Mucosal vaccination with pili from Group A Streptococcus expressed on Lactococcus lactis generates protective immune responses

Loh, Jacelyn M. S.; Lorenz, Natalie; Tsai, Catherine Jia-Yun; Khemlani, Adrina Hema J.; Proft, Thomas

doi:10.1038/s41598-017-07602-0

Cited by 33 publications

(57 citation statements)

References 33 publications

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“…In this study, we use the T18.1 antigen found in emm18, emm71, and emm217 strains as a model two-domain antigen to comprehensively investigate the nature of type-specific and cross-reactive T antigen antibody responses. This builds on a previous study that included just three recombinant two-domain T antigens (T1, T18.1, and T28.1), in which type-specific and weak cross-reactive immune responses were observed (22). FVB/n mice and New Zealand White (NZ White) rabbits were immunized with Lactococcus lactis carrying the complete T18.1 pilus and recombinant monomeric T18.1, respectively.…”

Section: Resultsmentioning

confidence: 98%

“…Antisera were generated and/or obtained from three different sources for this study. To generate polyclonal antiserum to T18.1, five FVB/n mice were intranasally immunized on days 0, 14, and 28 with 1 ϫ 10 8 CFU/mouse of Lactococcus lactis constitutively expressing the T18.1 pilus operon, as previously described (22). Serum was collected on day 52.…”

Section: Methodsmentioning

confidence: 99%

“…Understanding the structural features that are the basis of a unique "tee type" will inform molecular epidemiological and vaccine studies for GAS. The pilus and T antigen are attractive GAS vaccine candidates, with previous smallanimal studies showing that anti-AP1 antibodies inhibit bacterial adhesion while anti-T antigen antibodies can reduce adhesion and promote killing (5,22). The intramolecular isopeptide bonds also provide exceptional protein stability, which is advantageous for vaccine development.…”

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confidence: 99%

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Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design

et al. 2019

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Group A Streptococcus (GAS) (Streptococcus pyogenes) is an important human pathogen associated with significant global morbidity and mortality for which there is no safe and efficacious vaccine. The T antigen, a protein that polymerizes to form the backbone of the GAS pilus structure, is a potential vaccine candidate. Previous surveys of the tee gene, which encodes the T antigen, have identified 21 different tee types and subtypes such that any T antigen-based vaccine must be multivalent and carefully designed to provide broad strain coverage. In this study, the crystal structures of three two-domain T antigens (T3.2, T13, and T18.1) were determined and found to have remarkable structural similarity to the previously reported T1 antigen, despite moderate overall sequence similarity. This has enabled reliable modeling of all major two-domain T antigens to reveal that T antigen sequence variation is distributed along the full length of the protein and shields a highly conserved core. Immunoassays performed with sera from immunized animals and commercial T-typing sera identified a significant cross-reactive antibody response between T18.1, T18.2, T3.2, and T13. The existence of shared epitopes between T antigens, combined with the remarkably conserved structure and high level of surface sequence divergence, has important implications for the design of multivalent T antigen-based vaccines.

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Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design

et al. 2019

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“…39 However, in the context of these studies the possibility of direct microbial antagonism is unlikely because even wild-type S. pyogenes is typically cleared from the nasal mucosa of mice in <3 days and infection with only a select number of strains results in enduring colonization of the nares in FVB/n mice, which are more susceptible than BALB/c mice to infection with S. pyogenes. 40 However, completely ruling out this possibility will require additional studies to determine whether the PilM1 strain has the capacity to colonize mucosal sites in the mouse.…”

Section: Discussionmentioning

confidence: 99%

PilVax, a novel Lactococcus lactis‐based mucosal vaccine platform, stimulates systemic and mucosal immune responses to Staphylococcus aureus

et al. 2020

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Most pathogens initiate infection via the mucosa, therefore delivery of vaccines directly to the mucosa is likely to be advantageous for stimulating protective immunity at the site of entry. PilVax is a novel mucosal vaccine platform that harnesses Lactococcus lactis bacteria engineered to stably express multiple copies of vaccine peptide antigens within pili, hair-like structures which extend from the cell wall. This strategy elicited systemic and mucosal antibody responses to a model antigen after intranasal immunization, but has not been tested for its capacity to stimulate protective mucosal immunity. A well-characterized linear B-cell epitope, D3 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) , from the fibronectin-binding protein A of Staphylococcus aureus was successfully introduced into PilVax and delivered intranasally to mice. Specific antipeptide immunoglobulin (Ig) G and IgA antibodies were detected in the serum and respiratory mucosa of vaccinated mice. Responses to the major pilus backbone protein Spy0128 were also assessed; robust antibody responses to this antigen were generated both systemically and in the respiratory and intestinal mucosa. Mice were challenged intranasally with the mouse-adapted S. aureus JSNZ strain and the S. aureus load quantified 7 days after challenge. Unexpectedly, exposure to PilVax, irrespective of the presence of the peptide, resulted in a significant reduction in S. aureus load in both the intestine and nasal mucosa (both P < 0.05) when compared with unvaccinated control mice. The mechanism(s) of protection are unclear, but merit further investigation to determine whether PilVax is a suitable platform for delivery of vaccine candidate antigens to the mucosa. RESULTS Characterization of L. lactis PilM1 vaccine strainsAttempts were made to express S. aureus FnBP peptides D1, D3 and FnBP10 (Supplementary table 1) within the bE-bF, b3-b4 and b9-b10 loop regions of L. lactis 370 PilVax elicits mucosal immunity to S. aureus F Clow et al.

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“…Unlike M type-specific antibodies, there is no known human host protective effect mediated via T type-specific serum; this may be a consequence of immunoreactivity directed toward trypsin-treated target antigens that are not encountered during natural infection. However, antiserum raised to recombinant pilin subunits or intact pili can be protective in experimental assays (48,102). Shortcomings of the T-typing cell agglutination assay include a general lack of good resolution, the time-consuming process, and the requirement for standardized rabbit serum.…”

Section: Figurementioning

confidence: 99%

Molecular Epidemiology, Ecology, and Evolution of Group A Streptococci

2018

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The clinico-epidemiological features of diseases caused by group A streptococci (GAS) is presented through the lens of the ecology, population genetics, and evolution of the organism. The serological targets of three typing schemes (M, T, SOF) are themselves GAS cell surface proteins that have a myriad of virulence functions and a diverse array of structural forms. Horizontal gene transfer expands the GAS antigenic cell surface repertoire by generating numerous combinations of M, T, and SOF antigens. However, horizontal gene transfer of the serotype determinant genes is not unconstrained, and therein lies a genetic organization that may signify adaptations to a narrow ecological niche, such as the primary tissue reservoirs of the human host. Adaptations may be further shaped by selection pressures such as herd immunity. Understanding the molecular evolution of GAS on multiple levels-short, intermediate, and long term-sheds insight on mechanisms of host-pathogen interactions, the emergence and spread of new clones, rational vaccine design, and public health interventions.

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Mucosal vaccination with pili from Group A Streptococcus expressed on Lactococcus lactis generates protective immune responses

Cited by 33 publications

References 33 publications

Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design

Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design

PilVax, a novel Lactococcus lactis‐based mucosal vaccine platform, stimulates systemic and mucosal immune responses to Staphylococcus aureus

Molecular Epidemiology, Ecology, and Evolution of Group A Streptococci

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