Indeed, reproductive failure cases of abortion and stillbirth in foxes, raccoon dogs, and minks were commonly observed in some farms with unknown reasons in Northeast China. Thus, a survey was conducted in China to acquire information concerning farmed fur animal species as possible reservoirs of Chlamydia spp. Samples from fur animals came from two farms located in the suburbs of Changchun city, Jilin province, China, and sampling was performed in November in a local slaughterhouse.
All samples were collected before the slaughtering of the animals and immediately transported on ice to the laboratory. A formal ethical approval is not required for this kind of study and sampling was performed by authorized veterinarians during routine medical and veterinary activities.
A total of 55 sampled animals included 9 male and 11 female foxes, 12 male and 3 female raccoon dogs, and 16 male and 4 female minks Table 1. All Chlamydiaceae -positive samples were retested with specific real-time PCR assays to identify Chlamydia species including C. An analytical cut-off value of Any Ct value above this defined limit would, thereafter, be considered unreliable. For further quantification DNA concentration from the positive samples, the target fragments for each detecting primer pairs were chemically synthesized and cloned into pMD18T vector Takara.
The Chlamydia DNA copies in the samples were tested and calculated according to the formulation obtained from the standard curves. The data were analysed using MEGA 5.
To assess the phylogenetic relationship between Chlamydia spp. Among 55 tested animals, 36 were shedders of Chlamydiaceae giving a prevalence rate of Positive results for Chlamydiaceae were obtained for all rectal swabs from foxes and raccoon dogs irrespective of gender.
Further testing with species-specific real-time PCR identified the detected agent in all Chlamydiaceae positive samples as C. Moreover in 7 rectal swabs from foxes the coexistence of C. No other Chlamydia species was identified.
Only one rectal swab from a male mink was tested positive for Chlamydiaceae and determined as C. To further confirm the presence of Chlamydia spp. All sequences obtained in this study were assigned to C.
In addition, phylogenetic analysis showed ompA sequences were clustered with the strains C. Chlamydiosis is common in livestock, poultry, companion, and wild animals [ 19 , 20 ]. In the available literature, there is a lack of reports about chlamydiosis cases in fur animals. In this study, evidence for the existence of C. It seemed that the gastrointestinal tract provided a major endemic habitat for C.
Another Chlamydia species found in this study as a coexisting pathogen in a few rectal swabs in foxes was C. These results suggested that C. However, due to the limited number of samples investigated in this study, more evidence is required to reveal the relationship between C. In addition, it is not clear whether fur animals are the natural hosts of Chlamydia spp.
It is worth mentioning that the feed for fur animals in China always contains fish, chicken, and occasionally pig products. As has been reported, the prevalence of Chlamydia spp. Therefore, feeding should be considered as a possible way for farmed fur animals to become infected with Chlamydia spp.
Frequent human contact with domestic livestock at work increases the risk of infection. According to data published in , the average number of notified cases of human chlamydiosis originating from C. Although the possible transmission of C. This is the first report confirming that farmed fur animals, foxes, raccoon dogs, and minks, mainly harbored C.
Further studies are needed to fully elucidate the epidemiology and pathogenicity of C. Moreover, an evaluation of the potential health risk to fur farm personnel and the creation of a strategy to preserve human safety are required. The data used to support the findings of this study are available from the corresponding author upon request.
Table S1: summary of real-time PCR results. Supplementary Materials. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues.
Academic Editor: Xiaofeng Fan. Received 08 Sep Darville and Hiltke [ 10 ] maintain that pathogenesis is dependent on ascension of chlamydiae from the cervix to the fallopian tubes, and they emphasize the importance of gaining a better understanding of what facilitates and predicts such ascension and how to prevent it. If the innate responses of infected epithelial cells are sufficient to drive pathology, then tissue-damaging responses could begin to occur as soon as the fallopian tube is infected and would continue throughout the course of active infection.
