science pharmaceutical expo biotech jobs

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rosenberg, H. F.
Right arrow Articles by Domachowske, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rosenberg, H. F.
Right arrow Articles by Domachowske, J. B.
(Journal of Leukocyte Biology. 2001;70:691-698.)
© 2001 by Society for Leukocyte Biology

Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens

Helene F. Rosenberg* and Joseph B. Domachowske{dagger}

* Eosinophil Biology Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
{dagger} Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York

Correspondence: Helene F. Rosenberg, M.D., EBU, Laboratory of Host Defenses, Building 10, Room 11N104, NIAID, NIH, Bethesda, Maryland 20892. E-mail: hr2k{at}nih.gov


arrow
ABSTRACT
 
Eosinophils remain among the most enigmatic of cells, as our appreciation of their detrimental activities—e.g., asthma and allergic disease—far outweighs our understanding of their beneficial effects. Among the major secretory effector proteins of eosinophils are the ribonucleases eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in primates and their orthologs, the eosinophil-associated ribonucleases (EARs) in rodents. The rapid diversification observed among these ribonucleases suggested that the ultimate target(s) might be similarly efficient at generating sequence diversity while maintaining an unalterable susceptibility to ribonucleolytic cleavage. This has prompted us to consider a role for these proteins and by extension, for eosinophils, in host defense against single-stranded RNA virus pathogens. We detail our studies of the antiviral activity of eosinophils and eosinophil ribonucleases against respiratory syncytial virus (RSV) in vitro and the related, natural rodent pathogen, pneumonia virus of mice (PVM), in vivo, and consider the possibility that antiviral host defense and the dysregulated responses leading to asthma represent opposing sides of an eosinophil-mediated double-edged sword.

Key Words: pneumonia virus of mice • major basic protein


arrow
EOSINOPHILS MISUNDERSTOOD
 
The eosinophilic leukocyte certainly ranks highly among the most misunderstood of all cells in mammalian physiology. Although we have a reasonably clear understanding of the signals and signaling cascades that result in eosinophil differentiation, recruitment to and activation in peripheral blood and tissues [1 2 3 4 ], the beneficial endpoints of these events to this day remain unclear. The recent reconsideration of the role of eosinophils as host defense against parasitic helminths is a case in point. Although no one disputes the actual presence of eosinophils in large number in peripheral blood and in affected tissues, the role of eosinophils as protective elements of this response has become the subject of great controversy. Several groups have demonstrated that eosinophil-deficient (antibody-treated, gene-deleted) mice clear parasites no less effectively than their eosinophil-sufficient counterparts, and others present contradictory results (reviewed in refs 5 6 ). At current writing, there is no consensus as to whether eosinophils actually serve a protective function against helminth infection in vivo.

The role of eosinophils in the pathophysiology of allergic respiratory disease and asthma is a different example of the way in which eosinophils are misunderstood. Eosinophils are clearly recruited to and activated in lung tissue as part of the pathophysiology of these conditions, and most available evidence indicates that they contribute to the characteristic bronchospasm and tissue destruction [7 8 9 ]. However, this is clearly a detrimental feature of eosinophils, and even the most rudimentary understanding of evolution and biology leads to the incontrovertible conclusion that the ability to induce severe pathology cannot possibly be a "raison d’être" for any existing cell type or function.

Lastly, we have no provocative "experiments of nature"—i.e, examples of unique eosinophil-deficiency states that might elucidate the beneficial role(s) of these cells by their defective functioning or absence. Among the few potentially relevant examples are eosinophil peroxidase (EPO) deficiency [10 ], a condition for which no physiologic sequelae have been described, and specific granule deficiency, a rare transcription-factor deficiency that results in derailed differentiation of multiple leukocyte lineages including eosinophils, which is not surprisingly associated with a broad spectrum of host-defense defects [11 , 12 ].


