Abstract
Francisella tularensis is an infectious, gram-negative, intracellular microorganism, and the cause of tularemia. Invasion of host cells by intracellular pathogens like Francisella is initiated by their interaction with different host cell membrane receptors and the rapid phosphorylation of different downstream signaling molecules. PI3K and Syk have been shown to be involved in F. tularensis host cell entry, and both of these signaling molecules are associated with the master regulator serine/threonine kinase mTOR; yet the involvement of mTOR in F. tularensis invasion of host cells has not been assessed. Here, we report that infection of macrophages with F. tularensis triggers the phosphorylation of mTOR downstream effector molecules, and that signaling via TLR2 is necessary for these events. Inhibition of mTOR or of PI3K, ERK, or p38, but not Akt signaling, downregulates the levels of phosphorylation of mTOR downstream targets, and significantly reduces the number of F. tularensis cells invading macrophages. Moreover, while phosphorylation of mTOR downstream effectors occurs via the PI3K pathway, it also involves PLCγ1 and Ca2+ signaling. Furthermore, abrogation of PLC or Ca2+ signaling revealed their important role in the ability of F. tularensis to invade host cells. Together, these findings suggest that F. tularensis invasion of primary macrophages utilize a myriad of host signaling pathways to ensure effective cell entry.
Highlights
Francisella tularensis subspecies tularensis (Type A) and subspecies holartica (Type B) are highly infectious, Gramnegative, intracellular pathogens that cause tularemia, a disease with significant morbidity and mortality in humans and other mammals
Since mammalian target of rapamycin (mTOR) is downstream of the PI3K/Akt pathway, we likewise assessed if signaling via PI3K was required for F. tularensis Live Vaccine Strain (LVS) invasion
These results indicate that PI3K and mTOR signaling play important roles in F. tularensis LVS invasion of primary murine macrophages
Summary
Francisella tularensis subspecies tularensis (Type A) and subspecies holartica (Type B) are highly infectious, Gramnegative, intracellular pathogens that cause tularemia, a disease with significant morbidity and mortality in humans and other mammals. Due to its ease of infection and means of dissemination, these F. tularensis subspecies are classified as select agents [1,2]. F. tularensis can infect a variety of host cells, but macrophages seem to be a very effective cell type for the replication and survival of this bacterium [3,4]. The F. tularensis Live Vaccine Strain (LVS) derived from subspecies holartica causes an attenuated form of infection in humans and has been used as a vaccine, it is not licensed. F. tularensis LVS infection of mice does cause a pathology that resembles that observed in humans infected with virulent Francisella strains. Since the intracellular life cycle of F. tularensis LVS is similar to that of type A Francisella, its use in research has been of great advantage [5]
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