Thus, control programs should focus on preventing new infections and detecting existing infections as soon as possible after acquisition. If adaptive chlamydialspecific cellular responses mainly cause disease, tissue damage would mainly occur later in the course of an initial infection, after meaningful cell-mediated immune responses have developed.
With repeat infection, this process could be substantially accelerated and augmented, and even small amounts of chlamydia in the fallopian tubes might provoke an enhanced T cell response. Thus, efforts could focus on screening women with longstanding infection, but particular attention would need to be paid to preventing repeat infection.
How do we determine the relative importance of one pathogenesis paradigm over the other? Much of the evidence related to the innate response to C. Darville and Hiltke [ 10 ] outline the usefulness of these models in determining potential mechanisms for development of genital tract tissue damage independent of T cell responses eg, the critical role for chlamydial activation of the innate immune receptor, Toll-like receptor 2, subsequent inflammatory cell influx, and release of tissue-damaging proteinases from activated neutrophils [ 20 , 21 ].
Data on the immunological pathogenesis paradigm come mainly from guinea pig and, especially, nonhuman primate models, in which limited tubal damage is noted during primary infection, but adaptive cell-mediated immune responses are enhanced during repeat chlamydial infection and are associated with enhanced tubal damage [ 10 , 24 , 25 ]. A number of limitations exist in extrapolating data from various animal models to humans.
A fundamental difference in the natural history of chlamydial infections between humans and, especially, rodent models is the duration of primary infection, which Miyairi et al [ 14 ] describe in detail in this supplement. Inoculation of mice with Chlamydia muridarum or guinea pigs with Chlamydia caviae generally leads to a selflimited genital infection with a rapid peak, plateau, and then rapid elimination; detection of viable chlamydiae from the lower genital tract is limited to 3—4 weeks [ 14 ].
In nonhuman primates, such as the pigtailed macaque, infections are more chronic and indolent in nature. Peak infection may not occur for months, and intermittent shedding of C. In another article in this supplement, Geisler [ 11 ] describes the limited human studies on the duration of untreated genital C.
Human natural history studies to date have major limitations, including the absence of precise data on the timing of infection acquisition, limited use of C. Ethical considerations make these types of studies difficult to conduct. Nonetheless, available studies show that the duration of chlamydial infection in humans is on the order of months to years rather than weeks. The differences in the duration of untreated infection between humans and animals may be related to differences between humans and animals in the innate and adaptive immune responses to chlamydial infection.
To gain a better understanding of which immune responses predict persistent infection versus clearance of infection in humans, both Geisler and Miyairi et al [ 11 , 14 ] call for more translational research to apply what has been learned thus far from animal models to human studies. Because of the ability of chlamydiae to cause chronic persistent infection in humans, a key question is whether and how C. One factor that may be at play is raised by Wyrick in this supplement [ 16 ].
Wyrick describes the normal developmental cycle of chlamydiae, in which infectious but metabolically inactive extracellular EBs cycle to noninfectious but metabolically active intracellular reticulate bodies RBs and then cycle back to EBs with release back into the extracellular milieu.
The condition is reversible to yield infectious EBs on removal of the inducers. Although all persistence- inducing conditions can exist in vivo, it is still unknown whether aberrant chlamydial RBs occur in vivo and, if so, whether they contribute to chronic inflammation, fibrosis, and scarring. To address this issue, Wyrick [ 16 ] urges that more translational research be done, using such techniques as electron microscopy, confocal microscopy, and molecular studies of inclusions in biopsy specimens from women selected from clinically well-defined cohorts.
Clearly, the balance between inflammation leading to infection clearance and inflammation leading to pathology is an important consideration in understanding the natural history of C.
Th2 cells primarily enhance the humoral immune response to extracellular pathogens and regulate the Th1 response through synthesis of antiinflammatory Th2 cytokines, especially IL-4 and IL [ 40 ]. Human studies of the cellular immune response to C.
However, nonhuman primate studies in particular have provided some evidence for the potential double-edged nature of the T cell response, linking Th1-type responses with pathology [ 25 ]. The specific immune responses and cytokine levels that lead to resolution of infection rather than promotion of tissue damage remain undefined, and pathogenic responses may be more complicated than simple Th1 versus Th2 T cell polarization.
