Letter to the Editor re: In Vivo Whole Animal Body Imaging Reveals Colonization of Chlamydia muridarum to the Lower Genital Tract at Early Stages of Infection

ABSTRACTPlasmid-freeChlamydia trachomatisandChlamydia muridarumfail to induce severe pathology. To evaluate whether the attenuated pathogenicity is due to insufficient infection or inability of the plasmidless chlamydial organisms to trigger pathological responses, we compared plasmid-competent and plasmid-freeC. muridaruminfections in 5 different strains of mice. All 5 strains developed hydrosalpinx following intravaginal inoculation with plasmid-competent, but not inoculation with plasmid-free,C. muridarum. The lack of hydrosalpinx induction by plasmid-freeC. muridarumcorrelated with significantly reduced live organism recovery from the lower genital tract and shortened infection in the upper genital tract. The plasmid-freeC. muridarumorganisms failed to induce hydrosalpinx even when the organisms were directly inoculated into the oviduct via an intrabursal injection, which was accompanied by significantly reduced survival of the plasmidless organisms in the genital tracts. Furthermore, plasmid-competentC. muridarumorganisms after UV inactivation were no longer able to induce hydrosalpinx even when directly delivered into the oviduct at a high dose. Together, these observations suggest that decreased survival of and shortened infection with plasmid-freeC. muridarummay contribute significantly to its attenuated pathogenicity. We conclude that adequate live chlamydial infection in the oviduct may be necessary to induce hydrosalpinx.

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In VivoandEx VivoImaging Reveals a Long-Lasting Chlamydial Infection in the Mouse Gastrointestinal Tract following Genital Tract Inoculation

Infection and Immunity ◽

10.1128/iai.00673-15 ◽

2015 ◽

Vol 83 (9) ◽

pp. 3568-3577 ◽

Cited By ~ 41

Author(s):

Qi Zhang ◽

Yumeng Huang ◽

Siqi Gong ◽

Zhangsheng Yang ◽

Xin Sun ◽

...

Keyword(s):

Genital Tract ◽

Chlamydial Infection ◽

Ex Vivo ◽

Mouse Strains ◽

Gi Tract ◽

Tubal Infertility ◽

Content Type ◽

Chlamydia Muridarum ◽

Rapid Ascent

Intravaginal infection withChlamydia muridarumin mice can ascend to the upper genital tract, resulting in hydrosalpinx, a pathological hallmark for tubal infertility in women infected withC. trachomatis. Here, we utilizedin vivoimaging ofC. muridaruminfection in mice following an intravaginal inoculation and confirmed the rapid ascent of the chlamydial organisms from the lower to upper genital tracts. Unexpectedly, theC. muridarum-derived signal was still detectable in the abdominal area 100 days after inoculation.Ex vivoimaging of the mouse organs revealed that the long-lasting presence of the chlamydial signal was restricted to the gastrointestinal (GI) tract, which was validated by directly measuring the chlamydial live organisms and genomes in the same organs. TheC. muridarumorganisms spreading from the genital to the GI tracts were detected in different mouse strains and appeared to be independent of oral or rectal routes. Mice prevented from orally taking up excretions also developed the long-lasting GI tract infection. Inoculation ofC. muridarumdirectly into the upper genital tract, which resulted in a delayed vaginal shedding of live organisms, accelerated the chlamydial spreading to the GI tract. Thus, we have demonstrated that the genital tract chlamydial organisms may use a systemic route to spread to and establish a long-lasting infection in the GI tract. The significance of the chlamydial spreading from the genital to GI tracts is discussed.

