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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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Related in: MedlinePlus

Survival curves of mouse groups immunized with 37 different Salmonella antigens (thin lines) or the control antigen GFP (thick dashed line).For better visualization, curves were slightly shifted. The longest survival was observed for antigens IroN and CirA. For statistical analysis by log-rank test see Table 1.
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ppat-1002966-g002: Survival curves of mouse groups immunized with 37 different Salmonella antigens (thin lines) or the control antigen GFP (thick dashed line).For better visualization, curves were slightly shifted. The longest survival was observed for antigens IroN and CirA. For statistical analysis by log-rank test see Table 1.

Mentions: Many of the tested Salmonella antigens were capable to induce cellular and humoral immune responses. To test if these responses could confer protective immunity, we tested the 21 recombinant Salmonella antigens in immunization/challenge infection experiments in genetically susceptible BALB/c mice. Based on the results, we selected 16 additional Salmonella antigens primarily from the outer membrane, and tested them using the same experimental immunization/challenge approach (however, we did not measure their immunogenicity in convalescent mice). For simplicity, we discuss results for both antigen sets together. Out of 37 tested antigens, only few antigens enabled prolonged survival after oral challenge infection with virulent Salmonella compared to control immunization with the unrelated antigen GFP (Fig. 2; Tab. 1; poor survival of PhoN-vaccinated animals confirmed recently published data [26]). In fact, only two antigens (T0937 and T2672) mediated protective immune responses with P-values below 0.05 in our small experimental groups of only five mice per antigen. Replicate experiments with larger group sizes might yield statistical significant results for additional candidates such as SseB that has already been shown to be protective in two independent previous studies. Such experiments will be required to select individual antigens for vaccine development in future studies. On the other hand, the primary focus of this study was to identify antigen properties that correlate with protectivity. For this purpose, the somewhat noisy survival times detected with small animal groups were still helpful.


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)

Survival curves of mouse groups immunized with 37 different Salmonella antigens (thin lines) or the control antigen GFP (thick dashed line).For better visualization, curves were slightly shifted. The longest survival was observed for antigens IroN and CirA. For statistical analysis by log-rank test see Table 1.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002966-g002: Survival curves of mouse groups immunized with 37 different Salmonella antigens (thin lines) or the control antigen GFP (thick dashed line).For better visualization, curves were slightly shifted. The longest survival was observed for antigens IroN and CirA. For statistical analysis by log-rank test see Table 1.
Mentions: Many of the tested Salmonella antigens were capable to induce cellular and humoral immune responses. To test if these responses could confer protective immunity, we tested the 21 recombinant Salmonella antigens in immunization/challenge infection experiments in genetically susceptible BALB/c mice. Based on the results, we selected 16 additional Salmonella antigens primarily from the outer membrane, and tested them using the same experimental immunization/challenge approach (however, we did not measure their immunogenicity in convalescent mice). For simplicity, we discuss results for both antigen sets together. Out of 37 tested antigens, only few antigens enabled prolonged survival after oral challenge infection with virulent Salmonella compared to control immunization with the unrelated antigen GFP (Fig. 2; Tab. 1; poor survival of PhoN-vaccinated animals confirmed recently published data [26]). In fact, only two antigens (T0937 and T2672) mediated protective immune responses with P-values below 0.05 in our small experimental groups of only five mice per antigen. Replicate experiments with larger group sizes might yield statistical significant results for additional candidates such as SseB that has already been shown to be protective in two independent previous studies. Such experiments will be required to select individual antigens for vaccine development in future studies. On the other hand, the primary focus of this study was to identify antigen properties that correlate with protectivity. For this purpose, the somewhat noisy survival times detected with small animal groups were still helpful.

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