Evolution of the Arsenal of Legionella pneumophila Effectors To Modulate Protist Hosts

Abstract

Within the human host, Legionella pneumophila replicates within alveolar macrophages, leading to pneumonia. However, L. pneumophila is an aquatic generalist pathogen that replicates within a wide variety of protist hosts, including amoebozoa, percolozoa, and ciliophora. The intracellular lifestyles of L. pneumophila within the two evolutionarily distant hosts macrophages and protists are remarkably similar. Coevolution with numerous protist hosts has shaped plasticity of the genome of L. pneumophila, which harbors numerous proteins encoded by genes acquired from primitive eukaryotic hosts through interkingdom horizontal gene transfer. The Dot/Icm type IVb translocation system translocates ∼6,000 effectors among Legionella species and >320 effector proteins in L. pneumophila into host cells to modulate a plethora of cellular processes to create proliferative niches. Since many of the effectors have likely evolved to modulate cellular processes of primitive eukaryotic hosts, it is not surprising that most of the effectors do not contribute to intracellular growth within human macrophages. Some of the effectors may modulate highly conserved eukaryotic processes, while others may target protist-specific processes that are absent in mammals. The lack of studies to determine the role of the effectors in adaptation of L. pneumophila to various protists has hampered the progress to determine the function of most of these effectors, which are routinely studied in mouse or human macrophages. Since many protists restrict L. pneumophila, utilization of such hosts can also be instrumental in deciphering the mechanisms of failure of L. pneumophila to overcome restriction of certain protist hosts. Here, we review the interaction of L. pneumophila with its permissive and restrictive protist environmental hosts and outline the accomplishments as well as gaps in our knowledge of L. pneumophila-protist host interaction and L. pneumophila's evolution to become a human pathogen.

FIG 1

Amino acid auxotrophy in human macrophages, Acanthamoeba, and L. pneumophila. There is considerable overlap in auxotrophy between L. pneumophila and its most common environmental host, Acanthamoeba. Many of these auxotrophies are also seen in human macrophages, the accidental host.

FIG 2

Interactions of L. pneumophila with protist and macrophage host cells. Resistant protist hosts prevent intracellular replication of L. pneumophila through three mechanisms: preventing attachment, releasing L. pneumophila in a vesicle, and digestion. Intracellular replication can be successful if L. pneumophila can attach and enter the host (step 1), where it can then establish the LCV by modifying the vacuole with ER-to-Golgi complex-derived vesicles and prevent lysosome fusion (step 2). Within the replicative LCV, the bacteria replicate in high numbers (step 3). After many rounds of replication, the bacteria break out of the LCV into the cytosol, undergo a couple of rounds of replication, and transition into the transmission stage, becoming flagellated to aid in egress from the host and finding the next host (step 4). The cycle is then repeated if the bacterium encounters another permissive host, which could be a human macrophage.