Interleukin-17 Contributes to Generation of Th1 Immunity and Neutrophil Recruitment during<i>Chlamydia muridarum</i>Genital Tract Infection but Is Not Required for Macrophage Influx or Normal Resolution of Infection

Scurlock, Amy M.; Frazer, Lauren C.; Andrews, Charles W.; O’Connell, Catherine M.; Foote, Isaac P.; Bailey, Sarabeth L.; Chandra-Kuntal, Kumar; Kolls, Jay K.; Darville, Toni

doi:10.1128/iai.00984-10

Cited by 108 publications

(107 citation statements)

References 48 publications

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“…Additionally, increased secretion of IL-17 and IFN-␥ were observed in IRF3 KO in comparison to WT mouse T cell supernatants, suggesting enhanced Th1 and Th17 responses. Recently, it was shown that IL-17 KO mice have a compromised Th1 response during C. muridarum infection (47), suggesting that elevated IL-17 may contribute to the enhanced Th1 response in IRF3 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Transcription Factor 3 Protects Mice from Uterine Horn Pathology during Chlamydia muridarum Genital Infection

et al. 2011

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Mice with the type I interferon (IFN) receptor gene knocked out (IFNAR KO mice) or deficient for alpha/beta IFN (IFN-␣/␤) signaling clear chlamydial infection earlier than control mice and develop less oviduct pathology. Initiation of host IFN-␤ transcription during an in vitro chlamydial infection requires interferon regulatory transcription factor 3 (IRF3). The goal of the present study was to characterize the influence of IRF3 on chlamydial genital infection and its relationship to IFN-␤ expression in the mouse model. IRF3 KO mice were able to resolve infection as well as control mice, overcoming increased chlamydial colonization and tissue burden early during infection. As previously observed for IFNAR KO mice, IRF3 KO mice generated a potent antigen-specific T cell response. However, in contrast to IFNAR KO mice, IRF3 KO mice exhibited unusually severe dilatation and pathology in the uterine horns but normal oviduct pathology after infection. Although IFN-␤ expression in vivo was dependent on the presence of IRF3 early in infection (before day 4), the IFN-independent function of IRF3 was likely driving this phenotype. Specifically, early during infection, the number of apoptotic cells and the number of inflammatory cells were significantly less in uterine horns from IRF3 KO mice than in those from control mice, despite an increased chlamydial burden. To delineate the effects of IFN-␤ versus IRF3, neutralizing IFN-␤ antibody was administered to wild-type (WT) mice during chlamydial infection. IFN-␤ depletion in WT mice mimicked that in IFN〈R KO mice but not that in IRF3 KO mice with respect to both chlamydial clearance and reduced oviduct pathology. These data suggest that IRF3 has a role in protection from uterine horn pathology that is independent of its function in IFN-␤ expression.The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infection in the world and can cause pelvic inflammatory disease and Fallopian tube pathology in women. The cellular paradigm for immune-mediated pathology posits that cytokines produced by persistently infected epithelial cells are necessary and sufficient for the development of pathology during chlamydial infection (49). This theory has generated interest in characterizing the types and classes of genes upregulated during infection (24,39,40,54). In addition to expressing proinflammatory genes, such as those for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-␣), infected cells upregulate the type I IFNs (IFN-␣ and IFN-␤), which can signal via the common type I IFN receptor (IFN-␣/␤R) (29), leading to subsequent induction of a broad assortment of interferon-stimulatory genes (ISGs) (30). Using Chlamydia muridarum and the mouse female genital tract infection models, our laboratory demonstrated that signaling via IFN-␣/␤R was detrimental to the host during infection, as mice with the gene for IFN-␣/␤ signaling knocked out (IFNAR KO mice) cleared infection sooner than wild-type (WT) mice and developed l...

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Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Transcription Factor 3 Protects Mice from Uterine Horn Pathology during Chlamydia muridarum Genital Infection

et al. 2011

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“…It is known that Th17 responses are induced in response to oral C. albicans infections and required for protection against OPC (16,17,27,32). However, Th17 responses have also been implicated in exacerbation of candidal infections (i.e., gastrointestinal [GI] tract) (43). Hence, either deficient or chronic Th17 responses could be playing a role in DS.…”

