Cryptosporidium hominisgene catalog: a resource for the selection of novelCryptosporidiumvaccine candidates

Abstract

Human cryptosporidiosis, caused primarily by Cryptosporidium hominis and a subset of Cryptosporidium parvum, is a major cause of moderate-to-severe diarrhea in children under 5 years of age in developing countries and can lead to nutritional stunting and death. Cryptosporidiosis is particularly severe and potentially lethal in immunocompromised hosts. Biological and technical challenges have impeded traditional vaccinology approaches to identify novel targets for the development of vaccines against C. hominis, the predominant species associated with human disease. We deemed that the existence of genomic resources for multiple species in the genus, including a much-improved genome assembly and annotation for C. hominis, makes a reverse vaccinology approach feasible. To this end, we sought to generate a searchable online resource, termed C. hominis gene catalog, which registers all C. hominis genes and their properties relevant for the identification and prioritization of candidate vaccine antigens, including physical attributes, properties related to antigenic potential and expression data. Using bioinformatic approaches, we identified ∼400 C. hominis genes containing properties typical of surface-exposed antigens, such as predicted glycosylphosphatidylinositol (GPI)-anchor motifs, multiple transmembrane motifs and/or signal peptides targeting the encoded protein to the secretory pathway. This set can be narrowed further, e.g. by focusing on potential GPI-anchored proteins lacking homologs in the human genome, but with homologs in the other Cryptosporidium species for which genomic data are available, and with low amino acid polymorphism. Additional selection criteria related to recombinant expression and purification include minimizing predicted post-translation modifications and potential disulfide bonds. Forty proteins satisfying these criteria were selected from 3745 proteins in the updated C. hominis annotation. The immunogenic potential of a few of these is currently being tested.Database URL: http://cryptogc.igs.umaryland.edu

Comparative genomics revealed adaptive admixture in Cryptosporidium hominis in Africa

“…An in vivo study implicated these genes in the process of host cell invasion, which makes them important virulence determinants adapted to particular host species [49]. These genes have also been suggested as vaccine targets [51,52]. However, the significant standing variation present at these genes implies that this pathogen would be able to rapidly evolve polymorphisms at these genes, thus escaping vaccine recognition.…”

The therapeutic efficacy of azithromycin and nitazoxanide in the acute pig model of Cryptosporidium hominis

“…It was originally obtained from a child with diarrhea in sub-Saharan Africa [ 25 ]. The genome of TU502 was sequenced twice [ 25 , 26 ] and the strain was tested in human volunteer challenge [ 27 ], displaying clinical characteristics distinct from C . parvum .…”

Vaccines Meet Big Data: State-of-the-Art and Future Prospects. From the Classical 3Is (“Isolate–Inactivate–Inject”) Vaccinology 1.0 to Vaccinology 3.0, Vaccinomics, and Beyond: A Historical Overview

“…Reverse vaccinology technique is being applied also to other microorganisms, including Leptospira ( 50 , 51 ), Streptococcus pneumoniae ( 52 , 53 ), malaria ( 54 ), Schistosoma ( 55 ), Echinococcus granulosus ( 56 ), Rickettsia prowazekii ( 57 ), Mycobacterium ( 58 ), Acinetobacter baumannii ( 59 ), Escherichia coli ( 60 ), Staphylococcus aureus ( 61 , 62 ), Corynebacterium pseudotuberculosis ( 63 ), Herpes simplex ( 64 ), Vibrio cholerae ( 65 ), and Cryptosporidium ( 65 , 66 ), among others.…”