A more recently defined CD4 T cell lineage, Th17, which has been implicated in several other immunopathological disorders [ 44 ], might explain how ongoing inflammation could cause pathogenesis without adequate clearance of C.
Thus, such lineages could cause pathological inflammation without mediating clearance of intracellular chlamydiae [ 45 ]. Further study of the role of Th17 cells in C. Although logistically very difficult, more prospective studies involving women with C. Another critical question related to chlamydial pathogenesis is what proportion of women infected with C. Analogous data on the proportion of women with C. Although numerous case-control studies have demonstrated the association between evidence of past chlamydial infection and either infertility [ 47—49 ] or ectopic pregnancy [ 50 , 51 ], the authors found no prospective data directly assessing rates of long-term reproductive complications after untreated C.
Some data were available, however, on the risk of symptomatic PID associated with untreated C. However, in 2 studies involving women at lower risk who had untreated infection and were followed up prospectively over longer periods, investigators did not observe proportionally higher percentages of PID diagnoses [ 55 , 56 ].
In a small study involving 30 women with untreated chlamydial infection, no women developed PID over 1 year [ 55 ]. In another, 4 3. All of the reviewed studies were relatively small and had major limitations that could affect the accuracy of risk estimates.
Natural history studies are inherently difficult, because it is unclear how long a woman has already had infection at the time it is detected through testing, and the standard of care is treatment of chlamydial infection after it is diagnosed. Another fundamental problem relates to outcome measurement. Clinical diagnosis of PID is notoriously insensitive and nonspecific [ 13 ] and may be dependent on clinician practices in a given setting. For example, clinicians may have a lower threshold for PID diagnosis in high-risk settings or if they know a patient has untreated infection.
Synthesis of data across studies is also limited by the populations studied and tests used. For example, women in populations at high risk are more likely to have concurrent coinfections or a history of chlamydial infection or PID. Use of highly sensitive nucleic acid amplification tests in some studies may detect C. In addition, women may seek care in high-risk settings, such as sexually transmitted diseases clinics, earlier in the course of a new chlamydial infection because of recent high-risk behavior.
Thus, higher rates of symptomatic PID in these settings may be attributable to higher rates of symptomatic PID early in the course of chlamydial infection. In a landmark study conducted from through , women with clinically suspected PID underwent laparoscopic examination and were followed up for several years for adverse outcomes [ 58 ]. A key finding was that severity of salpingitis as determined by laparoscopic examination was linked to subsequent infertility risk in a dose-response fashion, suggesting that the intensity of inflammation during acute infection predicts long-term fibrosis and scarring, even with treatment.
Although PID, regardless of etiology, is linked to adverse outcomes, data from the largest studies suggest that C. Several lines of evidence also suggest that C.
First, asymptomatic upper tract chlamydial infections have been documented [ 61 ]. Second, most women with tubal infertility do not have a history of symptomatic PID, even in studies showing strong associations between infertility and serologic evidence of past chlamydial infection [ 47 , 62 ]. Finally, pathological damage in tubal biopsy specimens from women with tubal factor infertility is similar with or without a history of diagnosed PID [ 63 ].
Thus, subclinical tubal infection with C. To gain a better understanding of the risks of sequelae after untreated C. Newer, noninvasive measures of tubal inflammation and damage should be explored as advancements are made in laboratory methods and radiological techniques eg, magnetic resonance imaging or power Doppler ultrasound [ 64 , 65 ].
Ultimately, additional prospective studies are needed on the risk of clinically suspected PID, subclinical tubal inflammation, and longterm tubal damage resulting from untreated C.
Because of the aforementioned limitations, such studies will be challenging, and creative new approaches will be needed. Haggerty et al [ 13 ] suggest that genital specimens from prospective studies of other infections eg, human immunodeficiency virus prevention trials and human papillomavirus vaccine trials might provide opportunities for evaluating the natural history of chlamydia.
