A new study published on “mBio” by researchers from the lab of Prof. Petr Broz, reveals how human guanylate-binding proteins (GBPs) mediate protection against Burkholderia infection.
Melioidosis is an infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei (B. pseudomallei). A hallmark of Burkholderia infections is the formation of so-called multinucleated giant cells (MNGCs) in the tissue of infected patients. MNGCs are formed when Burkholderia bacteria replicate and spread from cell to cell by actin-based motility and thereby fuse host cell membranes. In mouse infection model interferon (IFN)-induced non-canonical inflammasome activation mediates Burkholderia restriction, yet very little is known about the role of this cytokine and the inflammasome activation in human cells.
Dilucca et al. showed that in human epithelial cells infected with B. thailandensis, a bacterium closely related to B. pseudomallei and widely used as a laboratory model to study melioidosis, the interferon-induced host GTPase GBP1 (guanylate-binding protein 1) restricts B. thailandensis-induced MNGC formation. They demonstrate that GBP1 detect cytosolic Burkholderia, binds their surface and marks them for recognition by caspase-4. Once caspase-4 is recruited to cytosolic bacteria, it will bind LPS, activate and eliminate the infected cell by inducing pyroptotic cell death. These finding establish interferon-coordinate host defenses as a key defensive player against Burkholderia infections and could thus pave the way for new therapies against Melioidosis.
Figure: human GBP1 restricts MNGC formation by inducing the non-canonical inflammasome-dependent pyroptosis of infected cells.