Prediction of Host-Pathogen Interactions for Helicobacter pylori by Interface Mimicry and Implications to Gastric Cancer

Abstract

There is a strong correlation between some pathogens and certain cancer types. One example is Helicobacter pylori and gastric cancer. Exactly how they contribute to host tumorigenesis is, however, a mystery. Pathogens often interact with the host through proteins. To subvert defense, they may mimic host proteins at the sequence, structure, motif, or interface levels. Interface similarity permits pathogen proteins to compete with those of the host for a target protein and thereby alter the host signaling. Detection of host-pathogen interactions (HPIs) and mapping the re-wired superorganism HPI network-with structural details-can provide unprecedented clues to the underlying mechanisms and help therapeutics. Here, we describe the first computational approach exploiting solely interface mimicry to model potential HPIs. Interface mimicry can identify more HPIs than sequence or complete structural similarity since it appears more common than the other mimicry types. We illustrate the usefulness of this concept by modeling HPIs of H. pylori to understand how they modulate host immunity, persist lifelong, and contribute to tumorigenesis. H. pylori proteins interfere with multiple host pathways as they target several host hub proteins. Our results help illuminate the structural basis of resistance to apoptosis, immune evasion, and loss of cell junctions seen in H. pylori-infected host cells.

Keywords: computational prediction of host–pathogen interactions; interface mimicry; protein–protein interaction; structural network; superorganism network.

Fig. 1.

Workflow of our interface-based HPI modeling/prediction approach. We first extract human interfaces from the PDB. Then, we obtain the structures of the H. pylori proteins from the PDB. For docking, we need two target proteins. However, for a given pathogenic protein, we do not know the potential partner proteins in the human. Before docking, we need to identify the potential partners. To do so, we structurally align the pathogenic proteins with all human interfaces. If the pathogenic protein is aligned with the B-face of the interface, it can interact with the complementary A-face. Now, that we have potential partners of the pathogenic protein, we can perform docking for these pairs with PRISM [–48] and Rosetta (local refinement) [–51]. We employ these docking methods to select the energetically favorable HPIs, since structural complementarity may not necessarily confer electrochemical complementarity. Finally, we filter our energetically favorable HPI results according to tissue expression of the human proteins, checking whether the human partners of these pathogenic proteins are expressed in the same tissue where the pathogen is found. We further evaluate the HPI models based on the percent match of the interface residues with the template interface and probability of the template interface being a real biological interface.

Fig. 2.

H. pylori proteins mimic the interfaces between cytokines and their receptors. Thus, they may block the cytokine signaling, which may prevent T-cell recruitment to infected tissue and lifelong persistent infection. (a) Endogenous human PPI between INAR1 and IFNA2. (b) Our HPI model between INAR1 and gGT. (c) Superimposed view of PPI and HPI shows that gGT almost perfectly mimics the interface on IFNA2 to bind to INAR1. Panels d and e also show the superimposed structures of endogenous human PPIs and modeled HPIs. Cyan and pink proteins are human cytokines and cytokine receptors, respectively. Gray proteins are H. pylori proteins. Gray proteins bind to pink proteins by hijacking the interface on cyan proteins (only the interface is similar, not the global structure). Thus, they may block the pink–cyan protein interactions.

Fig. 3.

H. pylori proteins targeting the cell-cycle regulators (a and b), apoptosis regulators (c), estrogen receptors (d and e), Ras and Rho GTPase family members (f, g, h, and i), and glutathione metabolism (j and k). Figures show the superimposed structures of endogenous human PPIs and modeled HPIs. Pink and cyan proteins are human and gray ones are H. pylori proteins. Gray proteins bind to pink proteins by hijacking the interface on cyan proteins (only the interface is similar, not the global structure). Thus, they may block the pink–cyan protein interactions.

Fig. 4.

H. pylori proteins mimic not only host interactions, but also HPIs (a, b, and c). Our interface-based approach uncovered a known HPI for CagA (d). It is known that CagA interacts with ZO1, but their complex structure is not available. Figures show the superimposed structures of our HPI models for H. pylori with the known exogenous or endogenous human PPIs. Pink and cyan proteins are from human, greens are proteins from bacteria or virus, and gray proteins are H. pylori proteins. Gray proteins bind to pink proteins by hijacking the interfaces on green and cyan proteins (only the interface is similar, not the global structure).

Fig. 5.

MD results for four HPI models and their corresponding template PPIs. The first figure in each panel shows the initial conformation of the HPI/PPI, and the second figure shows the conformation after 100-ns simulation. The last figure shows the RMSD values with respect to the initial structures.

Fig. 6.

Structural inter-species interaction network for H. pylori. All pairwise interactions have structures as complexes. Endogenous human interactions (black edges) are obtained from crystal structures (our template interface set), where human proteins are shown as gray circular nodes. Exogenous interactions (red edges) are our HPI models for 10 H. pylori proteins and are shown as red edges. (a) H. pylori proteins (blue diamond-shaped nodes) target the highly connected part (hair-ball) of the human PPI. (b) Structural HPI network without the endogenous human interactions. Most of the targets of individual H. pylori proteins are distinct, but some are shared across different H. pylori proteins. Thus, multiple H. pylori proteins target the same pathway.

Fig. 7.

Structural interspecies network with all available HPI data for several bacterial, viral, and yeast species, and PPI data in PDB. (a) Combined HPIs and PPIs that are available in PDB. All endogenous (black edges) and exogenous interactions (red edges) have structures as complexes in PDB. There are 299 HPIs with proteins from bacterial, viral, and yeast species and 3366 endogenous interactions. Unlike our H. pylori HPI models, proteins from other bacterial, viral, and yeast species target both highly connected and less-connected part of the network. (b) All HPIs available in PDB. Some pathogenic proteins target the same host protein, whereas others have distinct targets. Some human proteins, such as 1A02, UBC, 2B11, and DRA, are hubs that are targeted by several non-human proteins.