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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

Structural models and exposed immune epitopes of various Salmonella outer membrane proteins.The outer membrane is shown as a grey area, predicted CD4 T cell epitopes in exposed loops are shown in red, potential antibody binding sites are shown in blue, and overlapping T and B cell epitopes are shown in magenta. Partially exposed epitopes are shown in pale colors. Amino acid residues that differ between Salmonella enterica serovars Typhimurium and Typhi are shown in green. For TolC only the outer membrane-associated part is shown. LPS structures as observed in FhuA-LPS crystals [93] are also shown.
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ppat-1002966-g005: Structural models and exposed immune epitopes of various Salmonella outer membrane proteins.The outer membrane is shown as a grey area, predicted CD4 T cell epitopes in exposed loops are shown in red, potential antibody binding sites are shown in blue, and overlapping T and B cell epitopes are shown in magenta. Partially exposed epitopes are shown in pale colors. Amino acid residues that differ between Salmonella enterica serovars Typhimurium and Typhi are shown in green. For TolC only the outer membrane-associated part is shown. LPS structures as observed in FhuA-LPS crystals [93] are also shown.

Mentions: On the other hand, surface localization alone was not sufficient for protectivity. As examples, membrane proteins PgtE, PagC, and Tsx were highly expressed in vivo and PgtE and PagC elicited potent CD4 T cell responses in convalescent individuals (Fig. 1A). PagC is also well recognized by antibodies and CD4 T cells of human typhoid fever patients [24]. However, PagC, PgtE, and Tsx failed to prolong survival. Interestingly, structural models revealed that these proteins were largely buried in the outer membrane bilayer (Fig. 5), and their extracellular loops contained at most one predicted CD4 T cell epitope each, and only up to two linear antibody epitopes, respectively. Importantly, key amino acids in exposed T cell epitopes differed among Salmonella serovars which might have impaired cross-protectivity of serovar Typhi antigens against serovar Typhimurium challenge infection. Similar observations were also made for non-protective TolC, OmpC, OmpD, and OmpF. By contrast, antigens IroN, CirA, and FepA that enabled extended survival after challenge infection, had extracellular loops with several highly conserved T and B cell epitopes (Fig. 5). Further studies with larger data sets will be required to validate the relevance of these structural properties 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)

Structural models and exposed immune epitopes of various Salmonella outer membrane proteins.The outer membrane is shown as a grey area, predicted CD4 T cell epitopes in exposed loops are shown in red, potential antibody binding sites are shown in blue, and overlapping T and B cell epitopes are shown in magenta. Partially exposed epitopes are shown in pale colors. Amino acid residues that differ between Salmonella enterica serovars Typhimurium and Typhi are shown in green. For TolC only the outer membrane-associated part is shown. LPS structures as observed in FhuA-LPS crystals [93] are also shown.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002966-g005: Structural models and exposed immune epitopes of various Salmonella outer membrane proteins.The outer membrane is shown as a grey area, predicted CD4 T cell epitopes in exposed loops are shown in red, potential antibody binding sites are shown in blue, and overlapping T and B cell epitopes are shown in magenta. Partially exposed epitopes are shown in pale colors. Amino acid residues that differ between Salmonella enterica serovars Typhimurium and Typhi are shown in green. For TolC only the outer membrane-associated part is shown. LPS structures as observed in FhuA-LPS crystals [93] are also shown.
Mentions: On the other hand, surface localization alone was not sufficient for protectivity. As examples, membrane proteins PgtE, PagC, and Tsx were highly expressed in vivo and PgtE and PagC elicited potent CD4 T cell responses in convalescent individuals (Fig. 1A). PagC is also well recognized by antibodies and CD4 T cells of human typhoid fever patients [24]. However, PagC, PgtE, and Tsx failed to prolong survival. Interestingly, structural models revealed that these proteins were largely buried in the outer membrane bilayer (Fig. 5), and their extracellular loops contained at most one predicted CD4 T cell epitope each, and only up to two linear antibody epitopes, respectively. Importantly, key amino acids in exposed T cell epitopes differed among Salmonella serovars which might have impaired cross-protectivity of serovar Typhi antigens against serovar Typhimurium challenge infection. Similar observations were also made for non-protective TolC, OmpC, OmpD, and OmpF. By contrast, antigens IroN, CirA, and FepA that enabled extended survival after challenge infection, had extracellular loops with several highly conserved T and B cell epitopes (Fig. 5). Further studies with larger data sets will be required to validate the relevance of these structural properties 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