A fundamental question in immunology is how immune cells recognize and mount a robust response to invading microorganisms. Genetically tractable pathogens capable of triggering distinct responses in immune cells are extremely useful in determining the microbial ligands or activity responsible for such responses and the corresponding host immune surveillance mechanisms. Legionella pneumophila is a ubiquitous bacterium, which in the environment is primarily associated with amoebae as an intracellular parasite. This bacterium also can replicate within mammalian alveolar macrophages and causes Legionnaires'disease, a severe inflammatory pneumonia. The amoebae host is believed to provide the primary or exclusive evolutionary pressure for its acquisition and maintenance of bacterial traits necessary for intracellular replication. Thus, L. pneumophila appears not to have evolved sophisticated immune-evasive mechanisms and can serve as an excellent model for identifying bacterial ligands or activity sensed by the host immune system. We found that an environmental isolate of L. pneumophila (strain LPE509) was unable to replicate in bone marrow-derived macrophages from A/J mice, which are permissive for intracellular replication by most, if not all examined clinic L. pneumophila isolates. Strain LPE509 grows robustly in the amoebae host Dictyostelium discoideum and the differentiated human macrophages U937 cells in a process that is dependent upon the Dot/Icm type IV secretin system, which is required for the virulence of all examined L. pneumophila strains. Further, we found that LPE509 induced extensive cell death in A/J macrophages in a process that required the Dot/Icm transporter but not flagellin or the NAIP5-NLRC4 inflammasome. Thus, we hypothesized that strain LPE509 codes for one or more factors that can be recognized by the host immune surveillance system, leading to host cell death. In this proposal, we will test this hypothesis by pursuing two specific Aims: First, we will identify the bacterial factor(s) responsible for the induction of cell death i A/J macrophages. Second, we will determine the host pathway involved in the recognition of the bacterial signal(s).

Public Health Relevance

Innate immunity is important not only in our defense against infection, but also in the development of many autoimmune diseases. We have established an infection system using an environmental isolate of the intracellular pathogen Legionella pneumophila to probe potentially novel immune recognition mechanisms. Information generated from this study will be important for the development of novel strategies for the prevention and/or treatment of infectious diseases as well as disorders resulting from defects in the innate immunity system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Innate Immunity and Inflammation Study Section (III)
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Perdue, Samuel S
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Purdue University
Schools of Arts and Sciences
West Lafayette
United States
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Liu, Yao; Zhu, Wenhan; Tan, Yunhao et al. (2017) A Legionella Effector Disrupts Host Cytoskeletal Structure by Cleaving Actin. PLoS Pathog 13:e1006186
Puvar, Kedar; Zhou, Yiyang; Qiu, Jiazhang et al. (2017) Ubiquitin Chains Modified by the Bacterial Ligase SdeA Are Protected from Deubiquitinase Hydrolysis. Biochemistry 56:4762-4766
Luo, Zhao-Qing (2017) Catch and arrest: exploiting the retromer by a Chlamydial effector. Signal Transduct Target Ther 2:17039
Qiu, Jiazhang; Luo, Zhao-Qing (2017) Hijacking of the Host Ubiquitin Network by Legionella pneumophila. Front Cell Infect Microbiol 7:487
Qiu, Jiazhang; Yu, Kaiwen; Fei, Xiaowen et al. (2017) A unique deubiquitinase that deconjugates phosphoribosyl-linked protein ubiquitination. Cell Res 27:865-881
Zhu, Wenhan; Luo, Zhao-Qing (2016) Cell biology and immunology lessons taught by Legionella pneumophila. Sci China Life Sci 59:3-10
Qiu, Jiazhang; Sheedlo, Michael J; Yu, Kaiwen et al. (2016) Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 533:120-4
Luo, Xi; Wasilko, David J; Liu, Yao et al. (2015) Structure of the Legionella Virulence Factor, SidC Reveals a Unique PI(4)P-Specific Binding Domain Essential for Its Targeting to the Bacterial Phagosome. PLoS Pathog 11:e1004965
Zhu, Wenhan; Tao, Lili; Quick, Marsha L et al. (2015) Sensing cytosolic RpsL by macrophages induces lysosomal cell death and termination of bacterial infection. PLoS Pathog 11:e1004704
Zhu, Wenhan; Luo, Zhao-Qing (2015) A new way to detect the danger: Lysosomal cell death induced by a bacterial ribosomal protein. J Nat Sci 1:

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