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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

Schematic model for cellular immunity to Salmonella.Salmonella (yellow) reside in intracellular vacuoles in infected host cells. Salmonella possesses internal (green) and surface-associated (red) antigens. Left) Live Salmonella shield internal antigens, but some of their surface-associated antigens are accessible for processing and presentation. As a consequence, T cells specific for Salmonella surface antigens can recognize these infected cells and initiate antibacterial immune effector mechanisms. In contrast, T cells specific for internal Salmonella antigens fail to detect host cells that contain exclusively intact Salmonella. Right) Dead Salmonella release internal antigens. As a consequence, both surface-exposed and internal antigens can be processed, presented, and recognized by cognate T cells. However, this recognition is unproductive for infection control since it targets Salmonella that are already dead.
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ppat-1002966-g008: Schematic model for cellular immunity to Salmonella.Salmonella (yellow) reside in intracellular vacuoles in infected host cells. Salmonella possesses internal (green) and surface-associated (red) antigens. Left) Live Salmonella shield internal antigens, but some of their surface-associated antigens are accessible for processing and presentation. As a consequence, T cells specific for Salmonella surface antigens can recognize these infected cells and initiate antibacterial immune effector mechanisms. In contrast, T cells specific for internal Salmonella antigens fail to detect host cells that contain exclusively intact Salmonella. Right) Dead Salmonella release internal antigens. As a consequence, both surface-exposed and internal antigens can be processed, presented, and recognized by cognate T cells. However, this recognition is unproductive for infection control since it targets Salmonella that are already dead.

Mentions: Instead, we propose an alternative explanation based on the observation that many live Salmonella resided alone, or together with other live Salmonella, in infected host cells with no dead Salmonella releasing their internal antigens. As a consequence, Salmonella internal antigens remained inaccessible for antigen processing and presentation in these cells. In contrast, surface-exposed Salmonella antigens, or antigens released by outer membrane vesicle shedding, could be accessible for processing and presentation to cognate CD4 T cells for initiation of protective anti-Salmonella effector mechanisms (Fig. 8). In comparison, CD4 T cells recognizing internal Salmonella antigens would have limited impact on infection control because they miss many cells containing live Salmonella and instead direct their responses to host cells containing already dead Salmonella. According to this model, surface-associated antigens thus differ fundamentally from internal antigens because they are uniquely accessible in host cells containing only live Salmonella.


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)

Schematic model for cellular immunity to Salmonella.Salmonella (yellow) reside in intracellular vacuoles in infected host cells. Salmonella possesses internal (green) and surface-associated (red) antigens. Left) Live Salmonella shield internal antigens, but some of their surface-associated antigens are accessible for processing and presentation. As a consequence, T cells specific for Salmonella surface antigens can recognize these infected cells and initiate antibacterial immune effector mechanisms. In contrast, T cells specific for internal Salmonella antigens fail to detect host cells that contain exclusively intact Salmonella. Right) Dead Salmonella release internal antigens. As a consequence, both surface-exposed and internal antigens can be processed, presented, and recognized by cognate T cells. However, this recognition is unproductive for infection control since it targets Salmonella that are already dead.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002966-g008: Schematic model for cellular immunity to Salmonella.Salmonella (yellow) reside in intracellular vacuoles in infected host cells. Salmonella possesses internal (green) and surface-associated (red) antigens. Left) Live Salmonella shield internal antigens, but some of their surface-associated antigens are accessible for processing and presentation. As a consequence, T cells specific for Salmonella surface antigens can recognize these infected cells and initiate antibacterial immune effector mechanisms. In contrast, T cells specific for internal Salmonella antigens fail to detect host cells that contain exclusively intact Salmonella. Right) Dead Salmonella release internal antigens. As a consequence, both surface-exposed and internal antigens can be processed, presented, and recognized by cognate T cells. However, this recognition is unproductive for infection control since it targets Salmonella that are already dead.
Mentions: Instead, we propose an alternative explanation based on the observation that many live Salmonella resided alone, or together with other live Salmonella, in infected host cells with no dead Salmonella releasing their internal antigens. As a consequence, Salmonella internal antigens remained inaccessible for antigen processing and presentation in these cells. In contrast, surface-exposed Salmonella antigens, or antigens released by outer membrane vesicle shedding, could be accessible for processing and presentation to cognate CD4 T cells for initiation of protective anti-Salmonella effector mechanisms (Fig. 8). In comparison, CD4 T cells recognizing internal Salmonella antigens would have limited impact on infection control because they miss many cells containing live Salmonella and instead direct their responses to host cells containing already dead Salmonella. According to this model, surface-associated antigens thus differ fundamentally from internal antigens because they are uniquely accessible in host cells containing only live Salmonella.

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