Mining host-pathogen protein interactions to characterize Burkholderia mallei infectivity mechanisms.
Burkholderia pathogenicity relies on protein virulence factors to control and promote bacterial internalization, survival, and replication within eukaryotic host cells. We recently used yeast two-hybrid (Y2H) screening to identify a small set of novel Burkholderia proteins that were shown to attenuate disease progression in an aerosol infection animal model using the virulent Burkholderia mallei ATCC 23344 strain. Here, we performed an extended analysis of primarily nine B. mallei virulence factors and their interactions with human proteins to map out how the bacteria can influence and alter host processes and pathways. Specifically, we employed topological analyses to assess the connectivity patterns of targeted host proteins, identify modules of pathogen-interacting host proteins linked to processes promoting infectivity, and evaluate the effect of crosstalk among the identified host protein modules. Overall, our analysis showed that the targeted host proteins generally had a large number of interacting partners and interacted with other host proteins that were also targeted by B. mallei proteins. We also introduced a novel Host-Pathogen Interaction Alignment (HPIA) algorithm and used it to explore similarities between host-pathogen interactions of B. mallei, Yersinia pestis, and Salmonella enterica. We inferred putative roles of B. mallei proteins based on the roles of their aligned Y. pestis and S. enterica partners and showed that up to 73% of the predicted roles matched existing annotations. A key insight into Burkholderia pathogenicity derived from these analyses of Y2H host-pathogen interactions is the identification of eukaryotic-specific targeted cellular mechanisms, including the ubiquitination degradation system and the use of the focal adhesion pathway as a fulcrum for transmitting mechanical forces and regulatory signals. This provides the mechanisms to modulate and adapt the host-cell environment for the successful establishment of host infections and intracellular spread.
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.
Vesna
V
Memišević
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.
Nela
N
Zavaljevski
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Seesandra V
SV
Rajagopala
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Keehwan
K
Kwon
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Rembert
R
Pieper
Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
David
D
DeShazer
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.
Jaques
J
Reifman
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America.
Anders
A
Wallqvist
D000465:Algorithms; D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology; D042726:Burkholderia mallei / Q000472:pathogenicity* / Q000502:physiology*; D016000:Cluster Analysis; D019295:Computational Biology; D022001:Focal Adhesions; D005896:Glanders / Q000382:microbiology / Q000503:physiopathology; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D051379:Mice; D060066:Protein Interaction Maps / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D037521:Virulence Factors / Q000378:metabolism
D001426:Bacterial Proteins; D037521:Virulence Factors