IU Indianapolis ScholarWorks :: Browsing by Subject "Chlamydia"

Browsing by Subject "Chlamydia"

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A Member of an Ancient Family of Bacterial Amino Acids Transporters Contributes to Chlamydia Nutritional Virulence and Immune Evasion
(American Society for Microbiology, 2023) Banerjee, Arkaprabha; Sun, Yuan; Muramatsu, Matthew K.; Toh, Evelyn; Nelson, David E.; Microbiology and Immunology, School of Medicine
Many obligate intracellular bacteria, including members of the genus Chlamydia, cannot synthesize a variety of amino acids de novo and acquire these from host cells via largely unknown mechanisms. Previously, we determined that a missense mutation in ctl0225, a conserved Chlamydia open reading frame of unknown function, mediated sensitivity to interferon gamma. Here, we show evidence that CTL0225 is a member of the SnatA family of neutral amino acid transporters that contributes to the import of several amino acids into Chlamydia cells. Further, we show that CTL0225 orthologs from two other distantly related obligate intracellular pathogens (Coxiella burnetii and Buchnera aphidicola) are sufficient to import valine into Escherichia coli. We also show that chlamydia infection and interferon exposure have opposing effects on amino acid metabolism, potentially explaining the relationship between CTL0225 and interferon sensitivity. Overall, we show that phylogenetically diverse intracellular pathogens use an ancient family of amino acid transporters to acquire host amino acids and provide another example of how nutritional virulence and immune evasion can be linked in obligate intracellular pathogens.
Advances and Obstacles in the Genetic Dissection of Chlamydial Virulence
(Springer, 2018) Brothwell, Julie A.; Muramatsu, Matthew K.; Zhong, Guangming; Nelson, David E.; Microbiology and Immunology, School of Medicine
Obligate intracellular pathogens in the family Chlamydiaceae infect taxonomically diverse eukaryotes ranging from amoebae to mammals. However, many fundamental aspects of chlamydial cell biology and pathogenesis remain poorly understood. Genetic dissection of chlamydial biology has historically been hampered by a lack of genetic tools. Exploitation of the ability of chlamydia to recombine genomic material by lateral gene transfer (LGT) ushered in a new era in chlamydia research. With methods to map mutations in place, genetic screens were able to assign functions and phenotypes to specific chlamydial genes. Development of an approach for stable transformation of chlamydia also provided a mechanism for gene delivery and platforms for disrupting chromosomal genes. Here, we explore how these and other tools have been used to test hypotheses concerning the functions of known chlamydial virulence factors and discover the functions of completely uncharacterized genes. Refinement and extension of the existing genetic tools to additional Chlamydia spp. will substantially advance understanding of the biology and pathogenesis of this important group of pathogens.
Association of Chlamydia trachomatis infection with redetection of human papillomavirus after apparent clearance
(Oxford, 2013-11) Shew, Marcia L.; Ermel, Aaron C.; Weaver, Bree A.; Tong, Yan; Tu, Wanzhu; Kester, Laura M.; Denski, Cheryl; Fortenberry, J. Dennis; Brown, Darron R.; Pediatrics, School of Medicine
BACKGROUND: Persistent infection with oncogenic human papillomavirus (HPV) is associated with an increased risk of cervical malignancy. Redetection of type-specific HPV after a period of nondetection may be caused by reactivation of a low-level persistent infection. Little is known about factors associated with type-specific HPV redetection. METHODS: For a longitudinal cohort of adolescent women with frequent behavioral and sexually transmitted infection (STI) information (every 3 months), Cox proportional hazard models were used to assess the influence of sexual behaviors and STIs on the redetection of oncogenic or high-risk HPV infections. RESULTS: A total of 210 type-specific high-risk HPV detection episode periods were identified in this longitudinal cohort; 71 (33.8%) were characterized by a period of nondetection followed by redetection. Chlamydia trachomatis (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.44-6.86) was associated with redetection; redetection was >2 times more likely with each additional self-reported sex partner in the past 3 months (HR, 2.26; 95% CI, 1.35-3.78). CONCLUSIONS: This study demonstrates the role of C. trachomatis and number of recent sexual partners in type-specific HPV redetection. Given that persistent oncogenic HPV infections are associated with cancer-related outcomes, understanding the potential role of such factors in the pathogenesis of HPV-related outcomes is important.
Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors
(American Society for Microbiology, 2018-06-21) Morrison, Sandra G.; Giebel, Amanda M.; Toh, Evelyn C.; Spencer, Horace J., III; Nelson, David E.; Morrison, Richard P.; Microbiology and Immunology, School of Medicine
Some members of the genus Chlamydia, including the human pathogen Chlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within the Chlamydia muridarum plasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute to C. muridarum GI tropism. Infectivity and shedding of wild-type (WT) C. muridarum and three mutants containing nonsense mutations in different cytotoxin genes, tc0437, tc0438, and tc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation in tc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of the tc0439 mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation in tc0600 The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.
