Abstract. The Legionella genus has more than 60 species from which 20 are associated with Legionnaires’
disease, a form of atypical pneumonia. More than 90% of Legionnaires’ disease cases are caused by L.
pneumophila serogroup 1. Legionella tends to colonize plumbing system biofilms and amoebae cysts which are
resistant to water purification treatment. The ability of Legionella spp. to persist and multiply in amoeba and
humans and cause clinical disease depends on a set of virulence genes and on the coordinate regulation of gene
functions that combat the effects of innate and acquired host defenses. Therefore, the main objective of this
proposal is to elucidate the molecular mechanisms that Legionella pneumophila has evolved to overcome host
innate immune responses and allow it to establish an infection.
The L. pneumophila genome contains clusters of genes that encode two types of type IV (TIVSS) secretion
systems; lvh and dot/icm. While the genetic organization of dot/icm, and its role in virulence is well established,
there is limited information about the role of Lvh TIVSS. The Legionella strains that lack Lvh TIVSS have
markedly reduced cytotoxicity. Additionally, Lvh TIVSS plays an important role in host-cell infection by L.
pneumophila grown at 30°C, and in the effective delay of phagosome acidification. The L. pneumophila lvh locus
is required for the restoration of entry and intracellular multiplication in dot/icm mutants following incubation
in water and amoeba encystment. We have demonstrated that Legionella pneumophila’s Lvh TIVSS machinery
localize at cell poles, and such localization has been reported to be important for virulence in other pathogens.
We also demonstrated that Lvh TIVSS is important for host-cell caspase-3/7 activation when Legionella strains
are grown under 30°C. Based on our preliminary data and data from the literature, our central hypothesis is that
Lvh contributes to Legionella virulence under infection from the environment and regulates late stages of cellular
infection and further dissemination of bacteria. We will test our central hypothesis and attain our objective by
evaluating the role of Lvh TIVSS in the modulation of host cell immunity, gene expression, and
programmed cell death.
Revealing Lvh functions will uncover sites of potential weakness in bacterial pathogens that may be exploited
for therapeutic intervention, development of rational, optimally efficacious vaccines, and disease control. Thus,
the main goal of this project is to understand how the host-cell immune system recognizes microbial virulence
factors during infection, produces a protective response, and the mechanism by which Legionella Lvh can inhibit
this protective response. The results from this work will have an important positive impact on human health
because they will provide important information about pathways or networks altered by L. pneumophila Lvh
TIVSS in the host, which may lay the groundwork for the development of a new class of targeted treatments.