Amebae of Naegleria fowleri and Naegleria gruberi were cytopathic for nine established mammalian cell cultures, including mouse and human fibroblasts, rabbit and monkey kidney cells, rat and mouse neuroblastoma cells, baby hamster kidney cells, and human epithelioma and carcinoma cells. Nine strains of N. fowleri were equally cytopathic for rodent neuroblastoma cells. As few as one ameba per million neuroblastoma cells destroyed the mammalian target cells after 9 days. The N. fowleri grew and destroyed rat neuroblastoma cells at 30 to 37 C whereas N. gruberi grew and destroyed the target cells at 25 to 30 C. Both N. fowleri and N. gruberi attached efficiently to the target cells at 30 to 37 C; N. gruberi but not N. fowleri attached efficiently at 25 C. Electron microscopic observations of mixed cultures of N. fowleri and neuroblastoma cells established that the amebae, after 12 hr, had ingested portions of the neuroblastoma target cells without causing cell lysis. Conversely, N. gruberi amebae, after attaching to target cells, disrupted the plasma membrane and cytoplasm of the target cells although the target cell nucleus remained intact. The amebae then ingested the target cell debris.
MEP1A, which encodes the α subunit of meprin metalloproteinases, is a susceptibility gene for inflammatory bowel disease (IBD), and decreased intestinal meprin-α expression is associated with enhanced IBD in humans. Mice lacking meprin α (α knockout, αKO) have more severe colitis induced by dextran sulfate sodium (DSS) than wild-type (WT) mice, indicating an anti-inflammatory role for meprin A. Previous studies and those herein indicate the meprin B has proinflammatory activities. Therefore, mice lacking both meprin A and B (dKO mice) were generated to determine how their combined absence alters the inflammatory response to DSS. Unchallenged dKO mice grow and reproduce normally and have no obvious abnormal phenotype, except for a slightly elevated plasma albumin in both males and females and a lower urine creatinine level in dKO males. Upon oral administration of 3.5% DSS, the dKO mice have more severe colitis than the WT and βKO mice but significantly less than the αKO mice. The dKO mice lose more weight and have elevated MPO and IL-6 activities in the colon compared with WT mice. Systemic inflammation, monitored by plasma nitric oxide levels, is absent in DSS-treated dKO mice, unlike WT mice. The severity of experimental IBD in dKO mice is intermediate between αKO and WT mice. The data indicate that the absence of meprin A aggravates chronic inflammation and the lack of meprin B affords some protection from injury. Manipulation of the expression of meprin gene products may have therapeutic potential.
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