Abstract
Leptospirosis is an emerging infectious disease caused by pathogenic Leptospira spp. A universal vaccine against leptospirosis is likely to require highly conserved epitopes from pathogenic leptospires that are exposed on the bacterial surface and that generate a protective and sterilizing immune response. Our group recently identified several genes predicted to encode TonB-dependent receptors (TBDR) in Leptospira interrogans using a reverse vaccinology approach. Three leptospiral TBDRs were previously described and partially characterized as ferric-citrate, hemin, and cobalamin transporters. In the current study, we designed a fusion protein composed of predicted surface-exposed epitopes from three conserved leptospiral TBDRs. Based on their three-dimensional structural models and the prediction of immunogenic regions, nine putative surface-exposed fragments were selected to compose a recombinant chimeric protein. A Mycobacterium bovis BCG strain expressing this chimeric antigen encoded in the pUP500/PpAN mycobacterial expression vector was used to immunize Syrian hamsters. All animals (20/20) vaccinated with recombinant BCG survived infection with an endpoint dose of L. interrogans (p < 0.001). No animal survived in the negative control group. Immunization with our recombinant BCG elicited a humoral immune response against leptospiral TBDRs, as demonstrated by ELISA and immunoblot. No leptospiral DNA was detected by lipL32 qPCR in the kidneys of vaccinated hamsters. Similarly, no growth was observed in macerated kidney cultures from the same animals, suggesting the induction of a sterilizing immune response. Design of new vaccine antigens based on the structure of outer membrane proteins is a promising approach to overcome the impact of leptospirosis by vaccination.Key points• Predicted surface-exposed epitopes were identified in three leptospiral TBDRs.• An M. bovis BCG strain expressing a chimeric protein (rTBDRchi) was constructed.• Hamsters vaccinated with rBCG:TBDRchi were protected from lethal leptospirosis.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00253-021-11726-9.
Highlights
Leptospirosis is a major zoonosis worldwide in terms of morbidity and mortality rates
We identified highly conserved surfaceexposed regions containing B and T CD4 + cell epitopes in three leptospiral TonB-dependent receptors (TBDR): LIC10896, LIC10964, and LIC12374
Orthologs for each L. interrogans TBDR were identified by BlastP (NCBI) in 10 pathogenic (P1 clade) Leptospira spp. proteomes (Online Resource 1, Table S1)
Summary
Leptospirosis is a major zoonosis worldwide in terms of morbidity and mortality rates. The global incidence is estimated to be over one million cases every year, resulting in ~ 60,000. Rodents are the primary reservoir hosts of pathogenic Leptospira spp., while humans are incidental hosts. The disease affects several wild and domestic animals (Ellis 2015; Haake and Levett 2015). Leptospirosis in humans can vary from mild symptoms, such as fever and myalgia to severe outcomes, with the development of acute kidney injury and pulmonary hemorrhage syndrome (Haake and Levett 2015). Leptospiral vaccines currently available are inactivated whole-cell preparations (bacterins) with widespread veterinary applications, but limited use in humans. Bacterins confer a short-term immune response that is protective only against the serovars included in the vaccine formulation (Adler 2015).
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