Section: Figmentioning

confidence: 99%

Development of a Contemporary Animal Model of Candida albicans-Associated Denture Stomatitis Using a Novel Intraoral Denture System

et al. 2012

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bDenture stomatitis (DS) is a fungal infection characterized by inflammation of the oral mucosa in direct contact with the denture and affects up to 50% of denture wearers. Despite the prevalence, very little is known about the role of fungal or host factors that contribute to pathogenesis. Recently, we developed a novel intraoral denture system for rodent research. This denture system consists of custom-fitted fixed and removable parts to allow repeated sampling and longitudinal studies. The purpose of this study was to use this denture system to develop a clinically relevant animal model of DS. To establish DS, rats were inoculated with pelleted Candida albicans, which resulted in sustained colonization of the denture and palate for 8 weeks postinoculation. Biofilm formation on the denture was observed by week 4 and on the palate by week 6 postinoculation. Rats were monitored for clinical signs of disease by assigning a clinical score after macroscopic examination of the palate tissue according to Newton's method. By week 4 postinoculation, the majority of inoculated rats with dentures exhibited a clinical score of 1 (pinpoint erythema). By week 6 and week 8 postinoculation, increasing percentages of rats exhibited a clinical score of 2 (diffuse erythema/ edema). Histological analysis of palate tissue demonstrated progressively increasing inflammatory cell recruitment throughout the time course of the infection. Palatal biofilm formation was commensurate with development of palatal erythema, which suggests a role for biofilm in the inflammatory response.

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“…Samples were considered positive for ompA if a band of the appropriate size (614 bp) was visible after gel electrophoresis. Chlamydial DNA was quantified via real-time PCR analysis of the 16S rRNA gene as previously described (24).…”

Section: Methodsmentioning

confidence: 99%

Comparable Genital Tract Infection, Pathology, and Immunity in Rhesus Macaques Inoculated with Wild-Type or Plasmid-Deficient Chlamydia trachomatis Serovar D

Frazer

O’Connell

et al. 2015

Infect Immun

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e Rhesus macaques were studied to directly address the potential for plasmid-deficient Chlamydia trachomatis to serve as a live attenuated vaccine in the genital tract. Five repeated cervical inoculations of rhesus macaques with wild-type serovar D strain D/UW-3/Cx or a plasmid-deficient derivative of this strain, CTD153, resulted in infections with similar kinetics and induced comparable levels of protective immunity. After all animals received five challenges with D/UW-3/Cx, levels of inflammation observed grossly and histologically were similar between the groups. Animals in both groups developed evidence of oviduct dilatation; however, reduced oviduct dilatation was observed for "controllers," i.e., animals without detectable chlamydial DNA in the fimbriae at weeks 5 and 12. Grouping animals into "ascenders" and "controllers" revealed that elevated early T cell responses were associated with protection, whereas higher antibody responses were associated with ascension. Protected animals shared common major histocompatibility complex (MHC) alleles. Overall, genetic differences of individual animals, rather than the presence or absence of the chlamydial plasmid in the primary infecting strain, appeared to play a role in determining the outcome of infection. Infections with the obligate intracellular bacterium Chlamydia trachomatis are a major public health concern. In developing nations, repeated conjunctival infections with serovars A to C cause trachoma, the leading cause of preventable blindness worldwide (1). Genitourinary infections with serovars D to K and L1 to L3 are the most prevalent sexually transmitted bacterial infections in the world. An effective vaccine is not available, and increased screening and treatment have been associated with a rise in the incidence of chlamydial genital tract infection (2). Although antibiotic therapy effectively eliminates infection, it does not reverse established pathology. Serious sequelae resulting from genital tract infection with Chlamydia include pelvic inflammatory disease (PID), ectopic pregnancy, chronic pelvic pain, and infertility in women (reviewed in reference 3). Since the majority of infected women are asymptomatic and do not seek treatment, the consequences of infection often do not become apparent until years after infection, when affected women are unable to conceive.An effective immune response is required for resolution of infection, but overly robust immune activation is responsible for Chlamydia-induced pathology. Studies of mice and guinea pigs have clearly demonstrated that innate immune responses cause tissue damage, while CD4 ϩ T cells and antibody provide protection against challenge infection (reviewed in reference 4). Although specific mediators of protection have been more difficult to delineate for women, correlations between increased CD4 ϩ T cell gamma interferon (IFN-␥) responses and reduced antichlamydial antibody levels have been associated with disease control (reviewed in reference 4). The outcome of a chlamydial infection results...

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Interleukin-17 Contributes to Generation of Th1 Immunity and Neutrophil Recruitment duringChlamydia muridarumGenital Tract Infection but Is Not Required for Macrophage Influx or Normal Resolution of Infection

Cited by 108 publications

References 48 publications

Interferon Regulatory Transcription Factor 3 Protects Mice from Uterine Horn Pathology during Chlamydia muridarum Genital Infection

Interferon Regulatory Transcription Factor 3 Protects Mice from Uterine Horn Pathology during Chlamydia muridarum Genital Infection

Development of a Contemporary Animal Model of Candida albicans-Associated Denture Stomatitis Using a Novel Intraoral Denture System

Comparable Genital Tract Infection, Pathology, and Immunity in Rhesus Macaques Inoculated with Wild-Type or Plasmid-Deficient Chlamydia trachomatis Serovar D

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