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

Comparison of Salmonella antigen protectivity against primary infection and immunogenicity in convalescent resistant mice.A) Relationship between antigen protectivity against primary infection and cognate CD4 T cell responses in convalescent mice (same data as Fig. 1A). Protectivity is expressed as “survival time extension”, which is the difference in median survival time of a group of five immunized mice compared to a control group of five mice that were immunized with GFP. B) Relationship between antigen protectivity and serum antibody responses in convalescent mice (same data as Fig. 1B).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3475680&req=5

ppat-1002966-g003: Comparison of Salmonella antigen protectivity against primary infection and immunogenicity in convalescent resistant mice.A) Relationship between antigen protectivity against primary infection and cognate CD4 T cell responses in convalescent mice (same data as Fig. 1A). Protectivity is expressed as “survival time extension”, which is the difference in median survival time of a group of five immunized mice compared to a control group of five mice that were immunized with GFP. B) Relationship between antigen protectivity and serum antibody responses in convalescent mice (same data as Fig. 1B).

Mentions: As an example, survival times did not correlate with CD4 T cell responses (Fig. 3A) or serum antibody levels (Fig. 3B) during natural infection of resistant mice. This could partially reflect differences in MHC class II haplotypes (H2d in BALB/c vs. H2b in 129/Sv), courses of infection, and potential differences in Salmonella biology in susceptible vs. resistant mice. However, a recent large-scale study reports comprehensive immunogenicity data for BALB/c mice and other mouse strains that had been immunized with attenuated Salmonella, as well as for human patients [26]. Several antigens that prolonged survival of immunized BALB/c mice after Salmonella challenge infection in our experiments, elicit detectable antibody responses in various mouse strains including BALB/c. However, none of these antigens was found to be immunodominant [26] and antibodies to antigens IroN and CirA with the longest survival times were not detected in this and previous studies. This could reflect differential antigen expression in virulent vs. attenuated Salmonella, different routes of administration, and/or differential expression at various stages of disease progression. Together, these data provide no evidence for immunodominance in convalescent or immune individuals as a prerequisite for protectivity.


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)

Comparison of Salmonella antigen protectivity against primary infection and immunogenicity in convalescent resistant mice.A) Relationship between antigen protectivity against primary infection and cognate CD4 T cell responses in convalescent mice (same data as Fig. 1A). Protectivity is expressed as “survival time extension”, which is the difference in median survival time of a group of five immunized mice compared to a control group of five mice that were immunized with GFP. B) Relationship between antigen protectivity and serum antibody responses in convalescent mice (same data as Fig. 1B).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002966-g003: Comparison of Salmonella antigen protectivity against primary infection and immunogenicity in convalescent resistant mice.A) Relationship between antigen protectivity against primary infection and cognate CD4 T cell responses in convalescent mice (same data as Fig. 1A). Protectivity is expressed as “survival time extension”, which is the difference in median survival time of a group of five immunized mice compared to a control group of five mice that were immunized with GFP. B) Relationship between antigen protectivity and serum antibody responses in convalescent mice (same data as Fig. 1B).
Mentions: As an example, survival times did not correlate with CD4 T cell responses (Fig. 3A) or serum antibody levels (Fig. 3B) during natural infection of resistant mice. This could partially reflect differences in MHC class II haplotypes (H2d in BALB/c vs. H2b in 129/Sv), courses of infection, and potential differences in Salmonella biology in susceptible vs. resistant mice. However, a recent large-scale study reports comprehensive immunogenicity data for BALB/c mice and other mouse strains that had been immunized with attenuated Salmonella, as well as for human patients [26]. Several antigens that prolonged survival of immunized BALB/c mice after Salmonella challenge infection in our experiments, elicit detectable antibody responses in various mouse strains including BALB/c. However, none of these antigens was found to be immunodominant [26] and antibodies to antigens IroN and CirA with the longest survival times were not detected in this and previous studies. This could reflect differential antigen expression in virulent vs. attenuated Salmonella, different routes of administration, and/or differential expression at various stages of disease progression. Together, these data provide no evidence for immunodominance in convalescent or immune individuals as a prerequisite for protectivity.

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