arrow
EOSINOPHILS AND EOSINOPHIL RIBONUCLEASES
 
Light and electron microscopic views of human eosinophilic leukocytes are shown in Figure 1 , with the hallmark bilobed nucleus and large cytoplasmic or specific granules marked as indicated. The granules are the storage sites for numerous mediators (reviewed in [13 ]), including the four major cationic granule proteins: EPO, major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN). The biology of these proteins and their role in disease were reviewed recently by Walsh [14 ] and thus will not be discussed in depth here. In 1963, Archer and Hirsch [15 ] demonstrated the association of ribonuclease activity with the specific granule fraction. More than 20 years later, Gleich and colleagues [16 ] noted the marked similarity of the amino termini of two of these granule proteins, ECP and EDN, to the amino terminus of a bovine protein, pancreatic ribonuclease, also known as RNase A. Slifman and colleagues [17 ] and Gullberg and colleagues [18 ] demonstrated that EDN and ECP functioned as active ribonucleases in vitro, with the results of molecular cloning indicating that EDN and ECP were members of what has come to be recognized as the RNase A superfamily (reviewed in refs 19 20 ]). The RNase A superfamily represents a highly divergent group of proteins that have been identified primarily in mammalian orders but include members from specific species of birds and amphibians and will probably ultimately include members from all vertebrate species (Fig. 2 ). As a group, RNase A ribonucleases are characterized by a specific disulfide-bond structure that is crucial for relative positioning of the amino acids (histidines and lysine) contributing to the catalytic site, and all function to varying degrees in endo- and/or exonucleolytic cleavage of polymeric RNA. With respect to the eosinophil ribonucleases, ECP (also known as RNase 3) is the more cationic (pI~11) and less ribonucleolytically active of the two eosinophil ribonucleases, is expressed uniquely in eosinophils, and has been characterized more or less as a membrane-disruptive cationic toxin with nonspecific toxicity to bacteria, helminths, and a variety of eukaryotic cellular targets [14 ]. It is interesting that neither anti-heminth nor antibacterial activities were dependent on ECP’s ribonuclease activity [21 , 22 ]. EDN, the less cationic (pI~8), less specific (expressed also in liver and spleen), and ~100-fold more powerful ribonuclease, shares none of ECP toxicity except for that observed against rabbit Purkinje cells in an unrelated, nonphysiologic assay system [23 , 24 ].



View larger version (92K):
[in this window]
[in a new window]
  		Figure 1. The human eosinophilic leukocyte. (A) Light microscopic view of human peripheral blood eosinophils prepared with Giemsa stain. (B) Electron micrograph of a human peripheral blood eosinophil demonstrating the characteristic bilobed nucleus (n) and cytoplasmic specific granules (sg) that contain the eosinophil secretory ribonucleases EDN and ECP. The electron micrograph was courtesy of Dr. Arne Egesten, Lund University, Sweden. (Both images were reprinted with permission from ref. [13 ].)



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. The ribonuclease A superfamily. Neighbor-joining tree documenting the relationships among selected members of the major RNase A superfamily lineages, including the EARs (eosinophil-associated ribonucleases, including human EDN and human ECP), the PRs (pancreatic-type ribonucleases), the R4s (ribonuclease 4s), the ANGs (angiogenins), and the RRs (ribonucleases from the bullfrog Rana). [Reprinted in modified form from Rosenberg, H. F., Zhang, J., Liao, Y-D., Dyer, K. D. (2001) Rapid diversification of RNase A superfamily ribonuclease genes of the bullfrog, Rana catesbeiana. J. Mol. Evol. 53, 31–38.]


arrow
EVOLUTION OF THE EOSINOPHIL RIBONUCLEASES
 
The role of ribonculease activity in the physiologic functioning of ECP and EDN, and by extension, in the physiologic functioning of eosinophilic leukocytes, emerged as a question worthy of some attention. Although it would seem that gene-targeting studies in mice could provide useful information about the function of EDN and ECP in vivo, we found this approach to be far from straightforward. First, using direct DNA hybridization techniques, we were surprised to find that sequences homologous to EDN and ECP could be detected only in primate genomes [25 ] (Fig. 3 ). Upon further analysis of EDN and ECP sequences isolated from these primate genomes, we found that the two eosinophil ribonucleases arose as a gene pair relatively recently, and since divergence, they have incorporated nonsilent mutations at rates exceeding those of all other coding sequences studied in primates, with clear evidence of positive (Darwinian) selection acting at the molecular level in the case of ECP [26 ]. Perhaps most significant, despite the rapid diversification, all EDNs and ECPs maintained the structural and catalytic elements necessary to preserve ribonuclease activity. From this work, we concluded that these elements—generation of sequence diversity and ribonuclease activity—needed to be considered in our understanding of the physiologic functioning of EDN and ECP and by extension, the physiologic function of eosinophils.



