L-DBF Elicits Cross Protection Against Different Serotypes of Shigella spp

Ti Lu,Siva Sai Kumar Ratnakaram,Debaki R Howlader,Wendy L Picking,Sean K Whittier,Sayan Das,William D Picking,Qi Zheng

doi:10.3389/fitd.2021.729731

Abstract

Shigellosis is a severe diarrheal disease caused by members of the genus Shigella, with at least 80 million cases and 700,000 deaths annually around the world. The type III secretion system (T3SS) is the primary virulence factor used by the shigellae, and we have previously demonstrated that vaccination with the type T3SS proteins IpaB and IpaD, along with an IpaD/IpaB fusion protein (DBF), protects mice from Shigella infection in a lethal pulmonary model. To simplify the formulation and development of the DBF Shigella vaccine, we have genetically fused LTA1, the active subunit of heat-labile toxin from enterotoxigenic E. coli, with DBF to produce the self-adjuvanting antigen L-DBF. Here we immunized mice with L-DBF via the intranasal, intramuscular, and intradermal routes and challenged them with a lethal dose of S. flexneri 2a. While none of the mice vaccinated intramuscularly or intradermally were protected, mice vaccinated with L-DBF intranasally were protected from lethal challenges with S. flexneri 2a, S. flexneri 1b, S. flexneri 3a, S. flexneri 6, and S. sonnei. Intranasal L-DBF induced both B cell and T cell responses that correlated with protection against Shigella infection. Our results suggest that L-DBF is a candidate for developing an effective serotype-independent vaccine against Shigella spp.

Highlights

The shigellae are intracellular bacteria that cause the intestinal disease shigellosis, which can result in severe diarrhea or dysentery
We show that IN immunization with L-DBF protects mice against lethal challenges with heterologous S. flexneri 1b, S. flexneri 3a, S. flexneri 6, and S. sonnei. These results show that L-DBF elicits broad protective efficacy against multiple Shigella serotypes and is a viable vaccine candidate against shigellosis
When incubated with biotin-labeled NAD+, L-DBF was found to conjugate biotinylated ADP-ribose to itself and to the LTA1 allosteric activator protein ARF4 (Supplementary Figure S1). This result does not in itself guarantee that the LTA1 domain retains adjuvanticity, the absence of enzymatic activity would have precluded the use of L-DBF as a self-adjuvanting vaccine candidate

Summary

Introduction

The shigellae are intracellular bacteria that cause the intestinal disease shigellosis, which can result in severe diarrhea or dysentery. Shigellosis is a significant public health problem, with children especially vulnerable to increased morbidity and mortality [1, 2]. While most cases of shigellosis occur in developing nations, the shigellae cause diarrhea among travelers and military personnel from developed countries [3]. S. flexneri is the primary cause of endemic diarrhea in developing countries where there is limited access to hygienic resources, whereas S. sonnei is the leading cause of illness in developed countries [3]. S. flexneri is responsible for a greater number of total deaths from shigellosis than the other species, with

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Conclusion