Abstract
Reverse vaccinology (RV) has been widely used for screening of surface-exposed proteins (PSEs) of important pathogens, including outer membrane proteins (OMPs), and extracellular proteins (ECPs) as potential vaccine candidates. In this study, we applied a novel RV negative strategy and a pan-genome analysis for screening of PSEs from 17 L. interrogans strains covering 11 predominately epidemic serovars and 17 multilocus typing (MLST) sequence types (STs) worldwide. Our results showed, for instance, out of a total of 633 predicted PSEs in strain 56601, 92.8% were OMPs or ECPs (588/633). Among the 17 strains, 190 core PSEs, 913 dispensable PSEs and 861 unique PSEs were identified. Of the 190 PSEs, 121 were further predicted to be highly antigenic and thus may serve as potential vaccine candidates against leptospirosis. With the exception of LipL45, OmpL1, and LigB, the majority of the 121 PSEs were newly identified antigens. For example, hypothetical proteins BatC, LipL71, and the OmpA family proteins sharing many common features, such as surface-exposed localization, universal conservation, and eliciting strong antibody responses in patients, are regarded as the most promising vaccine antigens. Additionally, a wide array of potential virulence factors among the predicted PSEs including TonB-dependent receptor, sphingomyelinase 2, leucine-rich repeat protein, and 4 neighboring hypothetical proteins were identified as potential antigenicity, and deserve further investigation. Our results can contribute to the prediction of suitable antigens as potential vaccine candidates against leptospirosis and also provide further insights into mechanisms of leptospiral pathogenicity. In addition, our novel negative-screening strategy combined with pan-genome analysis can be a routine RV method applied to numerous other pathogens.
Highlights
Leptospirosis, caused by pathogenic spirochete bacteria of the genus Leptospira, is one of the most common zoonotic diseases worldwide
A total of 3,702 proteins were analyzed using our novel Reverse vaccinology (RV) strategy; 2,706 consensus CYTs and IMPs, 666 non-consensus proteins, and 330 PSEs were predicted. Among these 2,706 proteins, 2,166 proteins were predicted as CYTs and 540 as IMPs by at least two of the three software (PSORTb3.0, CELLO and SOSUIGramN). These 666 non-consensus proteins predicted as CYT or IMP by only one of the three software were further assessed according to the following rules: For example, LA_0012 was predicted to be unknown in PSORT, outer membrane proteins (OMPs) in Cello and CYT in SoSui-GramN, respectively; And LA_0009 was predicted to be unknown in PSORT, OMP in Cello, IMP in SoSui-GramN
The subcellular localization of 45 proteins was unknown and the remaining proteins were almost all predicted as OMPs or extracellular proteins (ECPs)
Summary
Leptospirosis, caused by pathogenic spirochete bacteria of the genus Leptospira, is one of the most common zoonotic diseases worldwide. Pathogenic Leptospira spp. are transmitted mainly by direct contact with infected animals or by exposure to water or soil contaminated by the urine of infected animals (Faine, 1994). More than 250 serovars have been observed in pathogenic Leptospira (Zhang et al, 2012). Available leptospira vaccines are inactivated whole cell products that provide inadequate protection against most serovars and cannot provide cross-protection against a large number of serogroups of pathogenic leptospires (Faisal et al, 2008). There is an urgent need to develop a long-term and cross-protective vaccine set against leptospirosis
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