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The Plasmid-Encoded pGP3 PromotesChlamydiaEvasion of Acidic Barriers in Both Stomach and Vagina

Infection and Immunity ◽

10.1128/iai.00844-18 ◽

2019 ◽

Vol 87 (5) ◽

Cited By ~ 9

Author(s):

Tianyuan Zhang ◽

Zhi Huo ◽

Jingyue Ma ◽

Cheng He ◽

Guangming Zhong

Keyword(s):

Lactic Acid ◽

Gastrointestinal Tract ◽

Genital Tract ◽

Sexual Transmission ◽

Content Type ◽

Chlamydia Muridarum ◽

Lower Genital Tract ◽

Colonization Ability ◽

Gastric Barrier

ABSTRACTAlthoughChlamydia trachomatisis a human genital tract pathogen, chlamydial organisms have frequently been detected in both vaginal and rectal swab samples of animals and humans. The plasmid-encoded pGP3, a genital tract virulence factor, is essential forChlamydia muridarumto colonize the mouse gastrointestinal tract. However, intracolon inoculation to bypass the gastric barrier rescued the colonization ability of a pGP3-deficientC. muridarummutant, suggesting that pGP3 is required forC. muridarumto reach but not to colonize the large intestine. The pGP3-deficient mutant was rapidly cleared in the stomach and was 100-fold more susceptible to gastric killing. In mice genetically deficient in gastrin, a key regulator for gastric acid production, or pharmacologically treated with a proton pump inhibitor, the ability of pGP3-deficientC. muridarumto colonize the gastrointestinal tract was rescued. The pGP3-dependent resistance was further recapitulatedin vitrowith treatments with HCl, pepsin, or sarkosyl. In the genital tract, deficiency in pGP3 significantly reducedC. muridarumsurvival in the mouse vagina and increasedC. muridarumsusceptibility to vaginal killing by ∼8 times. The pGP3-deficientC. muridarumwas more susceptible to lactic acid killing, and the pGP3 deficiency also significantly increasedC. trachomatissusceptibility to lactic acid. The above-described observations together suggest thatChlamydiamay have acquired the plasmid-encoded pGP3 to overcome the gastric barrier during its adaptation to the gastrointestinal tract and the pGP3-dependent resistance may enable chlamydial evasion of the female lower genital tract barrier during sexual transmission.

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In VitroPassage Selects for Chlamydia muridarum with Enhanced Infectivity in Cultured Cells but Attenuated Pathogenicity in Mouse Upper Genital Tract

Infection and Immunity ◽

10.1128/iai.03158-14 ◽

2015 ◽

Vol 83 (5) ◽

pp. 1881-1892 ◽

Cited By ~ 31

Author(s):

Chaoqun Chen ◽

Zhou Zhou ◽

Turner Conrad ◽

Zhangsheng Yang ◽

Jin Dai ◽

...

Keyword(s):

Genital Tract ◽

Selection Pressure ◽

Cultured Cells ◽

Serial Passage ◽

Host Cells ◽

Content Type ◽

Chlamydia Muridarum ◽

Low Incidence

Although modernChlamydia muridarumhas been passaged for decades, there are no reports on the consequences of serial passage with strong selection pressure on its fitness. In order to explore the potential for Pasteurian selection to induce genomic and phenotypic perturbations toC. muridarum, a starter population was passaged in cultured cells for 28 generations without standard infection assistance. The resultant population, designated CMG28, displays markedly reducedin vitrodependence on centrifugation for infection and low incidence and severity of upper genital tract pathology following intravaginal inoculation into mice compared to the parentalC. muridarumpopulation, CMG0. Deep sequencing of CMG0 and CMG28 revealed novel protein variants in the hypothetical genes TC0237 (Q117E) and TC0668 (G322R).In vitroattachment assays of isogenic plaque clone pairs with mutations in either TC0237 and TC0668 or only TC0237 reveal that TC0237(Q117E) is solely responsible for enhanced adherence to host cells. Paradoxically, double mutants, but not TC0237(Q117E) single mutants, display severely attenuatedin vivopathogenicity. These findings implicate TC0237 and TC0668 as novel genetic factors involved in chlamydial attachment and pathogenicity, respectively, and show that serial passage under selection pressure remains an effective tool for studyingChlamydiapathogenicity.

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The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia muridarum

Infection and Immunity ◽

10.1128/iai.01171-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 467-479 ◽

Cited By ~ 31

Author(s):

Turner Allen Conrad ◽

Siqi Gong ◽

Zhangsheng Yang ◽

Patrick Matulich ◽

Jonathon Keck ◽

...