Coinfection with Chlamydial and Gonorrheal Infection among US Adults with Early Syphilis
(Wolters Kluwer, 2022) Dionne-Odom, Jodie; Workowski, Kimberly; Perlowski, Charlotte; Taylor, Stephanie N.; Mayer, Kenneth H.; McNeil, Candice J.; Hamill, Matthew M.; Dombrowski, Julia C.; Batteiger, Teresa A.; Sena, Arlene C.; Wiesenfeld, Harold C.; Newman, Lori; Hook, Edward W., III; Medicine, School of Medicine
Among 865 adults with early syphilis considered for a multicenter treatment trial, 234 (27%) were excluded before enrollment because of bacterial sexually transmitted infection coinfection. Coinfection with Neisseria gonorrhoeae (29%), Chlamydia trachomatis (22%), or both (23%) was common. Study findings highlight the need for comprehensive bacterial sexually transmitted infection screening in patients with syphilis.
Diagnosis and Management of Uncomplicated Chlamydia trachomatis Infections in Adolescents and Adults: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines
(Oxford University Press, 2022) Geisler, William M.; Hocking, Jane S.; Darville, Toni; Batteiger, Byron E.; Brunham, Robert C.; Medicine, School of Medicine
To prepare for the development of the 2021 Centers for Disease Control and Prevention (CDC) sexually transmitted infections treatment guidelines, the CDC convened a committee of expert consultants in June 2019 to discuss recent abstracts and published literature on the epidemiology, diagnosis, and management of sexually transmitted infections.This paper summarizes the key questions, evidence, and recommendations for the diagnosis and management of uncomplicated Chlamydia trachomatis (CT) infections in adolescents and adults that were reviewed and discussed for consideration in developing the guidelines. The evidence reviewed mostly focused on efficacy of doxycycline and azithromycin for urogenital, rectal, and oropharyngeal CT infection, CT risk factors in women, performance of CT nucleic acid amplification tests on self-collected meatal specimens in men, and performance of newer CT point-of-care tests.
Endocervical miRNA Expression Profiles in Women Positive for Chlamydia trachomatis with Clinical Signs and/or Symptoms Are Distinct from Those in Women Positive for Chlamydia trachomatis without Signs and Symptoms
(American Society for Microbiology, 2020-09-18) Batteiger, Teresa A.; Spencer, Nicole; Washam, Charity L.; Byrum, Stephanie; Eledge, Michael; Batteiger, Byron E.; Rank, Roger G.; Yeruva, Laxmi; Medicine, School of Medicine
Chlamydia trachomatis is the leading cause of sexually transmitted infections that may progress to pelvic inflammatory disease and infertility. No effective vaccine exists for Chlamydia, nor are there biomarkers available that readily predict disease progression. In this cross-sectional pilot study, we recruited symptomatic and asymptomatic women with C. trachomatis (CT) infection and asymptomatic, uninfected control women from an urban sexually transmitted disease clinic to determine if there were differences in microRNA (miRNA) expression. Infected women with signs and/or symptoms (CTSS) have distinct miRNA profiles compared to asymptomatic infected women (CTNS). In the CTSS group, miR-142 and -147 showed 2.2- to 6.9-fold increases in expression. In the CTNS group, miR-449c, -6779, -519d, -449a, and -2467 showed 3.9- to 9.0-fold increases in expression. In the CTNS group, cyclins and cell cycle regulation and IL-17 pathways were likely downregulated, while the same signaling pathways were upregulated in the CTSS group. In addition, in the CTSS group, additional inflammatory pathways associated with TNFR1 and IL-8 appear to be upregulated. The miRNA expression patterns differ between CT-infected symptomatic and asymptomatic women, and these differences may warrant further study.
Findings From a Scoping Review: Presumptive Treatment for Chlamydiatrachomatis and Neisseria gonorrhoeae in the United States, 2006-2021
(Wolters Kluwer, 2023) Allen, Katie S.; Hinrichs, Rachel; Heumann, Christine L.; Titus, Melissa K.; Duszynski, Thomas J.; Valvi, Nimish R.; Wiensch, Ashley; Tao, Guoyu; Dixon, Brian E.; University Library
Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are the two most common reported sexually transmitted infections in the USA. Current recommendations are to presumptively treat CT and/or GC in persons with symptoms or known contact. This review characterizes the literature around studies with presumptive treatment, including identifying rates of presumptive treatment and over- and under-treatment rates. Of the 18 articles that met our inclusion criteria, six pertained to outpatient settings. In the outpatient setting, presumptive treatment rates, for both asymptomatic and symptomic patients, varied from 12% - 100%, and the percent positive of those presumptively treated ranged from 25% - 46%. Three studies also reported data on positive results in patients not presumptively treated, which ranged from 2% - 9%. Two studies reported median follow-up time for untreated, which was roughly nine days. The remaining 12 articles pertained to the emergency setting where presumptive treatment rates, for both asymptomatic and symptomic patients, varied from 16% - 91%, the percent positive following presumptive treatment ranged from 14% - 59%. Positive results without presumptive treatment ranged from 4% - 52%. Two studies reported the percent positive without any treatment (6% and 32% respectively) and one reported follow-up time for untreated infections (median: 4.8 days). Rates of presumptive treatment, as well as rates of over- or under- treatment vary widely across studies and within care settings. Given large variability in presumptive treatment, the focus on urban settings, and minimal focus on social determinants of health, additional studies are needed to guide treatment practices for CT and GC in outpatient and emergency settings.
