Limits...
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.

Show MeSH

Related in: MedlinePlus

Cellular and humoral immune responses of convalescent Salmonella-infected mice to recombinant Salmonella antigens.A) Antigen-specific CD4 T cell frequencies as detected by CD154 upregulation (red) and IFNγ (green) or IL-17 (blue) secretion. The data represent means ± SE of three mice. Responses to Salmonella antigens in non-infected control mice were subtracted (see also Fig. S1). B) Serum antibody responses to Salmonella antigens. The data represent means ± SE of 11 convalescent mice (filled circles) and means ± SE for ten non-infected control mice (open circles).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3475680&req=5

ppat-1002966-g001: Cellular and humoral immune responses of convalescent Salmonella-infected mice to recombinant Salmonella antigens.A) Antigen-specific CD4 T cell frequencies as detected by CD154 upregulation (red) and IFNγ (green) or IL-17 (blue) secretion. The data represent means ± SE of three mice. Responses to Salmonella antigens in non-infected control mice were subtracted (see also Fig. S1). B) Serum antibody responses to Salmonella antigens. The data represent means ± SE of 11 convalescent mice (filled circles) and means ± SE for ten non-infected control mice (open circles).

Mentions: We determined immune responses to these antigens in genetically resistant, convalescent mice that had survived infection with virulent Salmonella enterica serovar Typhimurium. We detected antigen-specific CD4 T cells in spleen using a sensitive CD154 assay [41] and measured serum IgG antibody responses using ELISA. All tested antigens were recognized by CD4 T cells (Fig. 1A; Tab. 1), many of which secreted IFNγ or IL-17 upon stimulation. Both cytokines play crucial roles in immunity to Salmonella[10]. Frequencies of responsive CD4 T cells were in the same range as for flagellin, which has been considered an immunodominant antigen [42]. These data suggested that Salmonella infection elicited a broad cellular immune response against a large number of in vivo expressed antigens from all Salmonella compartments in agreement with data observed for S. Typhi infected human patients [43]. There was no correlation between in vivo antigen abundance as determined by proteome analysis of ex vivo purified Salmonella, and CD4 T cell frequency or cytokine profile (Tab. 1).


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)

Cellular and humoral immune responses of convalescent Salmonella-infected mice to recombinant Salmonella antigens.A) Antigen-specific CD4 T cell frequencies as detected by CD154 upregulation (red) and IFNγ (green) or IL-17 (blue) secretion. The data represent means ± SE of three mice. Responses to Salmonella antigens in non-infected control mice were subtracted (see also Fig. S1). B) Serum antibody responses to Salmonella antigens. The data represent means ± SE of 11 convalescent mice (filled circles) and means ± SE for ten non-infected control mice (open circles).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002966-g001: Cellular and humoral immune responses of convalescent Salmonella-infected mice to recombinant Salmonella antigens.A) Antigen-specific CD4 T cell frequencies as detected by CD154 upregulation (red) and IFNγ (green) or IL-17 (blue) secretion. The data represent means ± SE of three mice. Responses to Salmonella antigens in non-infected control mice were subtracted (see also Fig. S1). B) Serum antibody responses to Salmonella antigens. The data represent means ± SE of 11 convalescent mice (filled circles) and means ± SE for ten non-infected control mice (open circles).
Mentions: We determined immune responses to these antigens in genetically resistant, convalescent mice that had survived infection with virulent Salmonella enterica serovar Typhimurium. We detected antigen-specific CD4 T cells in spleen using a sensitive CD154 assay [41] and measured serum IgG antibody responses using ELISA. All tested antigens were recognized by CD4 T cells (Fig. 1A; Tab. 1), many of which secreted IFNγ or IL-17 upon stimulation. Both cytokines play crucial roles in immunity to Salmonella[10]. Frequencies of responsive CD4 T cells were in the same range as for flagellin, which has been considered an immunodominant antigen [42]. These data suggested that Salmonella infection elicited a broad cellular immune response against a large number of in vivo expressed antigens from all Salmonella compartments in agreement with data observed for S. Typhi infected human patients [43]. There was no correlation between in vivo antigen abundance as determined by proteome analysis of ex vivo purified Salmonella, and CD4 T cell frequency or cytokine profile (Tab. 1).

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