View larger version (89K):
[in this window]
[in a new window]
  		Figure 3. Detection of EDN and ECP in mammalian genomes by Southern blot analysis. Above, restriction maps of human EDN and human ECP. The (intron-less) coding sequence of EDN (shown in black; also detects ECP by this method) was used to probe the Pst-I restriction-digested genomic DNA shown on the blot below. The genus/species identification is noted above each lane. Lanes 1–10 are from the order Primata; lanes 11–13, from Rodentia; lane 14, from Lagomorpha; lanes 15 and 16, from Carnivora; and lanes 17 and 18, from Artiodactyla. (Reprinted with permission from ref. [25 ].)

Ultimately, Larson and colleagues [27 ] identified two eosinophil-associated ribonucleases from mice, mEAR-1 and mEAR-2, and presented DNA-DNA hybridization evidence, suggesting that there were other mouse eosinophil-associated ribonucleases to be identified. At current count, at least 15 mEARs have been identified in genomic DNAs and/or cDNAs isolated from the mouse Mus musculus [28–30 and unpublished results]. In our initial study, we noted that the mEARs grouped together in a cluster, with each sequence more closely related to another mEAR than any one is to any of the primate EDNs or ECPs (see Fig. 2 ). It is interesting that similar, nonoverlapping clusters with distinct sequences were identified in the genomes of other, closely related rodents (rats, hamsters, gerbils) as well as in other species of mice [30 ]. This outcome—the existence of unique clusters of related but nonoverlapping sequences in closely related species—is a result of an unusual pattern of evolutionary development known as rapid birth death and gene sorting [30 ]. The rodent EARs share this pattern with only three other gene families, T-cell receptors, immunoglobulins, and major histocompatibility complex genes, all families whose physiologic function rests directly on the ability to generate diversity. Taken together, we conclude that primate and rodent eosinophil ribonucleases are undergoing similar but clearly independent modes of rapid diversification, suggesting the possibility that these ribonucleases may be responding to similar but likewise independent evolutionary constraints promoting rapid diversification and retention of ribonuclease activity.


arrow
THE LARGER PICTURE
 
Apart from its inherent interest as an evolutionary paradigm, we hoped to extend our findings on the evolution of these proteins toward issues of even larger biologic significance, with the intent of generating some new hypotheses, vis a vis eosinophils and their physiologic function. We know that eosinophils are recruited to tissues in response to various stimuli, primarily to portals of pathogen entry, such as the lungs and gastrointestinal tract. Among major eosinophil secretory products are ribonucleases that are responding to unusual evolutionary constraints promoting sequence diversity and at the same time maintaining specific elements necessary for ribonuclease activity. These results suggest that the ultimate target(s) of these proteins may be similarly efficient at generating sequence diversity while maintaining, at some level, an unalterable susceptibility to ribonuclease activity. To this end, we have begun to consider the possibility of a relationship between eosinophils and eosinophil-secretory ribonucleases and a role in host defense against a previously unrecognized group of target pathogens—ones that in many ways fit this description: single-stranded RNA virus pathogens.


arrow
EOSINOPHILS, EOSINOPHIL RIBONUCLEASES, AND RESPIRATORY SYNCYTIAL VIRUS (RSV)
 
