Fc receptor-targeted mucosal vaccination as a novel strategy for the generation of enhanced immunity against mucosal and non-mucosal pathogens

Gosselin, Edmund J.; Bitsaktsis, Constantine; Li, Ying; Iglesias, Bibiana V.

doi:10.1007/s00005-009-0040-y

Cited by 30 publications

(28 citation statements)

References 122 publications

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“…Blockade of the Fc-␥ receptor led to a clear reduction in uptake of L. monocytogenes, lending support to the hypothesis that anti-Frl MAb-mediated opsonization is the most likely mechanism of antilisterial immune resistance. Indeed, some recent studies have focused on using the Fc-␥ receptors as vaccine targets to induce both cellular and humoral immune responses against extracellular and intracellular pathogens (1,22). Importantly, it has been shown that the targeting of the Fc-␥ receptor with Francisella tularensis, an intracellular bacterium, combined with an anti-Francisella tularensis lipopolysaccharide MAb, led to enhancement of protective immunity against subsequent challenge with this pathogen (34).…”

Section: Discussionmentioning

confidence: 99%

Antibody Targeting the Ferritin-Like Protein ControlsListeriaInfection

et al. 2010

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). Since the solubility of iron is low and it is toxic at low concentrations, following uptake, iron is stored in subcellular microenvironments in the iron storage protein ferritin (C. Cheers and M. Ho, J. Reticuloendothel. Soc. 34:299-309, 1983). Here, we show that ferritin-like proteins (Frl) are highly conserved in the genus Listeria and demonstrate that these proteins are present in both the cytoplasm and cell wall fractions of these bacteria. Even though Frl is expressed under different growth conditions, transcriptional mapping revealed that its regulation is complex. When bacteria are grown in brain heart infusion medium, extracellular expression involves both sigma A (SigA)-and sigma B (SigB)-dependent promoters; however, during intracellular growth, initiation of transcription is additionally SigB dependent. The expression of Frl is greatly enhanced in bacteria grown in the presence of blood, and a mutant strain lacking the frl gene was defective for growth in this medium. Using the monoclonal antibody (MAb) specific for Frl, we demonstrate that administration of anti-Frl MAb prior to infection confers antilisterial resistance in vivo, evidenced in reduced bacterial load and increased survival rates, thereby demonstrating the in vivo significance of upregulated cell surface-associated Frl expression. In vitro studies revealed that the antilisterial resistance is due to increased listerial phagocytosis.Listeria monocytogenes, the causative agent of listeriosis, is a well-described food-borne pathogen known to infect immunocompromised individuals, leading to severe clinical symptoms, such as meningitis and septicemia (16,29,38). L. monocytogenes is widely considered to be one of the leading causes of food-borne infections with high case fatalities (40). Also, infection with L. monocytogenes during pregnancy can lead to choriomeningitis and miscarriage (29, 37). Immunity to systemic infections in listeriosis has been linked to cellular immunity and more recently to components of the innate immune response (4). The role of the humoral response is less studied, and only a few listerial antigens have been identified as targets of antibodies following listerial infections (23). Nevertheless, taking the severity of clinical manifestations associated with L. monocytogenes infection into consideration, an understanding of the pathogenesis and role of bacterial antigens targeted for recognition by different arms of the immune response is required to design effective strategies for inducing resistance against L. monocytogenes infection.Recently, we identified the listerial ferritin-like protein as a target of the humoral response following infection of mice with pathogenic L. monocytogenes. The ferritin-like protein of L. monocytogenes (Frl) (9, 30, 32) is a member of the family of bacterial Dps proteins (DNA binding proteins from starved cells). These proteins bear resemblance to ferritins and hemecontaining ferritins (bacterioferritins) in both structure and function (2,3,25) and are iron storage proteins that re...

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Section: Discussionmentioning

confidence: 99%

Antibody Targeting the Ferritin-Like Protein ControlsListeriaInfection

et al. 2010

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“…Both human and mouse Fc␥RI are high-affinity Fc␥R, which means that they can bind the Fc region of IgG when in monomeric form (25). Unlike the more ubiquitously expressed Fc␥RII and Fc␥RIII, Fc␥RI receptors are constitutively expressed primarily on professional antigen-presenting cells (APCs) (dendritic cells [DC] and macrophages [M]) (25,52), and their expression can be induced on polymorphonuclear leukocytes (PMN) (42,60). Fc␥RI receptors are activating receptors, providing solely stimulatory signals to the antigen-presenting cell (25).…”

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confidence: 99%

Mucosal Immunization with an Unadjuvanted Vaccine That Targets Streptococcus pneumoniae PspA to Human Fcγ Receptor Type I Protects against Pneumococcal Infection through Complement- and Lactoferrin-Mediated Bactericidal Activity

Bitsaktsis

Iglesias

et al. 2012

Infect Immun

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Targeting an antigen to Fc receptors (FcR) can enhance the immune response to the antigen in the absence of adjuvant. Furthermore, we recently demonstrated that intranasal immunization with an Fc␥R-targeted antigen enhances protection against a category A intracellular mucosal pathogen, Francisella tularensis. To determine if a similar strategy could be applied to the important pathogen Streptococcus pneumoniae, we used an improved mucosal FcR-targeting strategy that specifically targets human Fc␥R type I (hFc␥RI). A humanized single-chain antibody component in which the variable domain binds to hFc␥RI [antihFc␥RI (H22)] was linked in a fusion protein with the pneumococcal surface protein A (PspA). PspA is known to elicit protection against pneumococcal sepsis, carriage, and pneumonia in mouse models when administered with adjuvants. Anti-hFc␥RI-PspA or recombinant PspA (rPspA) alone was used to intranasally immunize wild-type (WT) and hFc␥RI transgenic (Tg) mice in the absence of adjuvant. The hFc␥RI Tg mice receiving anti-hFc␥RI-PspA exhibited elevated S. pneumoniae-specific IgA, IgG2c, and IgG1 antibodies in serum and bronchoalveolar lavage fluid. Neither immunogen was effective in protecting WT mice in the absence of adjuvant, but when PspA was targeted to hFc␥RI as the anti-hFc␥RI-PspA fusion, enhanced protection against lethal S. pneumoniae challenge was observed in the hFc␥RI Tg mice compared to mice given nontargeted rPspA alone. Immune sera from the anti-hFc␥RI-PspA-immunized Tg mice showed enhanced complement C3 deposition on bacterial surfaces, and protection was dependent upon an active complement system. Immune serum also showed an enhanced bactericidal activity directed against S. pneumoniae that appears to be lactoferrin mediated.

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“…These results further suggest that Hc may transport R4 as "cargo" across the mucosal interface, as has been observed for other protein domains fused to Hc (27). Future studies will be needed to determine whether R4 can augment responses to nasal vaccination by targeting Hc to Fc␥Rs expressed on DCs and APCs located in the nasal mucosa (14). During the early phase of the primary immune response, antibodies directed against appropriate neutralizing epitopes may lack sufficient avidity to neutralize BoNT.…”

Section: Discussionmentioning

confidence: 54%