Ongoing research provides further understanding of the biology of RNase A ribonucleases that promote innate immunity (the eosinophil RNase 2 and RNase 3, tissue RNases 7 and 8, and leukocyte RNase A-2) with efforts focused toward understanding their mechanisms of action in health and disease. We report on two studies: The first report details progress on our study focused on eosinophil ribonucleases and their interactions with respiratory virus pathogens in vivo. As noted above, the first indication that eosinophil ribonucleases might function to promote antiviral host defense came from a series of studies we performed with the human pathogen, respiratory syncytial virus (RSV). Specifically, we determined that eosinophils, acting in part via their secreted ribonucleases, RNase 2 (EDN) and RNase 3 (ECP), could reduce the infectivity of RSV for target epithelial cells in culture (Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF. 1998. Recombinant human eosinophil-derived neurotoxin / RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis 177: 1458-1464.) We have recently documented accelerated clearance of the highly pathogenic mouse pneumovirus pathogen, pneumonia virus of mice (PVM), from the lungs of infected eotaxin-2 / IL-5 double-transgenic (hE2/IL5tg) mice, a unique mouse model featuring eosinophils that undergo profound and extensive degranulation and release of mouse eosinophils ribonucleases. Virus recovery from lung tissue of hE2IL5tg mice is reduced dramatically -- nearly one-thousand fold -- when compared to those from infected wild-type, hE2 single tg, or IL5 single tg mice;RNase activity in bronchoalveolar fluid correlates inversely with virus recovery in these individual mouse strains. Experiments underway with RNase inhibitors will address the specific relationship between ribonuclease activity and virus recovery from lung tissue of PVM-infected mice;examination of additional pathogens and mechanism of action will follow. We also report progress on our study on human RNase 8. RNase 8 has sequence similar to, and is likely a recent duplication from the lysine-enriched, antimicrobial RNase 7, but RNase 8 has no clear function nor has its gene product been identified. We isolated transcripts encoding RNase 8 via rapid amplification of cDNA ends (RACE) and RT-PCR and thereby elucidated the full open reading frame, which includes a distal start methionine and an additional 30 amino acids preceding what had been previously identified as a hydrophobic signal sequence. This newly-identified amino terminal sequence is hydrophilic, and is conserved in the genomes of several higher primates. Given these observations, taken together with our recent appreciation of the RNase A ribonuclease genes as scaffolds for evolutionary change (Nitto T, Dyer KD, Czapiga M, Rosenberg HF. 2006. Evolution and function of leukocyte RNase A ribonucleases of the avian species, Gallus gallus. J Biol Chem. 281:25622-25634), it is apparent that we need to consider the possibility that RNase 8 may be something other than a standard secretory ribonuclease, perhaps only partially related to its original role. Studies in progress consider the possibility that RNase 8 has evolved into a transmembrane protein that senses and signals in response to polymeric RNA.

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Rosenberg, Helene F; Druey, Kirk M (2018) Modeling asthma: Pitfalls, promises, and the road ahead. J Leukoc Biol 104:41-48
Ma, M; Redes, J L; Percopo, C M et al. (2018) Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza virus infection. Clin Exp Allergy 48:691-702
Foster, Paul S; Maltby, Steven; Rosenberg, Helene F et al. (2017) Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma. Immunol Rev 278:20-40
Percopo, Caroline M; Brenner, Todd A; Ma, Michelle et al. (2017) SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice. J Leukoc Biol 101:321-328
Kraemer, Laura S; Brenner, Todd A; Krumholz, Julia O et al. (2017) A flow-cytometric method to evaluate eosinophil-mediated uptake of probiotic Lactobacillus reuteri. J Microbiol Methods 137:19-24
Rosenberg, Helene F; Druey, Kirk M (2016) Eosinophils, galectins, and a reason to breathe. Proc Natl Acad Sci U S A 113:9139-41
Rosenberg, Helene F (2015) Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense. Int J Mol Sci 16:15442-55
Yamada, Kelsey J; Barker, Tolga; Dyer, Kimberly D et al. (2015) Eosinophil-associated ribonuclease 11 is a macrophage chemoattractant. J Biol Chem 290:8863-75
Percopo, Caroline M; Dyer, Kimberly D; Ochkur, Sergei I et al. (2014) Activated mouse eosinophils protect against lethal respiratory virus infection. Blood 123:743-52
Yang, Ming; Eyers, Fiona; Xiang, Yang et al. (2014) Expression profiling of differentiating eosinophils in bone marrow cultures predicts functional links between microRNAs and their target mRNAs. PLoS One 9:e97537

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