An In silico analysis to study the molecular host-microbe in Brucella melitensis infection: inhibition of immune responses by inactivation of GSK۳β

BACKGROUND AND OBJECTIVESBrucellosis is the most common zoonotic disease worldwide. The Gram-negative coccobacillus, Brucella melitensis, is identified often as the leading cause of this disease. Treating and preventing brucellosis is challenging because microorganism can induce host cells to provide a favorable environment for proliferation and survival. It destroys the host's immune system, leading to persistent chronic infection. Host-microbe protein interactions play an important role in various diseases. This interaction can alter the host signaling, metabolic, and cellular processes. Recently, the computational bioinformatics analyses have dramatically advanced our understanding of the host-microbe protein interactions. In this study, we used several bioinformatics tools to evaluate the host-bacteria protein interactions, helping us for better understanding the molecular mechanism of B. melitensis pathogenesis.MATERIALS AND METHODSThe ImitateDB database was used to identify bacterial motifs that interact with human proteins. The B. melitensis biotype ۱ (strain ۱۶M / ATCC ۲۳۴۵۶) was selected and proteins interacting with human cells were recognized. Then, host interactor protein IDs were extracted. These codes were converted into gene symbols through BioDBnet database, and then their function was determined using String and EnrichR database.RESULTS AND DISCUSSIONThe ImitateDB database showed that B. melitensis protein, Winged helix-turn-helix domain-containing protein, with an unknown function, mainly interacts with MYD۸۸ (Myeloid differentiation primary response ۸۸) protein. In contrast, this bacterial protein and TcpB (probable ۲' cyclic ADP-D-ribose synthase TcpB) bind to the human TIRAP (TIR domain containing adaptor protein) protein. As presented in Figure ۱, MYD۸۸ and TIRAP proteins are also related to ۲۸ human proteins through different motifs. Functional analysis by EnrichR revealed that all these human proteins are significantly involved in Toll-like receptor recognition, NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) signaling, and inactivation of GSK۳β (Glycogen synthase kinase-۳ beta) by Akt (Protein kinase B), causing accumulation of β-catenin in alveolar macrophages (Figure ۲). Since the activated GSK۳β promotes the activation of NF-κB, leading to a proinflammatory response, it seems Brucella inhibits immune signal transduction by inhibiting the GSK۳β (۲).CONCLUSIONBioinformatics approaches can be used for understanding of the molecular mechanisms of Brucella pathogenesis and host protective immunity against Brucella infections, and to facilitate vaccine design and development.

Keywords:

Brucella melitensis , Bioinformatics analysis , protein-protein interaction , molecular mechanism