Abstract
Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing leptospirosis, a public health problem with global implications. Thousands of people die every year due to leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) vaccine; however, success has been limited. A prospective vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to vaccine development.
Highlights
Leptospirosis is a zoonosis caused by spirochetes belonging to the Leptospira genus
We report the application of reverse vaccinology (RV) and structural vaccinology (SV) toward the discovery of leptospiral vaccine candidates, i.e., β-barrel transmembrane proteins (βb-outer membrane protein (OMP)) and outer membrane (OM) lipoproteins, structural modeling, the in silico identification of major histocompatibility complex (MHC-II)-binding epitopes, and the selection of surface-related immunogenic epitopes
Reverse vaccinology was employed for the identification of surface-exposed proteins, including βb-OMPs and OM lipoproteins in the genome of L. interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC)
Summary
Leptospirosis is a zoonosis caused by spirochetes belonging to the Leptospira genus. More than 250 antigenically distinct serovars have been described for 15 infectious Leptospira spp. Leptospirosis is a neglected tropical disease with an estimated incidence of over one million severe cases in humans, resulting in ~60,000 fatalities [3]. The disease has a major impact on the health of agricultural and companion animals, with serious economic consequences [4]. Recombinant vaccine development is a major research focus because of the lack of effective control measures. Classical immunization strategies based on whole-cell, inactivated leptospires (bacterins), or cell wall components have been well documented [5]. While bacterin vaccines are highly efficacious, they cause serious adverse reactions and confer short-term immunity that is restricted to the serovars used in the bacterin preparation [6]
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