Studies of C. Although risk estimates are not precise and many gaps in knowledge remain, it is nonetheless clear that most women with C.
In this supplement, Byrne [ 9 ] discusses potential virulence properties of C. Traditionally, strain distinctions have been made primarily on the basis of variations in the chlamydial major outermembrane protein gene ompA [ 66 , 67 ]. However, differences in genital C. Byrne [ 9 ] describes a number of other candidate factors that might more accurately distinguish chlamydial strains with respect to pathogenic potential on the basis of their likely functional characteristics.
These include the polymorphic outer membrane autotransporter family of proteins Pmps [ 68 ], type III secretion system effectors [ 69 ], and the putative large cytotoxin [ 70 ]. Ultimately, Byrne [ 9 ] emphasizes the critical importance of expanding the definitions of chlamydial strains beyond the major outer membrane protein paradigm to better understand virulence properties and how these properties might reflect disease severity.
Continued work on development of a chlamydial gene transfer system and the application of genomic approaches to large collections of wellcharacterized clinical isolates may aid in identifying important virulence factors. The association between specific chlamydial gene products and disease outcomes cannot be interpreted without considering many factors, including host genetics, history of infection, and the hormonal and polymicrobial milieu at the time of infection [ 71 , 72 ].
Thus, complex data sets, including both host and pathogen factors, will likely be needed, as will innovative new biostatistical analytic approaches [ 9 ]. Because of the likely role of both innate and adaptive immune responses in pathogenesis, it is not surprising that genetic variation in host responses may play a role in determining why some women develop pathology and others do not. Various genetic determinants, such as HLA class I and II variants and functional polymorphisms in cytokine and cellular receptor genes, have been assessed in relation to chlamydia-related outcomes in disparate populations [ 10 , 73—75 ].
However, it has been difficult to clearly define specific alleles or polymorphisms that reliably predict pathology because of the complex nature of the immune response, the likelihood of finding associations by chance when evaluating a large number of potential determinants, potential linkage disequilibrium with closely related determinants, and the generalizability of findings given the populations evaluated [ 74 ]. Unbiased genome-wide delineation of important human genetic determinants of sequelae would enable a better understanding of chlamydial pathogenesis and could also lead to development of useful biomarkers.
Noninvasive markers that could reliably predict increased risk of complications would be extremely valuable, not only for the optimization of natural history studies, but also for targeted public health strategies that, for example, identify women who need more frequent screening or more intensive follow-up of sex partners. Biomarkers that could reliably predict susceptibility to incident and recurrent infection would have similar public health implications [ 11 , 76 , 77 ].
More detailed evaluations of host immune responses against a wider range of chlamydial antigens and use of newer high throughput DNA sequencing technologies to screen a larger number of genetic determinants may add insight [ 11 , 78 ]. Such approaches will rely on rapidly evolving advancements in genomics, transcriptomics, proteomics, and bioinformatics [ 78 , 79 ].
Researchers have attempted to identify clinically useful biomarkers by using currently available technologies. For example, vaginal neutrophil defensin levels, a measure of neutrophil activation, have been associated with the presence of endometritis in a cross-sectional study [ 80 ].
However, the precise role of defensins in the innate immune response to C. Serological markers have also been assessed. Studies have consistently shown that women with adverse reproductive outcomes, such as infertility or ectopic pregnancy, are more likely to have chlamydia-associated antibodies or higher titers of these antibodies than are women without these outcomes [ 47 , 48 , 50 , 51 ]. Some but not all studies show that serum antibodies predictive of sequelae frequently recognize Chlamydia heat shock protein 60 cHSP60 [ 75 , 81 ], an antigen known to be up-regulated during in vitro chlamydial persistence [ 16 ].
Among women with a history of C. However, these antibodies may simply be markers of greater exposure to chlamydiae through either persistent or repeated infection , which is in turn associated with pathogenesis, rather than implicating these antibodies in pathogenesis of disease [ 10 ]. Chlamydial antibodies may also be markers of a Th2-weighted cellular response in certain women who, thus, are less likely to have a protective Th1 response.