Keyword(s):

Missense Mutation ◽

Genital Tract ◽

Hypothetical Protein ◽

Genital Tract Infection ◽

Content Type ◽

Chlamydia Muridarum ◽

Pathogenicity Factor ◽

Lower Genital Tract ◽

Lower Genital Tract Infection

We previously associated a missense mutation of thetc0668gene of serialin vitro-passagedChlamydia muridarum, a murine model of human urogenitalC. trachomatis, with severely attenuated disease development in the upper genital tract of female mice. Since these mutants also contained a TC0237 Q117E missense mutation that enhances theirin vitroinfectivity, an effort was made here to isolate and characterize atc0668single mutant to determine its individual contribution to urogenital pathogenicity. Detailed genetic analysis ofC. muridarumpassages revealed a truncated variant with a G216* nonsense mutation of the 408-amino-acid TC0668 protein that does not produce a detectable product. Intracellular growth and infectivity ofC. muridarum in vitroremain unaffected in the absence of TC0668. Intravaginal inoculation of the TC0668 null mutant into C3H/HeJ mice results in a typical course of lower genital tract infection but, unlike a pathogenic isogenic control, is unable to elicit significant chronic inflammation of the oviduct and fails to induce hydrosalpinx. Thus, TC0668 is demonstrated as an important chromosome-encoded urogenital pathogenicity factor ofC. muridarumand the first with these characteristics to be discovered for aChlamydiapathogen.

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Lack of Long-Lasting Hydrosalpinx in A/J Mice Correlates with Rapid but Transient Chlamydial Ascension and Neutrophil Recruitment in the Oviduct following Intravaginal Inoculation with Chlamydia muridarum

Infection and Immunity ◽

10.1128/iai.00055-14 ◽

2014 ◽

Vol 82 (7) ◽

pp. 2688-2696 ◽

Cited By ~ 32

Author(s):

Hongbo Zhang ◽

Zhou Zhou ◽

Jianlin Chen ◽

Ganqiu Wu ◽

Zhangsheng Yang ◽

...

Keyword(s):

Genital Tract ◽

Inflammatory Responses ◽

Chronic Phase ◽

Mouse Strains ◽

Genital Tract Infection ◽

Content Type ◽

Chlamydia Muridarum ◽

Lower Genital Tract ◽

Lower Genital Tract Infection

ABSTRACTLower genital tract infection withChlamydia trachomatisandC. muridarumcan induce long-lasting hydrosalpinx in the upper genital tract of women and female mice, respectively. However, A/J mice were highly resistant to induction of long-lasting hydrosalpinx byC. muridarum. We further compared host inflammatory responses and chlamydial infection courses between the hydrosalpinx-resistant A/J mice and CBA/J mice known to be susceptible to hydrosalpinx induction. Both mouse strains developed robust pyosalpinx during the acute phase followed by hydrosalpinx during the chronic phase. However, the hydrosalpinges disappeared in A/J mice by day 60 after infection, suggesting that some early hydrosalpinges are reversible. Although the overall inflammatory responses were indistinguishable between CBA/J and A/J mice, we found significantly more neutrophils in oviduct lumen of A/J mice on days 7 and 10, which correlated with a rapid but transient oviduct invasion byC. muridarumwith a peak infection on day 7. In contrast, CBA/J mice developed a delayed and extensive oviduct infection. These comparisons have revealed an important role of the interactions of oviduct infection with inflammatory responses in chlamydial induction of long-lasting hydrosalpinx, suggesting that a rapid but transient invasion of oviduct by chlamydial organisms can prevent the development of the long-lasting hydrosalpinges.

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Candidiasis During Pregnancy May Result From Isogenic Commensal Strains

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744901000138 ◽

2001 ◽

Vol 9 (2) ◽

pp. 65-73 ◽

Cited By ~ 8

Author(s):

Wayne Daniels ◽

Douglas D. Glover ◽

Michael Essmann ◽

Bryan Larsen

Keyword(s):

Genital Tract ◽

Lower Genital Tract ◽

Regulation Of Growth

Conclusion:Symptomatic yeast vaginitis is usually due to strains ofC. albicansalready carried in the lower genital tract, underscoring the need to understand regulation of growth and virulence of the organismin vivo.

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