Induction of protective immunity against Chlamydia muridarum intravaginal infection with the chlamydial immunodominant antigen macrophage infectivity potentiator

Lu, Chunxue; Peng, Bo; Li, Zhihong; Lei, Lei; Li, Zhongyu; Chen, Lili; He, Qing; Zhong, Guangming; Wu, Yimou

doi:10.1016/j.micinf.2013.02.001

Cited by 32 publications

(21 citation statements)

References 40 publications

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“…Thus, this successful strategy used with meningococcal rMIP to obviate any concerns regarding cross-reactivity with human proteins could be applied also to other bacterial MIP antigens proposed as vaccine candidates, e.g., an immunodominant chlamydial MIP protein that has been shown to induce protective immune responses during murine intravaginal infection (48). Our current study results suggest also that a functional bactericidal epitope(s) possibly resides within surface-exposed N-terminal ␣-helix amino acid sequence 21 to 143.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins

et al. 2015

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A recombinant macrophage infectivity potentiator (rMIP) protein of Neisseria meningitidis induces significant serum bactericidal antibody production in mice and is a candidate meningococcal vaccine antigen. However, bioinformatics analysis of MIP showed some amino acid sequence similarity to human FK506-binding proteins (FKBPs) in residues 166 to 252 located in the globular domain of the protein. To circumvent the potential concern over generating antibodies that could recognize human proteins, we immunized mice with recombinant truncated type I rMIP proteins that lacked the globular domain and the signal leader peptide (LP) signal sequence (amino acids 1 to 22) and contained the His purification tag at either the N or C terminus (C-term). The immunogenicity of truncated rMIP proteins was compared to that of full (i.e., full-length) rMIP proteins (containing the globular domain) with either an N-or C-terminal His tag and with or without the LP sequence. By comparing the functional murine antibody responses to these various constructs, we determined that C-term His truncated rMIP (؊LP) delivered in liposomes induced high levels of antibodies that bound to the surface of wild-type but not ⌬mip mutant meningococci and showed bactericidal activity against homologous type I MIP (median titers of 128 to 256) and heterologous type II and III (median titers of 256 to 512) strains, thereby providing at least 82% serogroup B strain coverage. In contrast, in constructs lacking the LP, placement of the His tag at the N terminus appeared to abrogate bactericidal activity. The strategy used in this study would obviate any potential concerns regarding the use of MIP antigens for inclusion in bacterial vaccines. N eisseria meningitidis (meningococcus) infections contribute significantly to mortality and morbidity worldwide (1). Implementation of capsular polysaccharide-protein conjugate vaccines against serogroups A, C, Y, and W into the routine immunization schedules of developed countries has been successful (2-5), but this approach cannot be used for serogroup B strains. The polysaccharide capsule of serogroup B meningococci (MenB) shows structural mimicry of human fetal brain neural cell adhesion molecules (6). Licensed MenB vaccines based on lipooligosaccharide (LOS)-depleted outer membrane (OM) vesicles (V) have been used to control serosubtype strain-specific clonal outbreaks of MenB infection, e.g., in Norway (7), Cuba (8), Brazil (9), and New Zealand (10), but they do not provide cross-strain protection (11). Recently, the 4CMenB (Bexsero) vaccine, developed using a genome-based reverse-vaccinology approach (12), has received a license from the European Union and has been recommended by the Joint Committee for Vaccination and Immunization for the routine vaccination of infants in the United Kingdom since 2014. The vaccine consists of the factor H binding protein (fHbp, fused to GNA2091 carrier protein), neisserial heparin binding protein (NHBA, fused to GNA1030 carrier protein), and an adhesin, NadA, mixed with the Men...

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Section: Discussionmentioning

confidence: 99%

Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins

et al. 2015

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“…Although it is not clear at what time point hydrosalpinx becomes irreversible, what is certain is that hydrosalpinx observed in mice long after intravaginal infection with C. muridarum may be more relevant to hydrosalpinx observed in women. Mouse hydrosalpinx can be detected reproducibly between days 60 and 80 after intravaginal infection with C. muridarum (14,15,(20)(21)(22)(23)(24), suggesting that mouse hydrosalpinx detected 60 days after infection represents long-lasting upper genital tract pathology.…”

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confidence: 99%

“…Using this model in combination with antibody depletion and gene knockout (KO), a CD4 ϩ T cell-dependent and gamma interferon (IFN-␥)-mediated immunity has been identified as a major protective mechanism for mice to control chlamydial infection (7). However, the precise inflammatory mechanism of C. muridarum-induced hydrosalpinx is still unclear, although activation of many inflammatory signaling pathways has been detected during infection (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Signaling via Tumor Necrosis Factor Receptor 1 but Not Toll-Like Receptor 2 Contributes Significantly to Hydrosalpinx Development following Chlamydia muridarum Infection

et al. 2014

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Chlamydial infection in the lower genital tract can lead to hydrosalpinx, which is accompanied by activation of both pattern recognition receptor TLR2-and inflammatory cytokine receptor TNFR1-mediated signaling pathways. In the current study, we compared the relative contributions of these two receptors to chlamydial induction of hydrosalpinx in mice. We found that mice with or without deficiencies in TLR2 or TNFR1 displayed similar time courses of live organism shedding from vaginal swabs, suggesting that these receptor-mediated signaling pathways are not required for controlling chlamydial lower genital infection. However, mice deficient in TNFR1 but not TLR2 developed significantly reduced hydrosalpinx. The decreased pathogenicity correlated with a significant reduction in interleukin-17 by in vitro-restimulated splenocytes of TNFR1-deficient mice. Although TLR2-deficient mice developed hydrosalpinx as severe as that of wild-type mice, peritoneal macrophages from mice deficient in TLR2 but not TNFR1 produced significantly reduced cytokines upon chlamydial stimulation, suggesting that reduced macrophage responses to chlamydial infection do not always lead to a reduction in hydrosalpinx. Thus, we have demonstrated that the signaling pathways triggered by the cytokine receptor TNFR1 play a more significant role in chlamydial induction of hydrosalpinx than those mediated by the pattern recognition receptor TLR2, which has laid a foundation for further revealing the chlamydial pathogenic mechanisms.

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“…hlamydia muridarum infection in the mouse genital tract model has been used for investigation of the mechanisms of Chlamydia trachomatis pathogenesis and immune responses (1)(2)(3)(4)(5)(6). This is because a single inoculation of C. muridarum organisms in the mouse lower genital tract can cause hydrosalpinx and infertility (7)(8)(9), closely mimicking the tubal adhesion, hydrosalpinx, and infertility observed in women urogenitally infected with C. trachomatis (10)(11)(12).…”

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Intravenous Inoculation with Chlamydia muridarum Leads to a Long-Lasting Infection Restricted to the Gastrointestinal Tract

et al. 2016

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cChlamydia has been detected in the gastrointestinal tracts of both animals and humans. However, it remains unclear whether the chlamydial organisms can be introduced into the gastrointestinal tract via pathways independent of the oral and anal routes. We have recently shown that Chlamydia muridarum spreads from the genital tract to the gastrointestinal tract potentially via the circulatory system. To test whether hematogenous C. muridarum can spread to and establish a long-lasting colonization in the mouse gastrointestinal tract, we inoculated mice intravenously with a luciferase-expressing C. muridarum strain and monitored its distribution. After tail vein inoculation, most luciferase-generated bioluminescence signals were detected in the mouse abdominal area throughout the experiment. The ex vivo imaging revealed that the abdominal signals came from the gastrointestinal tract tissues. Simultaneous monitoring of chlamydial organisms in individual organs or tissues revealed an initial stage of systemic spreading followed by a long-lasting infection in the gastrointestinal tract. A retro-orbital vein inoculation of the C. muridarum organisms at a lower dose in a different mouse strain also led to colonization of the gastrointestinal tract. We have demonstrated that intravenous C. muridarum inoculation can result in colonization of the gastrointestinal tract, suggesting that the chlamydial organisms may use the sexual behavior-independent circulation pathway to infect the gastrointestinal tract.C hlamydia muridarum infection in the mouse genital tract model has been used for investigation of the mechanisms of Chlamydia trachomatis pathogenesis and immune responses (1-6). This is because a single inoculation of C. muridarum organisms in the mouse lower genital tract can cause hydrosalpinx and infertility (7-9), closely mimicking the tubal adhesion, hydrosalpinx, and infertility observed in women urogenitally infected with C. trachomatis (10-12). Although C. muridarum is not a natural sexually transmitted agent of mice, chlamydiologists have used this model not only to identify both chlamydial (13-17) and host (1, 5, 18-24) pathogenic determinants but also to define the roles of ascending infection and tubal inflammation in chlamydial induction of hydrosalpinx (9,16,25,26). Nevertheless, questions such as how a self-limited infection with C. muridarum in the mouse genital tract can trigger tubal fibrosis or hydrosalpinx that lasts long after the tubal infection is resolved (9, 25) remain unanswered.Although C. trachomatis is a sexually transmitted bacterial pathogen that causes pathologies in the genital tract (27, 28), it has also been detected in the gastrointestinal (GI) tract of humans (29-32). C. muridarum colonized the mouse GI tract when it was introduced to multiple mucosae (33) and established a long-lasting infection when directly inoculated into the mouse GI tract (34,35). The question is whether persistent colonization of the mouse GI tract can fill in the temporal gap between the self-limited infection...

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Induction of protective immunity against Chlamydia muridarum intravaginal infection with the chlamydial immunodominant antigen macrophage infectivity potentiator

Cited by 32 publications

References 40 publications

Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins

Recombinant Protein Truncation Strategy for Inducing Bactericidal Antibodies to the Macrophage Infectivity Potentiator Protein of Neisseria meningitidis and Circumventing Potential Cross-Reactivity with Human FK506-Binding Proteins

Signaling via Tumor Necrosis Factor Receptor 1 but Not Toll-Like Receptor 2 Contributes Significantly to Hydrosalpinx Development following Chlamydia muridarum Infection

Intravenous Inoculation with Chlamydia muridarum Leads to a Long-Lasting Infection Restricted to the Gastrointestinal Tract

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