Tripalmitoyl-<i>S</i>-Glyceryl-Cysteine-Dependent OspA Vaccination of Toll-Like Receptor 2-Deficient Mice Results in Effective Protection from<i>Borrelia burgdorferi</i>Challenge

Yoder, Alyson; Wang, Xiaohui; Ma, Ying; Philipp, Mario T.; Heilbrun, Marta E.; Weis, John H.; Kirschning, Carsten J.; Wooten, R. Mark; Weis, Janis J.

doi:10.1128/iai.71.7.3894-3900.2003

Cited by 29 publications

(21 citation statements)

References 27 publications

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“…It is plausible that the acylation of r27 provides the protein with an adjuvant-like property, as has been reported previously for other proteins (2,4). It was also shown that this property is related to TLR2 activation (30). Significant levels of IFN-␥ secretion and nitric oxide production (data not shown) were found in splenocytes of r27-immunized mice.…”

Section: Discussionsupporting

confidence: 50%

Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect

et al. 2004

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We reported previously that even though immunization with the recombinant mycobacterial 27-kDa lipoprotein (r27) induced a Th1-type response in mice, the vaccinated mice became more susceptible to challenge with Mycobacterium tuberculosis. In this study we show that r27 stimulates naive splenocytes to proliferate. Acylation of r27 was crucial for this effect, since a nonacylated mutant of r27, termed r27⌬SP, failed to stimulate splenocytes either in vitro or in vivo. Depletion experiments indicated that only B cells were proliferating in a T-cell-independent manner. We also found that r27 is recognized by TLR2, which is involved in mitogenic stimulation. Interestingly, r27 but not r27⌬SP induced high gamma interferon levels in splenocyte supernatants, whereas no significant interleukin-2 levels were detected. Since B-cell polyclonal activation might aggravate pathogen infection, we asked whether the antiprotective effect of the r27 lipoprotein is associated with its mitogenicity. We showed that, as in the case of r27, immunization of mice with the nonmitogenic r27⌬SP lipoprotein resulted in increased M. tuberculosis multiplication. We conclude that the antiprotective effect of the r27 lipoprotein must be linked to properties of the polypeptide portion of the lipoprotein rather than to its lipid moiety and its mitogenicity.The 27-kDa antigen, the product of the Mycobacterium tuberculosis lprG gene, is a putative lipoprotein that is present exclusively in the membrane of the M. tuberculosis species complex (5). Previously, it was reported that mice immunized with r27 were more susceptible to M. tuberculosis challenge than nonimmunized mice (15). Splenic CFU counts in mice immunized with the recombinant mycobacterial 27-kDa lipoprotein (r27) were significantly higher, by about 0.5 to 0.8 log unit, than those in nonimmunized mice. Furthermore, the protection afforded following immunization with the Mycobacterium bovis BCG vaccine was completely abolished when r27 was added to the BCG vaccine (15). These results were unexpected, because r27 induces a typical Th1-type immune response thought to be crucial for protection against intracellular pathogens such as M. tuberculosis. It was found recently that M. tuberculosis with a knockout of the 27-kDa (lprG) gene has an attenuated virulence phenotype in mice (A. Cataldi, personal communication). This finding supports our previous results and indicates that the native 27-kDa lipoprotein might also have a role in enhancing M. tuberculosis infection.Lipoproteins have been reported to be powerful antigens that induce strong antibody-and cell-mediated immune responses (7, 10). The lipid moiety on mature acylated lipoproteins or synthetic acylation of peptides increased their immunogenicity and induced their adjuvant-like properties (4). Bacterial lipoproteins are recognized by the innate immune system through toll-like receptor 2 (TLR2) together with TLR1 or TLR6, all of which induce antibacterial activity in macrophages (27-29). These findings indicate that lipoproteins migh...

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Section: Discussionsupporting

confidence: 50%

Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect

et al. 2004

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“…The importance of these lipoprotein-mediated events is confirmed by the severe impairment in spirochete clearance exhibited by these mutant lines both early and late after infection (23)(24)(25)38). Importantly, each of these mutant lines develop a B. burgdorferi-specific Ab repertoire that is of equal or greater magnitude than that of wild-type mice (23)(24)(25), and these Abs appear capable of prophylactically preventing spirochetal infection (81). However, these mice maintain abnormally high spirochetal loads in multiple tissues well beyond the time when Abs are believed to normally reduce spirochetal numbers during natural infection.…”

Section: Il-10mentioning

confidence: 75%

IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

Lazarus

Meadows

Lintner

et al. 2006

The Journal of Immunology

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Borrelia burgdorferi is capable of persistently infecting a variety of hosts despite eliciting potent innate and adaptive immune responses. Preliminary studies indicated that IL-10-deficient (IL-10−/−) mice exhibit up to 10-fold greater clearance of B. burgdorferi from target tissues compared with wild-type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. To further delineate these IL-10-mediated immune effects, kinetic studies indicated that spirochete dissemination to target tissues is similar in both wild-type and IL-10−/− mouse strains, and that enhanced clearance of B. burgdorferi in IL-10−/− mice is correlated with increased B. burgdorferi-specific Ab as early as 2 wk postinfection. Immunoblot analysis indicated that Abs produced by infected IL-10−/− and wild-type mice recognize similar ranges of spirochetal Ags. Immune sera from IL-10−/− and wild-type mice also exhibited similar bactericidal activity in vitro, and passive transfer of these immune sera into B. burgdorferi-infected SCID mice caused similar reductions of bacterial numbers in target tissues. Infectious dose studies indicated that 8-fold more B. burgdorferi were needed to efficiently infect naive IL-10−/− mice, suggesting these animals possess higher innate barriers to infection. Moreover, macrophages derived from IL-10−/− mice exhibit enhanced proinflammatory responses to B. burgdorferi stimulation compared with wild-type controls, and these responses are not significantly affected by the presence of immune serum. These findings confirm that B. burgdorferi clearance by innate immune responses is more efficient in the absence of IL-10, and these activities are not directly related to increased levels of B. burgdorferi-specific Ab.

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“…Early spirochete recognition most likely occurs through Toll-like receptors, which results in the production of cytokines and chemokines that recruit and activate phagocytic inflammatory cells and mediate spirochetal clearance (1,10,50,56). The balance of pro-and anti-inflammatory cytokines is thought to underlie disease resistance and susceptibility (54), and indeed, treatment modalities that alter cytokine activity can modulate disease severity (30,31,38).…”

Section: Discussionmentioning

confidence: 99%

Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

Brown

Lai²,

Callen³

et al. 2008

Infect Immun

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Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis-and carditissusceptible C3H mice. Infection of C3H IL-10 ؊/؊ mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10 ؊/؊ mice. However, in contrast to previous in vitro work, infection of C3H IL-10 ؊/؊ mice led to decreased in vivo expression of the cytokines KC, IL-1␤, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

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Tripalmitoyl-S-Glyceryl-Cysteine-Dependent OspA Vaccination of Toll-Like Receptor 2-Deficient Mice Results in Effective Protection fromBorrelia burgdorferiChallenge

Cited by 29 publications

References 27 publications

Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect

Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect

IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

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