NAD depletion as pathogen response: One way that plants respond to pathogen infection is by sacrificing the infected cells. The nucleotide-binding leucine-rich repeat immune receptors responsible for this hypersensitive response carry Toll/interleukin-1 receptor (TIR) domains. In two papers, Horsefield et al. and Wan et al. report that these TIR domains cleave the metabolic cofactor nicotinamide adenine dinucleotide (NAD ⁺ ) as part of their cell-death signaling in response to pathogens. Similar signaling links mammalian TIR-containing proteins to NAD ⁺ depletion during Wallerian degeneration of neurons. Science , this issue p. 793 , p. 799

Rapid shifts in microbial composition frequently occur during intestinal inflammation, but the mechanisms underlying such changes remain elusive. Here we demonstrate that an increased caecal sialidase activity is critical in conferring a growth advantage for some bacteria includingEscherichia coli (E. coli)during intestinal inflammation in mice. This sialidase activity originates among others fromBacteroides vulgatus, whose intestinal levels expand after dextran sulphate sodium administration. Increased sialidase activity mediates the release of sialic acid from intestinal tissue, which promotes the outgrowth ofE. coliduring inflammation. The outburst ofE. colilikely exacerbates the inflammatory response by stimulating the production of pro-inflammatory cytokines by intestinal dendritic cells. Oral administration of a sialidase inhibitor and low levels of intestinal α2,3-linked sialic acid decreaseE. colioutgrowth and the severity of colitis in mice. Regulation of sialic acid catabolism opens new perspectives for the treatment of intestinal inflammation as manifested byE. colidysbiosis.

Oseltamivir (Tamiflu) and zanamivir (Relenza), two extensively used clinically effective anti-influenza drugs, are viral sialidase (also known as neuraminidase) inhibitors that prevent the release of progeny virions and thereby limit the spread of infection. Recently mortalities and neuropsychiatric events have been reported with the use of oseltamivir, especially in pediatric cases in Japan, suggesting that these drugs might also inhibit endogenous enzymes involved in sialic acid metabolism, including sialidase, sialyltransferase, and CMP-synthase, in addition to their inhibitory effects on the viral sialidase. The possible inhibition could account for some of the rare side effects of oseltamivir. However, there has been little direct evidence in regard to the sensitivities of animal sialidases to these drugs. Here, we examined whether these inhibitors might indeed affect the activities of human sialidases, which differ in primary structures and enzyme properties but possess tertiary structures similar to those of the viral enzymes. Using recombinant enzymes corresponding to the four human sialidases identified so far, we found that oseltamivir carboxylate scarcely affected the activities of any of the sialidases, even at 1 mM, while zanamivir significantly inhibited the human sialidases NEU3 and NEU2 in the micromolar range ( K _i , 3.7 ± 0.48 and 12.9 ± 0.07 μM, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases.