title: Differential Cultivation ofFrancisella tularensisInduces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines.
abstract: Francisella tularensis(Ft) is a category A biothreat agent for which there is no Food and Drug Administration-approved vaccine.Ftcan survive in a variety of habitats with a remarkable ability to adapt to changing environmental conditions. Furthermore,Ftexpresses distinct sets of antigens (Ags) when inside of macrophages (itsin vivohost) as compared to those grownin vitrowith Mueller Hinton Broth (MHB). However, in contrast to MHB-grownFt, Ftgrown in Brain-Heart Infusion (BHI) more closely mimics the antigenic profile of macrophage-grownFt. Thus, we anticipated that when used as a vaccine, BHI-grownFtwould provide better protection compared to MHB-grownFt, primarily due to its greater antigenic similarity toFtcirculating inside the host (macrophages) during natural infection. Our investigation, however, revealed that inactivatedFt(iFt) grown in MHB (iFt-MHB) exhibited superior protective activity when used as a vaccine, as compared to iFtgrown in BHI (iFt-BHI). The superior protection afforded by iFt-MHB compared to that of iFt-BHI was associated with significantly lower bacterial burden and inflammation in the lungs and spleens of vaccinated mice. Moreover, iFt-MHB also induced increased levels ofFt-specific IgG. Further evaluation of early immunological cues also revealed that iFt-MHB exhibits increased engagement of Ag-presenting cells including increased iFtbinding to dendritic cells, increased expression of costimulatory markers, and increased secretion of pro-inflammatory cytokines. Importantly, these studies directly demonstrate thatFtgrowth conditions strongly impactFtvaccine efficacy and that the growth medium used to produce whole cell vaccines toFtmust be a key consideration in the development of a tularemia vaccine.
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Sunagar
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Giang
authors.initials: G
authors.lastname: Pham
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Franz
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Rosa
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Karsten R O
authors.initials: KR
authors.lastname: Hazlett
authors.affiliation: Center for Immunology and Microbial Diseases, Albany Medical College , Albany, NY , USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Gosselin
keywords: APC; Francisella tularensis; costimulatory molecules; growth factors; whole cell-based vaccines