Salmonella bacteria exploits host cell’s machinery to tether itself and replicate
02 Nov 2017
By Dr Mahak Sharma, Intermediate Fellow
Recently published research from our group shows that disease-causing bacteria, Salmonella enterica serovar typhimurium (hereafter Salmonella) ingeniously uses the mammalian cell’s (host) membrane transport machinery to attach itself and replicate, ensuring its survival inside the host cell.
Salmonella is a gram-negative facultative intracellular pathogen that causes gastroenteritis associated with intestinal inflammation and diarrhea in humans and a typhoid-like disease in mice. While the gastroenteritis is usually self-limiting, systemic infection of non-typhoidal S. enterica in immuno-compromised patients or in infants and aged population can result in a life-threatening outcome.
Mammalian cells have efficient transport machinery involving the organelles, endosomes and lysosomes that are responsible for transporting molecules (such as proteins, nutrients etc.) from the plasma membrane, sorting them and finally degrading/consuming them. Salmonella replicates inside host cells that have the capability of engulfing solid particles (phagocytosis) or in other cells without this property in a unique membrane-bound compartment known as the Salmonella-containing vacuole or SCV. To establish its replicative function, Salmonella redirects membranes and nutrients from the host cell’s recycling and sorting compartments to the SCV by establishing an interconnected network of tubules, also known as Salmonella-induced filaments (SIFs) forming a continuum with the SCVs. How Salmonella ensures a constant supply of endocytic cargo to the vacuole for its survival and replication remained unexplored.
Notably, Salmonella invasion into the host cell and its replication inside the SCV is facilitated by bacterial effector proteins translocated into the fluid portion (cytosol) of the host cell by its two secretion systems. Our recent work published in PLOS pathogens uncovers a strategy evolved by Salmonella wherein it secretes a bacterial effector protein known as SifA into the host cytosol that recruits component of host vesicle fusion machinery- HOPS complex to SCVs and SIFs. We found that Salmonella effector SifA in complex with its binding partner, SKIP, interacts with HOPS and mediates recruitment of this tethering factor to SCV compartments. HOPS complex promotes docking of the late endocytic compartments at the SCV membranes eventually leading to their fusion. Depletion of HOPS subunits both in cultured mammalian cell lines as well as in mouse model inhibits Salmonella replication, likely due to reduced access to host membranes and nutrients by the vacuolar bacteria.
Our findings suggest that Salmonella exploits the host’s endosomal and lysosomal membrane fusion machinery for access to host membrane and nutrients, ensuring its own intracellular survival and replication.
Aastha Sindhwani, Subhash B. Arya, Harmeet Kaur, Divya Jagga, Amit Tuli and Mahak Sharma. PLoS Pathogens 2017. October 2017
Image credit: Dr Mahak Sharma
Description: Salmonella enterica serovar typhimurium has the fascinating ability to form tubular structures known as Salmonella-induced filaments (SIFs). SIFs are formed by fusion of Salmonella-containing vacuole (SCV) with the late endocytic compartments of the host cell. Salmonella inhabits and replicates within the SCV, acquiring both membrane and nutrients from late endosomes and lysosomes. This image shows GFP-expressing Salmonella infected HeLa cells, fixed at 10 hr post infection. SIFs are recognized by immunostaining for the lysosomal marker- LAMP1 (pseudo colored in magenta).