Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

52Echoviruses are the main causative agents of aseptic meningitis worldwide and are particularly 53 devastating in the neonatal population, where they are associated with severe hepatitis, 54 neurological disease including meningitis and encephalitis, and even death. Here, we identify the 55 neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of 56 FcRn or its binding partner beta 2 microglubulin (b2M) renders human brain microvascular cells 57 resistant to infection by a panel of echoviruses at the stage of virus attachment and that a blocking 58 antibody to b2M inhibit echovirus infection in cell lines and in primary human fetal intestinal 59 epithelial cells. We also show that expression of human, but not mouse, FcRn renders non-60 permissive human and mouse cells sensitive to echovirus infection and that the extracellular 61 domain of human FcRn directly binds echoviral particles and neutralizes infection. Lastly, we 62 show that primary cells isolated from mice that express human FcRn are highly susceptible to 63 echovirus infection. Our findings thus identify FcRn as a pan-echovirus receptor, which may 64 explain the enhanced susceptibility of neonates to echovirus infections. 65 66 Significance 67 68 Echoviruses are associated with aseptic meningitis and induce severe disease, and even death, 69 in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-70 echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life 71 in intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the 72 blood-brain barrier. This pattern of expression is consistent with the organ sites targeted by 73 echoviruses in humans, with the primary entry site of infection in the intestinal tract and 74

Background: NF-B is an important signaling molecule in the development of acute pancreatitis. Results: Adeno-associated virus-NF-B-luciferase-infused mice showed a 77-and 140-fold increase in pancreas-specific NF-B bioluminescence following caerulein and caerulein ϩ LPS pancreatitis, respectively. Conclusion: NF-B activation can be examined in a live, dynamic fashion during pancreatic inflammation. Significance: This technique offers a valuable tool to study real-time activation of NF-B in vivo.

Objectives The most common etiology for acute pancreatitis results from the impaction of gallstones or sludge in the distal common bile duct (CBD). The result is pancreatic duct obstruction, diversion of bile into the pancreas, or cholestasis. In the current study, we examined whether combining both aspects, that is, infusion of the bile acid taurocholate (TC) followed by bile duct ligation (BDL), could yield a more severe form of pancreatitis that mimics biliary pancreatitis. Methods In mice, following laparotomy, the CBD was infused with either normal saline (NS) or TC. Subsequently, the CBD was ligated at the ampulla. Results Mice receiving TC infusion followed by BDL (TC+BDL) had higher mortality compared to animals receiving intra-ductal NS with BDL (NS+BDL). The TC+BDL arm developed more severe and diffuse pancreatic necrosis. In addition, serum amylase, IL-6, and bilirubin, were significantly higher. However, pancreatic edema as well as lung and liver injury were unchanged between TC+BDL and NS+BDL. Conclusions In summary, the combination of bile infusion into the pancreas followed by BDL causes a more severe, necrotizing pancreatitis. We believe this novel model of pancreatitis is useful because it can be employed in transgenic mice and recapitulates several aspects of biliary pancreatitis.

Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.