A mutant in the Listeria monocytogenes Fur-regulated virulence locus (frvA) induces cellular immunity and confers protection against listeriosis in mice

Abstract

Listeria monocytogenes is a Gram-positive intracellular pathogen that is responsible for listeriosis, a potentially fatal, food-borne illness. Due to its cytoplasmic location during infection, this pathogen can mediate a long-lasting cellular immune response, which makes attenuated strains strong candidates for vaccine development. Recently, our group identified and characterized frvA (Fur-regulated virulence factor A), and deletion of this gene resulted in disruption of iron homeostasis and a strong attenuation in virulence. Despite significant attenuation in the mouse infection model, the frvA mutant was capable of intracellular growth in antigen-presenting cells. Indeed, mice immunized with L. monocytogenes DfrvA were able to effectively stimulate specific CD8 + T cells to the listerial epitopes LLO 91-99 and P60 217-225 at levels comparable with L.monocytogenes strain EGDe. Most notably, mice immunized with DfrvA then subsequently challenged with the wild-type strain were completely protected from listerial infection. On the basis of these results, we advocate the use of DfrvA as a live attenuated listerial vaccine, and propose that this mutant may serve as a platform for the development of a future vaccine delivery vehicle.

The Listeria monocytogenes Fur‐regulated virulence protein FrvA is an Fe(II) efflux P1B4‐type ATPase

“…We demonstrate here that frvA is positively regulated by Fur, and that this provides a mechanism for the induction of frvA in response to high Fe(II) levels. The basis for the attenuated virulence of the frvA mutant strain is still unresolved (McLaughlin et al, 2013(McLaughlin et al, , 2012. We favour a model in which this attenuation is based on a defect in Fe(II) efflux and subsequent sensitivity to iron intoxication in the host.…”

“…The DfrvA strain is highly attenuated, but is still able to invade and replicate in a macrophage cell line. Inoculation into mice induces cellular immunity suggesting that this strain could be useful for vaccine development (McLaughlin et al, 2013).…”

Listeriosis in animals, its public health significance (food-borne zoonosis) and advances in diagnosis and control: a comprehensive review

“…Live attenuated vaccine causes stimulation of the innate as well as adaptive immune response ). Deletion of the frvA (Fur-regulated virulence factor A) leads to disruption of iron homeostasis and subsequent decrease in virulence of bacteria, thereby potentiating the use of this strain as live attenuated vaccine as well as a vehicle for vaccine delivery in future (McLaughlin et al 2013). Experiments on mice showed generation of high level of antibodies against L. monocytogenes using a combination of recombinant p60 and LLO (Luo & Cai 2012).…”

Ferrous iron efflux systems in bacteria

“…The frvA null mutant strain shows strong attenuation in virulence, but is still able to invade and propagate inside antigen-presenting cells 66 , suggesting an important link between iron homeostasis and virulence, but it is not clear at which stage(s) of the L. monocytogenes life cycle FrvA is important. The phagocytic vacuole is generally considered to be an iron-limited environment.…”