To gain a better understanding of the usefulness of serologic tests as markers of cumulative exposure to chlamydiae and predictors of disease, prospective studies should assess the proportion of C.
Another important factor that may determine why some women develop sequelae and others do not is the number of C.
Guinea pig and nonhuman primate models show that T cells infiltrate infected tissue more rapidly and in larger numbers and are associated with greater tissue destruction and fibrosis during repeat chlamydial infections, c ompA red with initial infection [ 25 , 82 , 83 ]. These animal model data have been widely interpreted as meaning that repeat infections are inherently more dangerous than initial infections ie, that risk of tubal damage per infection is not constant but rather increases with each additional infection.
However, the animal studies have a number of limitations. For one, studies on repeat infections in macaques have mostly used direct inoculation of fallopian tubes [ 82 ] or salpingeal pockets [ 85 ], which does not necessarily mimic natural sexually acquired ascending infection. With direct inoculation, potentially damaging memory T cells home directly to the fallopian tubes, whereas in sexually acquired infection, there is time for these cells to home to infection at the level of the cervix and, thus, potentially resolve infection before it ascends.
In addition, in nonhuman primate studies, repeated exposures were often given every 2—4 weeks, without treatment between exposures, even though natural infection in these primates may last several months [ 25 , 82 ].
This model does not resemble the human situation in which a woman with a detected and treated infection or with a naturally resolving infection is reinfected later, often after many months or even years. However, this animal model may parallel the situation in which a woman with C. If repeated inoculation is more often associated with ascension of the organism to the upper tract and pathology in humans, this could have important prevention implications. For example, condom use might provide additional benefit beyond primary prevention of sexually transmitted infections if it reduces risk of PID caused by repeated exposures among women already infected with C.
Available human epidemiologic studies have shown that the cumulative risk of PID [ 75 , 87 ] and long-term reproductive consequences [ 87 , 88 ] increases in parallel with the number of repeated C. Repeated C. However, it remains unclear from the available studies whether the risk of sequelae per infection increases with each additional repeat infection [ 75 ]. Thus, although a woman with 2 infections likely has a greater risk of sequelae than does a woman with 1 infection, it is unknown whether the cumulative risk is simply additive the same risk with each infection or more than additive greater risk of sequelae during each subsequent infection.
In some studies of repeat infections, clinicians' knowledge about prior positive C. It is also difficult to determine whether a first diagnosed infection is truly primary, the number and timing of past infections when there is evidence of past infection, and whether women with no detected infections have truly never had chlamydial infection.
In all of the published studies, past infections were treated. It is possible and, perhaps, even likely that pathologic immune responses may differ after infections that resolve on their own, c ompA red with those that are iatrogenically terminated. Additional studies assessing repeated C. In addition, the high rates of PID from any cause during the years after a detected chlamydial infection indicate a need for studies of prevention strategies focused on women who have already received a diagnosis of at least 1 infection.
Numerous studies have shown that repeat chlamydial infections are common. In a systematic review of repeat C. Surveillance data from British Columbia show that the number of repeat infections has been increasing over time, which likely contributes to observed increases in reported cases of C. It would be expected that, as more previously tested women are retested in a control program, the number of repeat infections will increase as a proportion of all detected infections. They postulated that shortening the mean duration of C.
Clearly, explanations other than arrested immunity could explain the observed epidemiologic trends. For example, increased screening coverage and frequency and increased use of more-sensitive diagnostic tests can lead to an increase in the number of reported chlamydia cases, even when there has been no true increase in the burden of genital C. In the United States, C. Nonetheless, the arrested immunity hypothesis raises fundamental questions about whether and to what extent women develop protective immunity against reinfection with C.
In this supplement, Rank and Whittum-Hudson [ 15 ] review the evidence for development of protective immunity in animal models.
In animal models, evidence strongly supports development of protective immunity; however, immunity against reinfection is complete only in the short term [ 15 ]. This short-term complete immunity is likely related to presence of antigen-specific T cells, which begin to decrease rapidly as soon as chlamydial antigen is no longer present [ 99 ]. IgG antibody, which unlike T cells, persists in the genital tract through constant transudation from serum, likely reduces the peak level of a reinfection through neutralization of EBs, and a rapid anamnestic T cell response then abbreviates the duration of the reinfection [ 15 ].
With regard to the effect of treatment on protective immunity, a published study of a mouse model clearly showed that antibiotics given at varying times up to 10 days after primary infection can attenuate development of protective immunity [ ]. However, it is difficult to extrapolate these results to humans because of the marked differences in the durations of natural infection between mice and humans.
Rank and Whittum-Hudson [ 15 ] also describe other reasons why animal models used to date might not parallel human infections and how to design better studies.
For example, rodents have typically been inoculated at 2 discrete times once for primary infection and once for repeat infection , whereas in humans, sexual activity with an infected partner may occur multiple times in a given time frame. In addition, in this supplement, Batteiger et al [ 8 ] review the evidence for the development of protective immunity in humans.
Several cross-sectional studies have demonstrated that younger age is associated with higher prevalence of chlamydia, higher organism load, and a higher degree of concordant infection status between sex partners [ — ]. Anyone with genital symptoms such as discharge, burning during urination, unusual sores, or rash should refrain from having sex until they are able to see a health care provider about their symptoms.
Also, anyone with an oral, anal, or vaginal sex partner who has been recently diagnosed with an STD should see a health care provider for evaluation. Because chlamydia is usually asymptomatic, screening is necessary to identify most infections. Screening programs have been demonstrated to reduce rates of adverse sequelae in women. Routine screening is not recommended for men. However, the screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia e.
Sexually active men who have sex with men MSM who had insertive intercourse should be screened for urethral chlamydial infection and MSM who had receptive anal intercourse should be screened for rectal infection at least annually; screening for pharyngeal infection is not recommended.. More frequent chlamydia screening at 3-month intervals is indicated for MSM, including those with HIV infection, if risk behaviors persist or if they or their sexual partners have multiple partners.
At the initial HIV care visit, providers should test all sexually active persons with HIV infection for chlamydia and perform testing at least annually during the course of HIV care. There are a number of diagnostic tests for chlamydia, including nucleic acid amplification tests NAATs , cell culture, and others. NAATs are the most sensitive tests, and can be performed on easily obtainable specimens such as vaginal swabs either clinician- or patient-collected or urine.
Vaginal swabs, either patient- or clinician-collected, are the optimal specimen to screen for genital chlamydia using NAATs in women; urine is the specimen of choice for men, and is an effective alternative specimen type for women.
NAATs have demonstrated improved sensitivity and specificity compared with culture for the detection of C. Chlamydia can be easily cured with antibiotics. Persons with chlamydia should abstain from sexual activity for 7 days after single dose antibiotics or until completion of a 7-day course of antibiotics, to prevent spreading the infection to partners.
It is important to take all of the medication prescribed to cure chlamydia. Medication for chlamydia should not be shared with anyone. Although medication will cure the infection, it will not repair any permanent damage done by the disease. Repeat infection with chlamydia is common. If a person has been diagnosed and treated for chlamydia, he or she should tell all recent anal, vaginal, or oral sex partners all sex partners within 60 days before the onset of symptoms or diagnosis so they can see a health care provider and be treated.
A person with chlamydia and all of his or her sex partners must avoid having sex until they have completed their treatment for chlamydia i. For tips on talking to partners about sex and STD testing, visit www. To help get partners treated quickly, healthcare providers in some states may give infected individuals extra medicine or prescriptions to give to their sex partners. This is called expedited partner therapy or EPT.
In published clinical trials comparing EPT to traditional patient referral i. Latex male condoms, when used consistently and correctly, can reduce the risk of getting or giving chlamydia. More information is available at www. Genital ulcers and concomitant complaints in men attending a sexually transmitted infections clinic: implications for sexually transmitted infections management. Sexually transmitted diseases ; White JA.
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