Yersinia pestis Caf1 Protein: Effect of Sequence Polymorphism on Intrinsic Disorder Propensity, Serological Cross-Reactivity and Cross-Protectivity of Isoforms

Abstract

Yersinia pestis Caf1 is a multifunctional protein responsible for antiphagocytic activity and is a key protective antigen. It is generally conserved between globally distributed Y. pestis strains, but Y. pestis subsp. microtus biovar caucasica strains circulating within populations of common voles in Georgia and Armenia were reported to carry a single substitution of alanine to serine. We investigated polymorphism of the Caf1 sequences among other Y. pestis subsp. microtus strains, which have a limited virulence in guinea pigs and in humans. Sequencing of caf1 genes from 119 Y. pestis strains belonging to different biovars within subsp. microtus showed that the Caf1 proteins exist in three isoforms, the global type Caf1NT1 (Ala48 Phe117), type Caf1NT2 (Ser48 Phe117) found in Transcaucasian-highland and Pre-Araks natural plague foci #4–7, and a novel Caf1NT3 type (Ala48 Val117) endemic in Dagestan-highland natural plague focus #39. Both minor types are the progenies of the global isoform. In this report, Caf1 polymorphism was analyzed by comparing predicted intrinsic disorder propensities and potential protein-protein interactivities of the three Caf1 isoforms. The analysis revealed that these properties of Caf1 protein are minimally affected by its polymorphism. All protein isoforms could be equally detected by an immunochromatography test for plague at the lowest protein concentration tested (1.0 ng/mL), which is the detection limit. When compared to the classic Caf1NT1 isoform, the endemic Caf1NT2 or Caf1NT3 had lower immunoreactivity in ELISA and lower indices of self- and cross-protection. Despite a visible reduction in cross-protection between all Caf1 isoforms, our data suggest that polymorphism in the caf1 gene may not allow the carriers of Caf1NT2 or Caf1NT3 variants escaping from the Caf1NT1-mediated immunity to plague in the case of a low-dose flea-borne infection.

Development of a dual antigen lateral flow immunoassay for detecting Yersinia pestis

“…The NT1 isoform (Ala 48 Phe 117 ) is most common and is expressed by the three global strains responsible for human infections [ 59 ]. Moreover, the adaptive immune response elicited by the NT1 isoform are cross-reactive to the NT2 (Ser 48 Phe 117 ) and NT3 (Ala 48 Val 117 ) isoforms suggesting these amino acid substitutions may not affect the binding of the described mAbs [ 61 ]. Y .…”

A search for new molecular targets for optimizing plague preventive vaccination and therapy

“…В целом ряде случаев различными группами были получены противоречивые данные о значимости отдельных факторов патогенности в пато-и иммуногенезе чумы [41], что может быть связано с использованием разных пород/линий лабораторных животных [172]. Однако целый ряд исследователей считает, что сосредотачиваться исключительно на Cаf1 и LcrV как на единственных протективных белках, подходящих для создания кандидатных чумных вакцин, было бы недальновидным по причине обнаружения структурного и серологического полиморфизма LcrV Y. pestis [13] и Caf1 [84]. Определенное беспокойство вызывают и высоковирулентные природные штаммы возбудителя чумы, лишенные способности продуцировать Cаf1 и благодаря этому преодолевающие иммунитет, индуцированный вакцинами на основе данного антигена [150,162].…”

Sequence Variability of pXO1-Located Pathogenicity Genes of Bacillus anthracis Natural Strains of Different Geographic Origin

“…However, mutations in the genes encoding pathogenicity factors have practically not been used before as additional markers for genotyping. Moreover, unlike many other pathogens [24][25][26][27][28][29], the allelic polymorphism of these genes in the anthrax microbe is practically not described. Only a few articles have been published in which the allelic polymorphism of individual pathogenicity genes was assessed among a small number of strains [30].…”