Mining Host-Pathogen Protein Interactions to Characterize Burkholderia mallei Infectivity Mechanisms

Abstract

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.

Global temporal dynamic landscape of pathogen-mediated subversion of Arabidopsis innate immunity

“…1 ). Likewise, the shortest paths in combination with other centrality measures revealed novel genes, pathways, and microbial communities in other biological systems 44 , 45 , 65 – 67 . For instance, network topology analyses, i.e .…”

“…shortest path on a large-scale dataset led to the discovery of a new signaling axes-related to Syk, a protein tyrosine kinase, which negatively affects tumor development and progression 66 . Similarly, network analysis in human- Burkholderia mallei recently showed that pathogen virulence factors interact with multifunctional host hub proteins to simultaneously manipulate a wide range of host cellular processes 65 . In another study, viral proteins also interact with key host proteins to hijack diverse signaling pathways for infectivity 44 , 45 .…”

Vaccines for the Prevention of Melioidosis and Glanders

“…Although no studies demonstrated complete sterilizing immunity, several promising LAV and subunit vaccines against Burkholderia have been proposed. Most notably, a mutant strain deficient in iron transport and a type IV SS [Δ tonB/hcp1 ) [32]] and several mutant strains lacking functional virulence factor genes [39, 40] demonstrated significant protection against a lethal Burkholderia challenge. Although LAVs are potent stimulators of immunity, safety concerns make them unlikely candidates for clinical applications; therefore, subunit vaccines become more practical.…”

“…(Table 1; [36, 23, 37]). Memisevic et al, used a bioinformatics and a yeast two-hybrid approach to identify uncharacterized and novel virulence factors that were conserved between both B. mallei and B. pseudomallei [38, 39]. Using this information, they created three B. mallei mutant strains (ΔBMAA0728, ΔBMAA1865, ΔBMAA0553), one of which (ΔBMAA0728) lacks the virulence gene encoding components of a type VI SS [38].…”

Impact Analysis of SARS-CoV2 on Signaling Pathways during COVID19 Pathogenesis using Codon Usage Assisted Host-Viral Protein Interactions

“…, 4]. Host-pathogen protein interactions provide important insights into the molecular mechanisms of pathogenecity [5].…”