Angiography Alone Versus Angiography Plus Optical Coherence Tomography to Guide Percutaneous Coronary Intervention: Outcomes From the Pan-London PCI Cohort

Objectives

This study aimed to determine the effect on long-term survival of using optical coherence tomography (OCT) during percutaneous coronary intervention (PCI).

SIK2 orchestrates actin-dependent host response upon Salmonella infection

Salmonella is an intracellular pathogen of a substantial global health concern. In order to identify key players involved in Salmonella infection, we performed a global host phosphoproteome analysis subsequent to bacterial infection. Thereby, we identified the kinase SIK2 as a central component of the host defense machinery upon Salmonella infection. SIK2 depletion favors the escape of bacteria from the Salmonella-containing vacuole (SCV) and impairs Xenophagy, resulting in a hyperproliferative phenotype. Mechanistically, SIK2 associates with actin filaments under basal conditions; however, during bacterial infection, SIK2 is recruited to the SCV together with the elements of the actin polymerization machinery (Arp2/3 complex and Formins). Notably, SIK2 depletion results in a severe pathological cellular actin nucleation and polymerization defect upon Salmonella infection. We propose that SIK2 controls the formation of a protective SCV actin shield shortly after invasion and orchestrates the actin cytoskeleton architecture in its entirety to control an acute Salmonella infection after bacterial invasion.

Salmonella enterica is a gram-negative, facultative intracellular human pathogen, annually causing more than 100 million food- and waterborne infections worldwide. Salmonella Typhimurium causes severe gastroenteritis, which could turn into a systemic infection in children, immune-compromised, or elderly people (1, 2). Concurrently, multidrug resistant bacteria are globally emerging and threatening our health systems, calling for a better understanding of the underlying virulence mechanism and host response.Pathogenic bacteria have evolved the inherent ability to infect and to establish their niche within host cells. For colonizing nonphagocytic cells such as epithelial cells, Salmonella uses a trigger mechanism–based entry mode. Bacterial virulence factors are then injected via a Type III-secretion system (T3SS) into the host cell to induce cytoskeletal rearrangements leading to membrane ruffling and macropinocytosis-driven internalization into a sealed phagosome (3, 4). This specialized compartment is referred to as the Salmonella-containing vacuole (SCV) and serves as the intracellular replicative niche by hiding the bacteria from the humoral and cell-autonomous immune response (5). Salmonella invasion requires a cooperative action of several bacterial effector proteins hijacking multiple host targets. One of the main targets forcing Salmonella´s uptake is the actin cytoskeleton by subverting the host Rho GTPases system. Bacterial effector proteins such as SopE/SopE2 mimic host nucleotide exchange factors (GEFs) to stimulate Rac1 and CDC42 activity (6, 7). Once GTP-activated, Rho GTPases stimulate downstream pathways to drive actin filament (F-actin) assembly and rearrangement.The actin cytoskeleton network is regulated by actin-binding proteins (ABPs), which orchestrate assembly and disassembly of actin in higher networks (8). Monomeric, globular actin (G-actin) is nucleated into new actin filaments, or the existing F-actin is elongated, stabilized, or disassembled by ABPs. The major actin nucleation factor is the multimeric Arp2/3 complex, which generates branched actin filament networks. Formins generate long unbranched actin filaments and represent another actin nucleation family. Together with actin nucleation-promoting factors, small Rho GTPases control ABPs in a spatiotemporal manner. Actin polymerization and membrane ruffling are necessary for Salmonella invasion. Following Salmonella internalization, the SCV undergoes SPI-1–dependent biogenesis and is transported to a juxtanuclear position at 1 to 2 h postinfection (pi). At later time-points (4 to 6 h pi), SPI-2–dependent effector proteins are expressed to further mature the SCV, allowing bacterial proliferation. Pioneering work described that, at later stages of the infection (≥6 h pi), an actin meshwork around the SCV stabilizes and protects the vacuolar niche (9–13).Here, we report SIK2 as a Salmonella resistance factor and a regulator of the actin cytoskeleton. SIK2 belongs to the AMPK kinase family and was named after its homolog SIK1, found to be expressed upon high-salt diet-induced stress in rats (14, 15). SIK2 has been implicated into multiple biological roles including melanogenesis, cancer progression, and gluconeogenesis (16–18). SIK2 depletion results in a loss of SCV integrity and bacterial escape into the host cytosol, causing intracellular Salmonella hyperproliferation. Notably, SIK2 depletion results in a severe pathological cellular actin nucleation and polymerization defect upon Salmonella infection. Hence, SIK2 may represent a cellular safeguard, which controls the actin cytoskeleton and SCV integrity, thereby serving as a prime regulator of Salmonella proliferation subsequent to cellular internalization.