Abstract
Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15-depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation.
Highlights
IntroductionA poorly understood component of the cytoskeleton, are highly-conserved guanosine triphosphate (GTP) binding proteins organized into 4 groups based on sequence homology (the SEPT2, SEPT3, SEPT6, and SEPT7 groups)
Septins, a poorly understood component of the cytoskeleton, are highly-conserved guanosine triphosphate (GTP) binding proteins organized into 4 groups based on sequence homology
We show that zebrafish septins can restrict inflammation and Shigella infection in vivo
Summary
A poorly understood component of the cytoskeleton, are highly-conserved guanosine triphosphate (GTP) binding proteins organized into 4 groups based on sequence homology (the SEPT2, SEPT3, SEPT6, and SEPT7 groups). Studies using human epithelial cells have revealed important roles for septins in cell-autonomous immunity, showing that septins assemble into cage-like structures to prevent the dissemination of cytosolic bacteria polymerizing actin tails [3,4,5]. New work has shown that components of the cytoskeleton play important roles in innate immunity and are required for inflammation control [5]. A separate study showed that actin depolymerization, as a consequence of mutations in WD repeat-containing protein (WDR1), can trigger disease by activation of the pyrin inflammasome [13, 14]. Other components of the cytoskeleton, including microtubules and the intermediate filament protein vimentin, promote NLRP3 activity by helping to recruit ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain) and stabilize NLRP3 inflammasomes, respectively [15, 16]. The role of the septin cytoskeleton in inflammation control has not yet been tested
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