As detailed in Materials and Methods, we used the largest connected component identified above to detect 93 sets of human PPIs in which, in each set, all human proteins interacted with at least one of the nine known B. mallei virulence factors and had the same GO biological process annotations; we denoted these sets interaction modules.

2 shows the subset of 116 proteins and 163 interactions from the largest connected component that were part of the 93 identified interaction modules and the location of six interaction modules.

Each of the interaction modules constituting ubiquitination and ligase activity, transcriptional regulation, immune response, cy-toskeleton organization, and mRNA processing, consisted of proteins and interactions that were closely grouped together in the largest connected component (Fig.

A further examination of sets of connected human proteins that also interacted with the virulence factors, revealed the presence of a single, large connected component , i.e., a subnetwork in which a path connects any two proteins to each other.

This largest connected component was composed of 202 proteins and contained the majority (95%) of the 325 interactions between the human proteins interacting with B. mallei (Table 3).

The other 11 connected components consisted of five or fewer proteins, an observation that was not statistically significant from a random selection of proteins (data not shown).

In the network-based enrichment analysis, we first identified the largest connected component in the human interactome that consisted of human proteins interacting with at least one B. mallei virulence factor (denoted as LCC).

We calculated the following topological properties for a set of human proteins interacting with B. mallei: 1) the number of human proteins interacting with B. mallei proteins (Np); 2) the average number of their interacting partners in the human PPI network (D); 3) the clustering coefficient, i.e., the number of interactions among the nearest neighbors (C); the average shortest path between any two proteins in the set (SP); the average number of interacting partners in the human PPI network where both partners interact with B. mallei proteins (Di); and the number of host proteins in the largest connected component (N itECG).

Interestingly, we further observe that crucial nodes whose removal will be most destructive are generally not part of the largest connected component of the initial seed set.

Examining the subgraphs consisting of proteins associated with the same disease, we found that the largest connected component (LCC) typically contains only 10%-30% of the disease proteins (Fig.

The largest connected component of the seed proteins aloneconsists of 24 (out of 45) proteins.

When 200 DIAMOnD proteins are added, the largest connected component of the resulting module integrates 11 additional, previously disconnected seed proteins, resulting in a module consisting of 234 proteins (Fig.

The largest connected component in the drug-target interaction network comprised 72 drugs, which is significantly larger (P < < 0.01) than what would be expected by chance; random sets of 83 drugs in the drug-drug network yield largest connected components with a median size of only 42 drugs (Fig.

83 significant drugs are represented in the drug-target network, and the largest connected component contains 72 drugs.

10,000 random draws of 83 drugs from the drug-target network resulted in smaller connected components (median size 42 drugs; P << 0.01 ).