Listreia monocytogenes strains lacking multi-drug resistance transporter (MDR) genes modulate type I interferon response and promote better adaptive immunity
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Listreia monocytogenes strains lacking multi-drug resistance transporter (MDR) genes modulate type I interferon response and promote better adaptive immunity
- RAMOT at Tel Aviv University Ltd.
- From Israel
- Responsive
- Innovative Products and Technologies
Summary of the technology
. monocytogenes is considered as one of the most promising bacterial vectors
to be used as live attenuated vaccine since it has multiple advantages as a vaccine platform.
Listeria signals to the innate immune system through multiple pathways, activating cell surface
Toll-like receptors and intracellular Nod-like receptors. The antigens delivered by this vector
behave as endogenous antigens, they are presented on the cell surface and generate cellmediated
immune response, Moreover, Listeria can be repeatedly administered and it is easy to
manufacture.
Immunization with the bacterium Listeria monocytogenes induces a robust protective immune
response mediated by cytotoxic lymphocytes that are efficient at killing infected cells upon
reinfection. When L. monocytogenes enters a cell, it secretes the small molecule cyclic diadenosine
monophosphate (c-di-AMP), which activates the host protein STING leading to a
type I interferon response. Recently, it was shown that IFN-beta production as part of the type I
interferon response is inversely correlated with adaptive immunity to Listeria. In the absence of
STING signaling, mice restricted bacterial growth and maintained higher numbers of cytotoxic
lymphocytes upon reinfection, whereas mice immunized in the presence of elevated levels of cdi-
AMP were less protected. These results suggest that the inflammation induced by a bacterial
pathogen can be detrimental to the development of adaptive immunity, which could provide new
insights into vaccine development.
Therefore, in agreement with the prediction that a strain of Listeria that doesn't induce type I
interferon response might be a better immunizing strain we generated several mutants lacking
sets of multi-drug resistance (MDR) transporters. With these mutants we illustrated for the first
time that it is the cohort of MDR transporters that together contribute to type I interferon
induction during infection and that c-di-AMP is involved in this phenotype.
In light of these results we expect the ?mdr L. monocytogenes strains to be better potentiators of
the adaptive immunity as antigen presentating platforms for live vaccine therapy
Project ID : 10-2014-783
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Abstract from publication in: http://jb.asm.org/content/195/23/5250#ref-list-1
The intracellular bacterial pathogen Listeria monocytogenes activates a robust type I interferon response upon infection. This response is partially dependent on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP (c-di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to this response are unknown. Here we report that it is not MdrM alone but a cohort of MDR transporters that together contribute to type I interferon induction during infection. In a search for a physiological function of these transporters, we revealed that they play a role in cell wall stress responses.
A mutant with deletion of four transporter genes (mdrMTAC) was found to be sensitive to sublethal concentrations of vancomycin due to an inability to produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase (PdeA) resulted in increased susceptibility of the mdrMTAC mutant to vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) reduced susceptibility to this drug. These observations suggest a physiological association between c-di-AMP and the MDR transporters and support the model that MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis in response to cell wall stress.