Abstract
Brucella melitensis is a facultative intracellular bacterium that causes brucellosis, the most prevalent zoonosis worldwide. The Brucella intracellular replicative niche in macrophages and dendritic cells thwarts immune surveillance and complicates both therapy and vaccine development. Currently, host-pathogen interactions supporting Brucella replication are poorly understood. Brucella fuses with the endoplasmic reticulum (ER) to replicate, resulting in dramatic restructuring of the ER. This ER disruption raises the possibility that Brucella provokes an ER stress response called the Unfolded Protein Response (UPR). In this study, B. melitensis infection up regulated expression of the UPR target genes BiP, CHOP, and ERdj4, and induced XBP1 mRNA splicing in murine macrophages. These data implicate activation of all 3 major signaling pathways of the UPR. Consistent with previous reports, XBP1 mRNA splicing was largely MyD88-dependent. However, up regulation of CHOP, and ERdj4 was completely MyD88 independent. Heat killed Brucella stimulated significantly less BiP, CHOP, and ERdj4 expression, but induced XBP1 splicing. Although a Brucella VirB mutant showed relatively intact UPR induction, a TcpB mutant had significantly compromised BiP, CHOP and ERdj4 expression. Purified TcpB, a protein recently identified to modulate microtubules in a manner similar to paclitaxel, also induced UPR target gene expression and resulted in dramatic restructuring of the ER. In contrast, infection with the TcpB mutant resulted in much less ER structural disruption. Finally, tauroursodeoxycholic acid, a pharmacologic chaperone that ameliorates the UPR, significantly impaired Brucella replication in macrophages. Together, these results suggest Brucella induces a UPR, via TcpB and potentially other factors, that enables its intracellular replication. Thus, the UPR may provide a novel therapeutic target for the treatment of brucellosis. These results also have implications for other intracellular bacteria that rely on host physiologic stress responses for replication.
Highlights
Brucellosis is a chronic debilitating disease with protean manifestations and insidious onset most frequently caused by the facultative intracellular bacteria Brucella melitensis [1]
We found that infection of macrophages with Brucella induces a host stress response called the Unfolded Protein Response (UPR), a conserved stress response originating in the endoplasmic reticulum (ER)
Inhibition of the UPR with the drug tauroursodeoxycholic acid significantly diminished Brucella replication. Together these results suggest Brucella induces the UPR to enable its own replication within host macrophages
Summary
Brucellosis is a chronic debilitating disease with protean manifestations and insidious onset most frequently caused by the facultative intracellular bacteria Brucella melitensis [1]. With over 500,000 new infections per year, brucellosis is the most prevalent zoonosis worldwide [2]. Brucellosis is most often acquired by consumption of contaminated dairy products. Brucella infects macrophages and dendritic cells that constitute the replicative reservoir [3]. The intracellular replicative niche thwarts immune surveillance, complicates vaccine development, and renders the organism refractory to antibiotics [1]. A greater understanding of host-pathogen interactions is critical for elucidating disease pathogenesis and improving therapeutic strategies
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