have proven to be even
stronger. Also of interest, antisperm antibodies on motile sperm
are found in 16.3% of asymptomatic MPIC, mostly associated
with the presence of antichlamydial IgA in semen ; thus,
previous chlamydial infection appears to be associated with the
development of antisperm antibodies, potentially affecting
Male Chlamydia Infection and Female Factor Infertility
The evidence presented strongly supports a link between CT
infection and male factor infertility, but male chlamydial
infection also is of great importance in the fertility of couples.
Because of the observed interaction of spermatozoa and
Chlamydia, it is postulated that CT infections in men serve
as reservoirs for transmission to females [35, 79]. It also is
possible that Chlamydia sp. may hitch a ride in leukocytes in
semen, such as neutrophils and macrophages, which are cells
that may be more prevalent during an infection [74, 107, 108].
Transmission between infected men and their sexual partners
has been established [62, 85], and it is interesting to note that
partners of men with symptomatic urethral infection are more
likely to be infected than are partners of men with
asymptomatic urethral infection , a probable corollary of
The presence of antichlamydial antibodies in males is
related to the presence of infertility factors in female partners
and subsequent reductions in pregnancy rates [78, 110, 111].
Furthermore, antibiotic treatment of MPIC with high levels of
sperm DNA fragmentation and CT infection was able to
increase assisted pregnancy rates significantly . Given the
high proportion of MPIC that have antibodies to Chlamydia
(Table 4), these findings have huge implications for assisted
reproduction. Furthermore, the cryopreservation process used
in assisted reproduction techniques is not able to affect the
presence of infectious Chlamydia in semen , indicating
that prescreening of these subjects is of the utmost importance.
These studies highlight the need to abrogate infection in both
males and females to alleviate successfully the problems of
DEVELOPMENT OF A CHLAMYDIA VACCINE
Efforts in Vaccine Development
Given the high rate of asymptomatic infections and the
potential of early antibiotic intervention to interfere with the
development of immunity within the population as a whole
, the need for a vaccine against Chlamydia is undeniable. A
computer modeling simulation examining the efficacy of
vaccination strategies against CT found that even a 50%
efficacious vaccine would result in a significant reduction in
the prevalence of disease . Given the structural differenc-
es between the male and female reproductive tracts, however,
and the differences in innate and adaptive immune induction
capacity, development of a vaccine that will prevent infection
in both males and females will need to account for these
Sperm production begins at puberty, after immune tolerance
to self is well established. Because of the need to avoid
development of antibodies against the immunogenic sperm, the
male reproductive tract is an immune-privileged site, which
results from the blood-testis barrier formed by the Sertoli cells
and the blood-epididymal barrier formed by the epididymal
epithelial cells (for review, see ). Inflammatory processes,
such as the activation of complement, are undesirable in the
male reproductive tract, because they may negatively affect
sperm development via disruption of this barrier. For example,
mice with a disruption in the CD59B complement regulatory
protein have decreased sperm production and increased
infertility . Furthermore, an interferon-c response is
considered to be necessary for clearance of a Chlamydia
infection in females (for review, see ), but such a response
is likely to affect the immune barrier of the male reproductive
tract and, potentially, contribute to infertility . Disruption
of the barrier in experimental animals by an infection results in
autoimmune orchitis and impaired spermatogenesis because of
infiltration of Th1 CD4þ T cells  and interferon-c .
Therefore, the induction of these responses by an experimental
vaccine should be avoided.
We would like to direct the reader to a comprehensive
review of immunity within the male reproductive tract for
further information . We require a good understanding of
the immune induction capacity of the male reproductive tract to
target suitable protective immunity to the correct site without
inducing immunopathologic inflammatory responses.
partners of infertile couples.
Prevalence of anti-chlamydial IgA in reproductive tract of male
StudyN Sample tested Positive (%)
Gdoura et al. 92 Semen
Penna Videau et al. 
Ochsendorf et al. 
Munoz et al. 
Eggert-Kruse et al. 
Witkin et al. 
