Significant advancement has been made in the development of vaccines against bacterial pathogens. However, several roadblocks have been found during the evaluation of vaccines against intracellular bacterial pathogens. Therefore, new lessons could be learned from different vaccines developed against unrelated intracellular pathogens. Bacillary dysentery and melioidosis are important causes of morbidity and mortality in developing nations, which are caused by the intracellular bacteria Shigella and Burkholderia pseudomallei, respectively. Although the mechanisms of bacterial infection, dissemination, and route of infection do not provide clues about the commonalities of the pathogenic infectious processes of these bacteria, a wide variety of vaccine platforms recently evaluated suggest that in addition to the stimulation of antibodies, identifying protective antigens and inducing T cell responses are some additional required elements to induce effective protection. In this review, we perform a comparative evaluation of recent candidate vaccines used to combat these two infectious agents, emphasizing the common strategies that can help investigators advance effective and protective vaccines to clinical trials.

Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-κB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-κB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-κB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-κB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM’s intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses.