Abstract
Modulation of host cell function is vital for intracellular pathogens to survive and replicate within host cells. Most commonly, these pathogens utilize specialized secretion systems to inject substrates (also called effector proteins) that function as toxins within host cells. Since it would be detrimental for an intracellular pathogen to immediately kill its host cell, it is essential that secreted toxins be inactivated or degraded after they have served their purpose. The pathogen Legionella pneumophila represents an ideal system to study interactions between toxins as it survives within host cells for approximately a day and its Dot/Icm type IVB secretion system (T4SS) injects a vast number of toxins. Previously we reported that the Dot/Icm substrates SidE, SdeA, SdeB, and SdeC (known as the SidE family of effectors) are secreted into host cells, where they localize to the cytoplasmic face of the Legionella containing vacuole (LCV) in the early stages of infection. SidJ, another effector that is unrelated to the SidE family, is also encoded in the sdeC-sdeA locus. Interestingly, while over-expression of SidE family proteins in a wild type Legionella strain has no effect, we found that their over-expression in a ∆sidJ mutant completely inhibits intracellular growth of the strain. In addition, we found expression of SidE proteins is toxic in both yeast and mammalian HEK293 cells, but this toxicity can be suppressed by co-expression of SidJ, suggesting that SidJ may modulate the function of SidE family proteins. Finally, we were able to demonstrate both in vivo and in vitro that SidJ acts on SidE proteins to mediate their disappearance from the LCV, thereby preventing lethal intoxication of host cells. Based on these findings, we propose that SidJ acts as a metaeffector to control the activity of other Legionella effectors.
Highlights
Legionella pneumophila, the causative agent of Legionnaires' disease, is a facultative intracellular bacterial pathogen that can replicate within fresh water amoeba and mammalian alveolar macrophages [1,2,3]
Since L. pneumophila remains within the host cells for approximately one day, continual poisoning of the eukaryotic cells by the bacterial effectors will result in the premature death of the host cell, restricting the growth of the pathogen
The L. pneumophila secreted protein LubX was described as a “metaeffector”, which has been defined as an effector that acts directly on another effector to modulate its function inside the host cell
Summary
Legionella pneumophila, the causative agent of Legionnaires' disease, is a facultative intracellular bacterial pathogen that can replicate within fresh water amoeba and mammalian alveolar macrophages [1,2,3]. Inactivation of individual (or even combinations of) Dot/ Icm substrates in genetically engineered mutant strains rarely has a strong effect on the intracellular growth of L. pneumophila, consistent with extensive functional redundancy between effectors [13,14,15]. Four of the encoded proteins, SidE, SdeC, SdeB and SdeA, share extensive homology with each other and are all *170 kDa in size, they have been referred to as “P170s” [16]. As the intracellular growth defect of the SuperΔP170 mutant could be complemented by expression of just one SidE family protein, SdeA, it was proposed that the SidE-like proteins were functionally redundant and the other two genes, lpg2154 and sidJ, must be dispensable for growth within host cells [16]. Subsequently it was shown that inactivation of sidJ alone conferred an intracellular growth defect on L. pneumophila [18], suggesting the situation is more complicated than initially perceived
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