Munoz and Witkin 
CUNNINGHAM AND BEAGLEY
Innate Immunity of the Male Reproductive Tract
Adaptive immunity in the male reproductive tract is tightly
regulated to avoid inflammatory processes; thus, immune cells,
such as tolerigenic antigen-presenting cells and regulatory T
cells, within the tract are functionally modified under the
regulation of androgens . Furthermore, the immune-
privileged nature of the male reproductive tract poses a barrier
to the entry of serum Igs, particularly IgG [119, 120].
Therefore, we see an enhanced capacity for innate immunity
at this site.
To illustrate this concept, incubation with semen results in a
dose-dependent reduction in chlamydial infectivity on McCoy
cells . In a guinea pig model of Chlamydia caviae
(formerly guinea pig inclusion conjunctivitis), female guinea
pigs infected by mating had a shorter duration of infection
compared to those inoculated experimentally with the deter-
mined transmission dose (102inclusion-forming units), sug-
gesting that semen may have innate stimulators or
antimicrobial activity . Zhao et al.  found that
human beta-defensin 1 transcripts were present in prostate and
testis epithelial cell lines. Human neutrophilic proteins 1–3
(alpha-defensins) also were present in the prostate cell line.
Furthermore, zinc salts inhibit the growth of Chlamydia in
McCoy, HeLa, and primary human prostate epithelial cell
cultures. The high levels of zinc in human prostatic secretions
may inhibit Chlamydia from infecting the prostate in vivo
. Another potential mediator is surfactant protein D,
which inhibits Chlamydia infection of epithelial cells by
binding to the bacteria .
Antimicrobials (e.g., defensins) in semen and urine may
serve to protect the lower reproductive tract from infection
[125, 126], but infection of rat prostate epithelial cells in vitro
also increases the secretion of innate immune mediators and
upregulates expression of Toll-like receptors [127, 128].
Whereas these mediators may aid in immune cell recruitment
to the site of infection, they have the potential to induce
inflammation. Despite the wide array of innate immune
mediators that can be induced in response to Chlamydia, in
many cases this immunity clearly is insufficient to block
infection and transmission to partners, and the potential of
innate immune responses to negatively affect spermatogenesis
via inflammation is not well characterized.
Adaptive Immunity of the Male Reproductive Tract
We can glean some information from animal models about
the time course of immune induction following chlamydial
infection. The induction of an adaptive immune response to
infection has been described most comprehensively by Pal et
al.  following intrapenile inoculation of C3H/HeN(H2-K1)
mice with C. muridarum. They demonstrated a very strong
cell-mediated immune bias, with IgG2a levels 16-fold greater
than IgG1, and high levels of interferon-c and tumor necrosis
factor-a. Unfortunately, the effect of such an inflammatory
response on sperm function and fertility was not examined in
their study. Serum antibodies peaked from 4 to 7 wk in mice
and rats, but antibody induction local to the genital tract was
not examined in these models [20, 21].
An infection in men results in significant inflammation, as
indicated by high interleukin 8 levels , a finding
supported by in vitro work demonstrating that infected prostate
epithelial cells secrete interleukins 6 and 8 . It is
anticipated, however, that these proinflammatory responses
have the potential to disrupt the immune-privileged nature of
the site; thus, the induction of these responses may need to be
avoided in a male vaccine so as not to affect fertility.
The induction of local IgA appears to be of great
significance in male Chlamydia infection, because whereas
the prevalence of antichlamydial antibodies of the IgG isotype
in the male genital tract is only one eighth that of IgG levels in
serum, the levels of seminal plasma IgA are two thirds those of
serum IgA levels . In contrast, IgM is barely detected in the
genital tract secretions of men with bacterial prostatitis  or
urethral swabs of CT-infected men , suggesting that this
Ig isotype is not required for protection against chlamydial
The groups of antigens that are recognized by serum
antibodies in infected male mice are similar to those observed
in a female salpingitis model [20, 132], including Major Outer
Membrane Protein/Outer Membrane Protein A, the 60-kDa
cysteine-rich protein, chlamydial heat shock protein 60, and
chlamydial lipopolysaccharide. Determining antigens common
to male and female infection may be useful in the design of an
efficacious vaccine. Vaccine-induced immunity will need to be
better than that elicited by a natural response to infection; thus,
a multiantigen vaccine with strong, rapid IgA antibody-
inducing mucosal-targeting adjuvants is likely to be the most
successful approach in males.
