Renewed awareness of the substantial morbidity and mortality that Shigella infection causes among young children in developing countries, combined with technological innovations in vaccinology, has led to the development of novel vaccine strategies in the past 5 years. Along with advancement of classic vaccines in clinical trials and new sophisticated measurements of immunological responses, much new data has been produced, lending promise to the potential for production of safe and effective Shigella vaccines. Herein, we review the latest progress in Shigella vaccine development within the framework of persistent obstacles.
"Dysentery caused by Shigella dysenteriae type 1 (Sd1) is a recurrent challenge in many parts of the world. Epidemics of this disease are associated with a high rate of mortality in young children
. Treatment is complicated by the rapid emergence of Sd1 strains resistant to the newest antibiotics
[Show abstract][Hide abstract] ABSTRACT: Background
Shigella dysenteriae type 1 (Sd1) causes recurrent epidemics of dysentery associated with high mortality in many regions of the world. Sd1 infects humans at very low infectious doses (10 CFU), and treatment is complicated by the rapid emergence of antibiotic resistant Sd1 strains. Sd1 is only detected in the context of human infections, and the circumstances under which epidemics emerge and regress remain unknown.
Phylogenomic analyses of 56 isolates collected worldwide over the past 60 years indicate that the Sd1 clone responsible for the recent pandemics emerged at the turn of the 20th century, and that the two world wars likely played a pivotal role for its dissemination. Several lineages remain ubiquitous and their phylogeny indicates several recent intercontinental transfers. Our comparative genomics analysis reveals that isolates responsible for separate outbreaks, though closely related to one another, have independently accumulated antibiotic resistance genes, suggesting that there is little or no selection to retain these genes in-between outbreaks. The genomes appear to be subjected to genetic drift that affects a number of functions currently used by diagnostic tools to identify Sd1, which could lead to the potential failure of such tools.
Taken together, the Sd1 population structure and pattern of evolution suggest a recent emergence and a possible human carrier state that could play an important role in the epidemic pattern of infections of this human-specific pathogen. This analysis highlights the important role of whole-genome sequencing in studying pathogens for which epidemiological or laboratory investigations are particularly challenging.
Electronic supplementary material
The online version of this article (doi: 10.1186/1471-2164-15-355) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: Shigella species Gram-negative bacteria which cause a diarrheal disease, known as shigellosis, by invading and destroying the colonic
mucosa and inducing a robust inflammatory response. With no vaccine available, shigellosis annually kills over 600,000 children
in developing countries. This study demonstrates the utility of combining high-throughput bioinformatic methods with in vitro and in vivo assays to provide new insights into pathogenesis. Comparisons of in vivo and in vitro gene expression identified genes associated with intracellular growth. Additional bioinformatics analyses identified genes
that are present in S. flexneri isolates but not in the three other Shigella species. Comparison of these two analyses revealed nine genes that are differentially expressed during invasion and that
are specific to S. flexneri. One gene, a DeoR family transcriptional regulator with decreased expression during invasion, was further characterized and
is now designated icgR, for intracellular growth regulator. Deletion of icgR caused no difference in growth in vitro but resulted in increased intracellular replication in HCT-8 cells. Further in vitro and in vivo studies using high-throughput sequencing of RNA transcripts (RNA-seq) of an isogenic ΔicgR mutant identified 34 genes that were upregulated under both growth conditions. This combined informatics and functional approach
has allowed the characterization of a gene and pathway previously unknown in Shigella pathogenesis and provides a framework for further identification of novel virulence factors and regulatory pathways.
Infection and immunity 06/2013; 81(9). DOI:10.1128/IAI.00537-13 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite intensive research efforts for more than 60 years, utilizing diverse vaccine strategies, a safe and efficacious vaccine against shigellosis is not available yet. We are currently witnessing innovative approaches based on elucidation of the virulence mechanisms of Shigella, understanding the immune response to the pathogen and progress in molecular technology for developing Shigella vaccines. It is hoped that these will lead to a licensed effective Shigella vaccine to protect humans against the significant worldwide morbidity and mortality caused by this microorganism.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.