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Immunity to intracellular Salmonella depends on surface-associated antigens.

Barat S, Willer Y, Rizos K, Claudi B, Mazé A, Schemmer AK, Kirchhoff D, Schmidt A, Burton N, Bumann D - PLoS Pathog. (2012)

Bottom Line: Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens.In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella.In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Invasive Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and changing Salmonella serovar spectrum. Novel vaccines with broad serovar coverage are needed, but suitable protective antigens remain largely unknown. Here, we tested 37 broadly conserved Salmonella antigens in a mouse typhoid fever model, and identified antigen candidates that conferred partial protection against lethal disease. Antigen properties such as high in vivo abundance or immunodominance in convalescent individuals were not required for protectivity, but all promising antigen candidates were associated with the Salmonella surface. Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens. Confocal microscopy of infected tissues revealed that many live Salmonella resided alone in infected host macrophages with no damaged Salmonella releasing internal antigens in their vicinity. In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella. In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens.

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Salmonella antigen protectivity does not correlate with in vivo antigen abundance but depends on antigen localization within the Salmonella cell.A) Relationship between antigen protectivity and in vivo abundance as determined by quantitative proteome analysis of ex vivo purified Salmonella (means ± SD for three independently infected mice; b.d., below detection threshold). B) Relationship between antigen protectivity and antigen localization within Salmonella (C, cytosol; IM, inner membrane; P, periplasm; LP, outer-membrane associated lipoprotein; OMP, outer membrane protein; S, surface). Statistical significance of differences between internal and outer membrane/surface antigens was tested using the non-parametric Mann-Whitney U test.
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ppat-1002966-g004: Salmonella antigen protectivity does not correlate with in vivo antigen abundance but depends on antigen localization within the Salmonella cell.A) Relationship between antigen protectivity and in vivo abundance as determined by quantitative proteome analysis of ex vivo purified Salmonella (means ± SD for three independently infected mice; b.d., below detection threshold). B) Relationship between antigen protectivity and antigen localization within Salmonella (C, cytosol; IM, inner membrane; P, periplasm; LP, outer-membrane associated lipoprotein; OMP, outer membrane protein; S, surface). Statistical significance of differences between internal and outer membrane/surface antigens was tested using the non-parametric Mann-Whitney U test.

Mentions: Interestingly, in vivo expression levels also did not correlate with survival times (Fig. 4A). In fact, the two antigens that enabled the longest survival, IroN and CirA, had in vivo expression levels that were below our detection threshold. By comparison, antigens T2461 and PhoN were highly expressed in vivo and induced potent CD4 T cell and humoral responses in convalescent individuals, yet failed to prolong survival (in agreement with previous observations [26]).


Immunity to intracellular Salmonella depends on surface-associated antigens.

Barat S, Willer Y, Rizos K, Claudi B, Mazé A, Schemmer AK, Kirchhoff D, Schmidt A, Burton N, Bumann D - PLoS Pathog. (2012)

Salmonella antigen protectivity does not correlate with in vivo antigen abundance but depends on antigen localization within the Salmonella cell.A) Relationship between antigen protectivity and in vivo abundance as determined by quantitative proteome analysis of ex vivo purified Salmonella (means ± SD for three independently infected mice; b.d., below detection threshold). B) Relationship between antigen protectivity and antigen localization within Salmonella (C, cytosol; IM, inner membrane; P, periplasm; LP, outer-membrane associated lipoprotein; OMP, outer membrane protein; S, surface). Statistical significance of differences between internal and outer membrane/surface antigens was tested using the non-parametric Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475680&req=5

ppat-1002966-g004: Salmonella antigen protectivity does not correlate with in vivo antigen abundance but depends on antigen localization within the Salmonella cell.A) Relationship between antigen protectivity and in vivo abundance as determined by quantitative proteome analysis of ex vivo purified Salmonella (means ± SD for three independently infected mice; b.d., below detection threshold). B) Relationship between antigen protectivity and antigen localization within Salmonella (C, cytosol; IM, inner membrane; P, periplasm; LP, outer-membrane associated lipoprotein; OMP, outer membrane protein; S, surface). Statistical significance of differences between internal and outer membrane/surface antigens was tested using the non-parametric Mann-Whitney U test.
Mentions: Interestingly, in vivo expression levels also did not correlate with survival times (Fig. 4A). In fact, the two antigens that enabled the longest survival, IroN and CirA, had in vivo expression levels that were below our detection threshold. By comparison, antigens T2461 and PhoN were highly expressed in vivo and induced potent CD4 T cell and humoral responses in convalescent individuals, yet failed to prolong survival (in agreement with previous observations [26]).

Bottom Line: Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens.In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella.In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Invasive Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and changing Salmonella serovar spectrum. Novel vaccines with broad serovar coverage are needed, but suitable protective antigens remain largely unknown. Here, we tested 37 broadly conserved Salmonella antigens in a mouse typhoid fever model, and identified antigen candidates that conferred partial protection against lethal disease. Antigen properties such as high in vivo abundance or immunodominance in convalescent individuals were not required for protectivity, but all promising antigen candidates were associated with the Salmonella surface. Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens. Confocal microscopy of infected tissues revealed that many live Salmonella resided alone in infected host macrophages with no damaged Salmonella releasing internal antigens in their vicinity. In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella. In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens.

Show MeSH
Related in: MedlinePlus