Fig 1.
Distinct microbial compositions may lead to different outcomes (hypothetical scenario).
Combinatorial effects of microbial effectors and the active host pathways determine the cell response. (a) Composition1 has certain microorganisms that secrete effector protein combination1. These effectors activate pathway1 in the host, which produces pro-inflammatory cytokines. (b) Composition2 secretes effector combination2 and activates pathway2 in addition to pathway1. Additive effects of these two pathways amplifies the signal and promotes inflammation (cross-activation). (c) Microbial composition3 utilize effector combination3 to activate both pathway 1 and 3, which have opposing outcomes. Subtractive effects of these pathways result in no inflammation (cross-inhibition).
Fig 2.
Endogenous (intra-species) and exogenous (inter-species) interface mimicry.
(a) A, B, C, D are host proteins and P is pathogenic protein. Protein A has two interfaces: through blue interface it binds to B and through grey interface it binds to C and D. C and D proteins employ similar interfaces to bind to A. So, endogenous interfaces mimic each other. Pathogenic protein P has similar interface as B and competes to bind to the blue interface on A. In this case, an exogenous interface mimics an endogenous interface. (b) The F1L protein of variola virus interacts with human BID protein (5ajj:AB.pdb) and inhibits apoptosis in the host cell by hijacking the interface between human BID-BCLXL (4qve:AB.pdb): an exogenous interface mimicking an endogenous one. Human MCL1 protein binds to human BID (5c3f:AB.pdb) in a very similar fashion that BCLXL does: endogenous interfaces mimicking each other.
Fig 3.
Subversion of TLR pathway by various bacterial and viral proteins at several steps.
This is a simplified representation of TLR pathway where the orange nodes are the host proteins and red nodes are the microbial proteins.
Fig 4.
(a) High-resolution metaorganism network where grey nodes represent host proteins, red nodes microbial proteins, black edges host PPIs, and red edges HMIs. If an exogenous interface–HMI–(red edges) overlaps endogenous ones, it can abolish the endogenous PPI. If the exogenous and endogenous interfaces do not overlap, then the HMI does not disrupt the endogenous PPI. Without 3D structure knowledge of PPIs and HMIs, we cannot infer whether the interfaces overlap or not. (b) Zoom-in views of blue boxes show whether the interfaces overlap. (c) 3D representations of the interactions shown in part (b). Above diagram shows the superimposed view of 4mi8:AC and 2p1l:AB where Gamma Herpesvirus vBcl2 (red) and human Bcl-XL (green) binds to the same site on human Beclin-1 (grey). Here, an exogenous interface mimics an endogenous interface. Below diagram shows the superimposed view of 1f5q:AB and 1buh:AB, where Gama Herpesvirus Cyclin (red) and human CKS1 (green) bind to distinct interfaces on human CDK2 (grey).