Cell biology at the host–microbe interface

Manipulation of membrane dynamics Nihal Altan-Bonnet (National Institutes of Health) described positive-sense RNA enteroviruses that manipulate the host to generate phosphatidylinositol 4-phosphate (PI4P) and cholesterol-rich membrane platforms for efficient viral replication. The enzyme PI4KIIIβ is hijacked by the enteroviral protein 3A to generate new pools of PI4P at these membrane platforms and to recruit RNAdependent polymerases that are important for viral replication. Indeed, inhibition of PI4K activity led to decreased viral replication, which might provide an antiviral strategy for positive-strand RNA viruses. Altan-Bonnet also described how enteroviruses stimulate endocytic uptake of cholesterol, which is re-rerouted to Rab11-positive recycling endosomes that eventually fuse with viral replication organelles. Increased cholesterol levels may facilitate viral replication by decreasing the fluidity of replication organelle membranes. This reprogramming of membrane trafficking is not unique to viruses. Charles Larson (Heinzen Laboratory, Rocky Mountain National Labs) described the manipulation of endocytosis by a secreted protein from the bacterial pathogen Coxiella burnetti, the causative agent of Q fever. In infected cells, Coxiella resides in a vacuole that shares many of the features of classical lysosomes. For the pathogen to survive in this organelle, it delivers specific “effector” proteins, including Coxiella vacuolar protein A (CvpA), which Larson described as being essential for bacterial replication in mammalian cells. CvpA localizes to the pathogenic vacuole and interacts with adaptor complex 2 (AP2). Depletion of cellular AP2 or clathrin with small interfering RNA impaired Coxiella replication, suggesting regulation of AP2–clathrin membrane transport events contributes to pathogen growth. Xing Liu (Yao Laboratory, Morehouse) provided an example of a bacterial toxin that reprograms proton secretion in the stomach. Normally, gastric acid secretion involves translocation of proton pumps by ACAP4 and associated proteins to the apical membrane, so protons can be released into lumen of gastric glands. VacA from the bacterium Helicobacter pylori, a leading cause of gastric ulcers and cancers, inhibits the dephosphorylation of ACAP4, resulting in the translocation of ACAP4 and the proton pump to the basolateral membrane, and low acid secretion to the gastric lumen.