Although several families of single-stranded RNA viruses might have served as appropriate models for this study, several important reasons prompted us to focus initially on RSV (family Paramyxoviridae, subfamily pneumovirus; 15,200 nucleotide nonsegmented, single-stranded genome). RSV is considered to be one of the most important respiratory pathogens worldwide, with infection resulting in a bronchiolitis affecting primarily the pediatric age group (ages 0–3 years) as well as the institutionalized elderly. For this undertaking, we noted the many studies that have implicated eosinophils in the pathogenesis of RSV disease. Several studies have shown that eosinophils are recruited to and degranulate into the lung parenchyma in association with severe RSV infection [31 , 32 ], and RSV-infected epithelial cells produce and secrete a variety of potential eosinophil chemoattractants (reviewed in [33 ]). As might be expected, eosinophils have been cast as the villains of RSV disease, and most of the aforementioned studies have focused on the role of eosinophils in promoting tissue damage and bronchospasm. From a different perspective, we initiated our studies by considering the possibility that eosinophils may also have a beneficial role to play and that eosinophilic inflammation associated with RSV disease may actually represent more of a "double-edged sword," discussed further below. Of note, although not nearly as well-characterized, pulmonary eosinophilia has also been noted in association with infection with the human pathogen, rhinovirus [34 ].

Our initial experiments provided several intriguing leads. When introduced into RSV-containing viral suspensions, we found that eosinophils mediated a dose-dependent reduction in virus infectivity (Fig. 4A ) [35 ]. This effect could be reversed by the addition of a placental ribonuclease inhibitor, a 55 kDa polypeptide that binds with extraordinary affinity (KdS~10-14 to 10-16) to EDN and ECP, indicating that the activities of one or both of the secreted eosinophil ribonucleases are crucial to the observed antiviral effect. Proceeding further, we have also shown that recombinant human EDN (rhEDN) acting alone also mediates a dose-dependent reduction in virus infectivity, an activity not shared with a ribonucleolytically inactived EDN point mutant, rhEDNdK38 (Fig. 4B) . ECP also has antiviral activity, although it functions less effectively than EDN on a molar basis in this specific in vitro experimental system [36 ]. However, ribonuclease activity per se, although necessary, is clearly not sufficient, because this antiviral activity is not shared by bovine RNase A, by the amphibian ribonuclease-toxin, onconase, nor even by the closely related human ribonuclease, RNase k6 [37 ].



View larger version (13K):
[in this window]
[in a new window]
  		Figure 4. Dose-dependent reduction in infectivity of RSV-B in response to (A) isolated human eosinophils or (B) rhEDN. (B) The final lane demonstrates the response to rhEDNdK38, a ribonucleolytically inactivated point mutant of rhEDN. (Reprinted with permission from ref. [35 ].)

The results of inhibition studies indicate that rhEDN’s interaction with its target is specific and saturable. When rhEDN antiviral activity is determined in the presence of increasing concentrations of a ribonucleolytically inactivated point mutant, rhEDNdK38, we observe a dose-dependent inhibition of antiviral activity. In constrast, when the identical experiment is done in the presence of increasing concentrations of rhRNase k6 (+ribonuclease activity; not antiviral), no such inhibition of antiviral effect is observed. Taken together, these results suggest that EDN interacts specifically with one (or more) as-yet unidentified target molecule(s) with ribonuclease activity as necessary but not sufficient to explain all features of the antiviral effect.


arrow
NATURE OF THE TARGET MOLECULE
 
The evolutionary arguments provide a tempting basis on which to presume the target(s) to be virally encoded (and we did so assume at one point, clearly prematurely) [37 ]. More recent results from dilution studies (unpublished results) and from the work of Lee-Huang and colleagues [38 ], demonstrating that EDN also has antiviral activity in a similar assay against the retrovirus pathogen, human immunodeficiency virus (HIV), suggest indirectly that the interaction is more likely to be associated with the target cell. This observation does not negate the implications of the evolutionary studies. In fact, the evolutionary constraints acting on these ribonucleases may be in response to a cellular target that is itself responding to a diverging virus, or they may be enhancing the fitness of these ribonucleases by providing them with means to engage multiple cellular targets. The nature and identity of these "ribonuclease receptors" remain to be elucidated.