Generation of conditional mutants to dissect essential gene fuction in chlamydia trachomatis
(2016-12-07) Brothwell, Julie Ann; Nelson, David E.; Bauer, Margaret E.; Gilk, Stacey D.; Sullivan, William J., Jr.
Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease. Chlamydia spp. are all obligate intracellular organisms that undergo a biphasic developmental cycle within a vacuole termed the inclusion. Infectious, non metabolically active elementary bodies (EBs) are endocytosed and differentiate into non infectious, metabolically active reticulate bodies (RBs) before re-differentiating back into EBs. The chlamydial factors that mediate these differentiation events are mostly unknown. Comparative genomics revealed that Chlamydia spp. have small, highly conserved genomes, suggesting that many of their genes may be essential. Genetic manipulation strategies for Chlamydia spp. are in their infancy, and most of these cannot be used to inactivate essential genes. We generated a clonal ethyl methanesulfonate (EMS)-mutagenized C. trachomatis library and screened it for temperature sensitive (TS) mutants that produced fewer inclusions at either 32°C or 40°C compared to 37°C. Because EMS mutagenesis elicited multiple mutations in most of the library isolates, we also developed a novel lateral gene transfer strategy for mapping mutations linked to TS phenotypes. We identified TS alleles of genes that are essential in other bacteria and that are involved in diverse biological processes including DNA replication, protein synthesis, carbohydrate metabolism, fatty acid biosynthesis, and energy generation, as well as in highly conserved chlamydial hypothetical genes. TS DNA polymerase (dnaEts) and glutamyl-tRNA synthestase (gltXts) mutants were characterized further. Both the dnaEts and gltXts mutants failed to replicate their genomes at 40°C but exhibited unique signs of stress. Chlamydial DNA replication begins by 12 hpi and protein synthesis begins by 2 hpi. However, inclusion expansion and replication of both of the mutants could be rescued by shifting to them to 37°C prior to mid-late development. Since gltXts is likely unable to produce aminoacyl-tRNAs at 40°C, our observation suggests that de novo chlamydial translation uses a pre-existing pool of aminoacyl-tRNA in EBs. Genetic suppressor analysis indicated that the inability of the dnaEts mutant to replicate its genome at 40°C might be linked to an inability of mutant DnaE to bind the DNA template. The tools and mutants we have identified will be invaluable assets for investigating many essential aspects of chlamydial biology.
Genetic Dissection of Chlamydia spp. Determinants of Tissue Tropism, Stress Response and Nutrient Acquisition
(2023-02) Banerjee, Arkaprabha; Nelson, David E.; Bauer, Margaret E.; Yang, X. Frank; Mosley, Amber L.
Chlamydia trachomatis (CT) is an obligate intracellular bacterium that transitions between two distinct morphological forms during its complex developmental cycle. During the intracellular portion of its developmental cycle, CT multiplies, evades host immunity, and acquires nutrients. CT is the causative agent of chlamydia, the most common bacterial sexually transmitted disease in the US. CT infection sometimes elicits a robust host immune response which drives most chlamydia-associated pathology. Chlamydia outcomes include urethritis in men and women, cervicitis in women, as well as severe complications including pelvic inflammatory disease and ectopic pregnancies in women and epididymitis in men. Sexually transmitted CT strains can also colonize multiple tissues in their hosts, apart from urogenital organs. For example, CT can infect cells of the gastrointestinal (GI) tract. Unlike urogenital infection, GI CT usually does not elicit inflammatory pathology. My goal was to identify genes that are central to CT pathogenesis. In one project, I characterized CTL0225, and showed that it is an amino acid transporter that helps CT acquire essential nutrients from the host cell. In another project, I identified a protease that helps CT survive stress, such as exposure to high temperature. I also found evidence that this protease plays a crucial role in the transition between morphological forms during CT development. Finally, I identified several novel genes that may contribute to CT tissue tropism using a genetic screen. Overall, I have identified and characterized several new CT factors that mediate the survival and virulence of this important pathogen.

Browsing by Subject "Chlamydia"

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