Lessons from Male Animal Models of Vaccination
Vaccination studies to date have focused primarily on
female animal models. A few studies, however, have examined
the induction of protective immunity against Chlamydia
infection in male animal models. Urethral infection with C.
caviae in male guinea pigs resulted in subsequent protection
from a second infection, while ultraviolet-irradiated elementary
bodies administered parenterally also were able to reduce the
infection [133, 134]. Similarly, Digiacomo et al.  found a
reduced secondary infection when male baboons were
inoculated first with CT serovar D. To highlight the importance
of these studies, Patterson and Rank  performed urethral
inoculation of both male and female guinea pigs with C. caviae
and, on secondary challenge, found that males were more
resistant to reinfection than females. Thus, they determined that
the vaccination of males should be a priority.
Intranasal immunization with the major outer membrane
protein of C. muridarum in combination with cholera toxin was
able to elicit high levels of locally produced, neutralizing IgA
in the prostatic fluid . This induction of IgA (and the
transepithelial transport involving the poly-Ig receptor) was
able to reduce levels of C. muridarum in all regions of the male
reproductive tract; however, sterilizing immunity was not
observed with the high challenge dose that was used (K.A.
Cunningham, unpublished data). Because IgA is a natural
response to chlamydial infection  and, in high levels, may
even serve to prevent the activation of complement , a
strong antichlamydial IgA response could suit the criteria for a
suitable male vaccine. Studies in females support this: Levels
of major outer membrane protein/Chlamydia-specific IgA
correlated with reduced shedding of Chlamydia in mice [138,
139] and in women .
Further studies will need to be undertaken in an attempt to
optimally target the male and female reproductive tracts and to
determine the antigen or combination of antigens that will best
afford protective immunity against infection, without the
potential for immunopathology. Thus, vaccine development
efforts could best be directed toward a combination of
microbicides and adaptive immune effectors, such as IgA, that
will not disrupt the immune-privileged nature of the male
MALE GENITAL TRACT CHLAMYDIAL INFECTION
Figure 1 summarizes the role of Chlamydia in the
development of male reproductive tract pathology and the
immune effectors that are present throughout the tract. Some
key questions have been raised that should direct future
research in this area:
?Can we accurately determine the magnitude of the problem
of Chlamydia infections in men and alter current treatment/
screening/experimental vaccine regimes to reflect this?
?Can we define an suitable method for determination of upper
reproductive tract infection in men, and examine its
relationship with sperm function more closely, as a means
of diagnosis for those at risk of developing infertility?
?Are sperm parameters and DNA fragmentation levels
different in men with CT versus case-matched men without
CT, regardless of fertility status?
?Whereas CT infection appears to affect male fertility based
on studies in MPIC, what is the prevalence of CT infection in
men with proven male factor infertility compared to that in
case-matched fertile men, and what is the relative impact of a
past or current infection?
?Will an IgA-inducing vaccine protect against Chlamydia
infection without affecting the immune-privileged nature of
the male reproductive tract?
The present review highlights the necessity for a vaccine to
protect against infection in both men and women, despite
current screening and treatment efforts targeting females. We
provide evidence of similar levels of prevalence in both sexes
and a role for Chlamydia infection in degenerative male
reproductive tract disease. A strong potential exists for an
effect on male fertility, but more well-designed studies are
required to prove conclusively a causal role of Chlamydia
infection. A role for male chlamydial infection and female
infertility via transmission, however, has been demonstrated. A
vaccine therefore will be optimal only if it can protect against
infection in both males and females. This will require either a
separate design for each of the sexes or one that is able to
induce protective immunity in the reproductive tracts of both
sexes despite their obvious structural differences. The difficul-
ties of targeting immunity to the male reproductive tract are the
barrier to serum Igs and the greater potential for inflammatory
processes to affect this barrier and, thus, allow the development
of antisperm antibodies or immunopathology, each of which
may potentially affect the fertility of males. We have found that
the male reproductive tract can produce local neutralizing IgA
following intranasal immunization, and this may provide a
basis for further rational design of vaccination strategies in
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