Nd 2Institute of Microbiology, Division of Biology, ETH Z ich, CH-8092 Z ich, SwitzerlandAren’t bugs a supply of continuous amazement Consider, by way of example, how cunningly bacteria conspire to shanghai the molecular machines of their mammalian hosts for their very own goals. Apart from serving the bugs, this evil intelligence is exploitable for studying cellular physiology, and the bewildering affinity of bacterial toxins for vital host cell proteins has taught us a lot of a issue on how cells operate. Perhaps Brucella may possibly assist teach us the function with the normal prion protein (1). Brucella species are Gram-negative facultative intracellular pathogens. They invade, resist intracellular killing, and replicate in phagocytic and nonphagocytic cells (two). But how does Brucella initiate replication in macrophages The speak to with the bug instructs the macrophage to internalize it; the mode of internalization (Fc and complement receptors vs. uptake of nonopsonized bugs) determines the fate in the bug (2). Brucella actively modulates its personal engulfment. It induces peculiar membrane ruffles at its web-site of make contact with with all the macrophage and slow “swimming internalization” into a macropinosome. Then, Brucella requires full control in the macropinosome. It inhibits its maturation into a degradative lysosome (3) and reprograms it to obtain endoplasmic reticulum markers and mature into a “replicative phagosome” where bacteria start off multiplying (Fig. 1; reference two). For playing these tricks, Brucella relies on a set of virulence components, which includes a bacterial injection organelle termed VirB or type IV secretion program (4). When exposed to macrophages in vitro, virB-deficient bugs PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20161343 can not modulate phagocytosis and are degraded inside the lysosome. But what does the VirB program specifically do within this context In line with Watarai et al. (1), it might be needed for transporting the bacterial heat shock protein Hsp60 onto the surface with the bug. Unexpectedly, the chaperonin Hsp60, which commonly hangs out within the cytoplasm and deals with unfolded proteins (9), turns out to reside around the surface of wild-type Brucella abortus but not virB mutants.Address correspondence to Adriano Aguzzi, Institute of Neuropathology, Department of Pathology, University Hospital of Z ich, Schmelzbergstr. 12, CH-8091 Z ich, Switzerland. Phone: 41-1-255-2869; Fax: 41-1255-4402; E-mail: [email protected] the macrophage surface, Brucella attaches to cholesterol-rich microdomains referred to as lipid “rafts” (102). There, Hsp60 appears to snatch at an unlikely pal, the cellular prion protein (PrPC), that is encoded by the Prnp gene and resides preferentially in rafts. PrPC is apparently recruited towards the macrophage’s membrane protrusions, which engulf the bacteria, and subsequently for the early macropinosome. In Prnpo/o macrophages, B. abortus will not modulate phagocytosis nor phagosome maturation. This can be strikingly equivalent for the behavior of Brucella virB mutants and suggests that the Hsp60 rPC interaction is instrumental for these actions. The latter presumption is backed up by animal research. Wild-type Brucella replicates in wild-type mice, whereas virB mutants do not (13). In Watarai’s (1) experiments, each wild-type and VirB-deficient bugs are avirulent in PrPC-deficient mice. Hence, the Hsp60 rPC connection is essential in genuine infections (Fig. 1). So, what can Brucella teach us about PrPC The prion may be the infectious agent causing transmissible spongiform Cucurbitacin I site encephalopathies (14). Its only recognized const.
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