Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Dulal, Hari P; Vance, David J.; Neupane, Durga; Chen, Xiangcheng; Tremblay, Jacqueline M.; Shoemaker, Charles B.; Mantis, Nicholas J.; Song, Jeongmin

doi:10.1128/iai.00515-21

“…Mice experiments were conducted according to a protocol approved by Cornell IACUC. Sex-matched groups of 7-to 11-week-old Cmah-null mice expressing the human-type glycan receptor (Jackson Laboratory, RRID: IMSR_JAX:017588) 47,57,59,60,63,83–85 were infected intraperitoneally with 8 x 10 5 S . Typhi WT, tviE K266N, or tviE P263S strain in 100 µL of PBS.…”

Section: Methodsmentioning

confidence: 99%

Single missense mutations in Vi capsule synthesis genes confer hypervirulence toSalmonellaTyphi

Lee,

Song

2024

Preprint

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Many bacterial pathogens, including the human exclusive pathogenSalmonellaTyphi, express capsular polysaccharides as a crucial virulence factor. Here, throughS.Typhi whole genome sequence analyses and functional studies, we found a list of single point mutations that makeS. Typhi hypervirulent. We discovered a single point mutation in the Vi biosynthesis enzymes that control the length or acetylation of Vi is enough to create different capsule variants ofS.Typhi. All variant strains are pathogenic, but the hyper-capsule variants are particularly hypervirulent, as demonstrated by the high morbidity and mortality rates observed in infected mice. The hypo-capsule variants have primarily been identified in Africa, whereas the hyper-capsule variants are distributed worldwide. Collectively, these studies increase awareness about the existence of different capsule variants ofS.Typhi, establish a solid foundation for numerous future studies onS.Typhi capsule variants, and offer valuable insights into strategies to combat capsulated bacteria.

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“…Two micrograms of purified recombinant typhoid toxin carrying a histidine hexamer on CdtB were administered via retro-orbital injections when a lethal-dose typhoid toxin challenge is indicated. Changes in the behavior, weight, and survival of the toxin-injected mice were closely monitored as previously described [ 11 , 14 – 16 , 47 ]. Balance beam tests were performed to evaluate toxin-mediated upper motor function deficits, as previously described [ 13 , 14 ].…”

Section: Methodsmentioning

confidence: 99%

Malnutrition and maternal vaccination against typhoid toxin

Neupane

¹

,

Ahn²,

Yang³

et al. 2022

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Children are particularly susceptible to typhoid fever caused by the bacterial pathogen Salmonella Typhi. Typhoid fever is prevalent in developing countries where diets can be less well-balanced. Here, using a murine model, we investigated the role of the macronutrient composition of the diet in maternal vaccination efficacies of two subunit vaccines targeting typhoid toxin: ToxoidVac and PltBVac. We found that maternal vaccinations protected all offspring against a lethal-dose typhoid toxin challenge in a balanced, normal diet (ND) condition, but the declined protection in a malnourished diet (MD) condition was observed in the PltBVac group. Despite the comparable antibody titers in both MD and ND mothers, MD offspring had a significantly lower level of typhoid toxin neutralizing antibodies than their ND counterparts. We observed a lower expression of the neonatal Fc receptor on the yolk sac of MD mothers than in ND mothers, agreeing with the observed lower antibody titers in MD offspring. Protein supplementation to MD diets, but not fat supplementation, increased FcRn expression and protected all MD offspring from the toxin challenge. Similarly, providing additional typhoid toxin-neutralizing antibodies to MD offspring was sufficient to protect all MD offspring from the toxin challenge. These results emphasize the significance of balanced/normal diets for a more effective maternal vaccination transfer to their offspring.

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“…In mice expressing "human-type" glycan receptors, typhoid toxin binds to immune cells and brain endothelial cells to intoxicate or pass the toxin to neighbor cells (e.g., neurons). Several typhoid toxins neutralizing IgG and alpaca-derived single domain antibodies have been generated and characterized in detail using mice whose ages were corresponding to human adolescents and adults [15][16][17].…”

Section: Smentioning

confidence: 99%

“…Two micrograms of purified recombinant typhoid toxin carrying a histidine hexamer on CdtB were administered via retro-orbital injections when a lethal-dose typhoid toxin challenge is indicated. Changes in the behavior, weight, and survival of the toxin-injected mice were closely monitored as previously described [11,[14][15][16]47]. Balance beam tests were performed to evaluate toxin-mediated upper motor function deficits, as previously described [13,14].…”

Section: In Vivo Mouse Experimentsmentioning

confidence: 99%

The role of diets in maternal vaccinations against typhoid toxin

Neupane

¹

,

Ahn

²

,

Yang

³

et al. 2022

Preprint

Self Cite

0

View full text Add to dashboard Cite

Children are particularly susceptible to typhoid fever caused by the bacterial pathogen Salmonella Typhi. Typhoid fever is prevalent in developing countries where diets can be less well-balanced. Here, using a murine model, we investigated the role of the macronutrient composition of the diet in maternal vaccination efficacies of two subunit vaccines targeting typhoid toxin: ToxoidVac and PltBVac. We found that maternal vaccinations protected all offspring against a lethal-dose typhoid toxin challenge in a balanced, normal diet (ND) condition, but the declined protection in a malnourished diet (MD) condition was observed in the PltBVac group. Despite the comparable antibody titers in both MD and ND mothers, MD offspring had a significantly lower level of typhoid toxin neutralizing antibodies than their ND counterparts. We observed a lower expression of the neonatal Fc receptor on the yolk sac of MD mothers than in ND mothers, agreeing with the observed lower antibody titers in MD offspring. Protein supplementation to MD diets, but not fat supplementation, increased FcRn expression and protected all MD offspring from the toxin challenge. Similarly, providing additional typhoid toxin-neutralizing antibodies to MD offspring was sufficient to protect all MD offspring from the toxin challenge. These results emphasize the significance of balanced/normal diets for a more effective maternal vaccination transfer to their offspring.Author summaryTyphoid fever is a life-threatening systemic infectious disease caused by Salmonella Typhi, which is prevalent in developing countries where diets can be less well-balanced. Here, we used mice to study the role of nutrition in maternal vaccination efficacies of two subunit vaccines targeting Salmonella’s typhoid toxin. We found maternal vaccinations protected all offspring from a lethal-dose typhoid toxin challenge in a balanced/normal diet (ND) condition, but the lack of protection in a malnourished diet (MD) condition was observed in the PltBVac group. Our data indicate that the difference in maternal vaccination outcomes between ND and MD offspring was due to the less effective maternal antibody transfer from MD mothers to their offspring. Providing additional proteins to MD mothers or additional toxin-neutralizing antibodies to MD offspring saved all malnourished offspring from a lethal-dose typhoid toxin challenge, highlighting the importance of balanced/normal diets for effective maternal vaccination outcomes.

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Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Cited by 9 publications

References 29 publications

Single missense mutations in Vi capsule synthesis genes confer hypervirulence toSalmonellaTyphi

Single missense mutations in Vi capsule synthesis genes confer hypervirulence toSalmonellaTyphi

Malnutrition and maternal vaccination against typhoid toxin

The role of diets in maternal vaccinations against typhoid toxin

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