arrow
OTHER ANTIVIRAL PROTEINS FROM EOSINOPHILS
 
Although the eosinophil ribonucleases may be essential for the antiviral activities observed in this particular assay system, there is no reason to believe that they are functioning alone. Adamko and colleagues [39 ] evaluated the activity of another granule protein, EPO, in vitro against the pathogen parainfluenza type I and have found that submicromolar concentrations resulted in significant inhibition of virus replication in a similar in vitro assay system using Rhesus monkey kidney cells as targets. Given all our findings, it would not be surprising to discover that the eosinophil granule proteins function in an additive, cooperative, or perhaps even synergistic way when combating virus infection in vivo.


arrow
EOSINOPHILS AND ANTIVIRAL HOST DEFENSE IN VIVO
 
The next crucial step in this series of experiments was moving from the observations made in a limited in vitro system into one in which we might evaluate the recruitment, activation, and physiologic contribution of eosinophils in an appropriate mouse model of acute respiratory virus infection. In this specific case, we considered several important issues. First was the issue of mouse versus human eosinophils, because the divergent mouse eosinophil ribonucleases might not be, and perhaps should not be, expected to handle the same pathogens met by their human counterparts. Add to this the fact that RSV, although a highly infectious agent among humans, is not a rodent pathogen and has very low infectivity in mice and related rodent species. Although much has been learned about the role of eosinophils in allergic responses to RSV challenge in mice presensitized with individual RSV components (reviewed in ref 40 ), our questions relate to the role of eosinophils in innate, nonallergic, antiviral host defense and as such, would be most suitably studied with a virus pathogen that naturally targets a rodent host. Toward this end, we have begun to explore the inflammatory responses of mice to infection with pneumonia virus of mice (PVM), which was first identified in mouse lungs in 1939 by Horsfall and colleagues and since that time has been identified as a significant pathogen in rodent colonies worldwide. Similar to RSV, PVM is a virus of the family Paramyxoviridae (enveloped, nonsegmented, single-stranded RNA viruses), subfamily pneumovirus, and is the closest phylogenetic relative of RSV currently identified. Easton and colleagues [41 42 43 44 ] have characterized this virus, found similarities in gene order, and shown that sequences of the PVM N protein and fusion region of the F protein are similar to those of the N and F proteins, respectively, encoded by RSV.

In our initial characterization, we found that severe illness with signs and symptoms similar to severe RSV infection in infants was established in wild-type mice in response to fewer than 30 plaque-forming units (pfu) of PVM, with significant morbidity and mortality accompanied by lung titers reaching as high as 107–108 pfu/gram lung tissue [45 ]. Virus infection was accompanied by a profound inflammatory response. Eosinophils and neutrophils were among the earliest of the cellular recruits (Fig. 5 ), with eosinophils peaking at 10%–30% of the total cells detected at the earliest time points, after which the infiltrate became virtually 100% neutrophilic in character. It is interesting that pulmonary eosinophilia always preceded the onset of morbidity (fur ruffling, hunching) regardless of the initial virus inoculum. This finding may explain in part why eosinophilia is not typically shown in response to respiratory virus infections in humans, as it suggests that any degree of eosinophilia detectable early on during the course of infection is likely to have dissipated before the onset of symptoms. Our findings with RSV-infected infants on ventilatory assistance are consistent with this interpretation, as eosinophil-degranulation products present in respiratory secretions denoted the presence of eosinophils in lung tissue at some earlier point during the infectious process [31 ].



View larger version (116K):
[in this window]
[in a new window]
  		Figure 5. Microscopic pathology observed in response to infection with PVM. (A–C) Original power views (40x, 100x, and 400x, respectively) of lung tissue sections obtained three days after inoculation with 300 pfu PVM. (C) The eosinophils are indicated by arrows. (D) A lung tissue section (40x) from a mouse inoculated with diluent alone. (Reprinted with permission from ref. [45 ].)


arrow
SIGNALS ELICITING PULMONARY EOSINOPHILIA IN RESPONSE TO VIRUS INFECTION
 
As part of an overall strategy to manipulate the eosinophilia observed in response to PVM infection, we were interested in identifying the signals and signaling cascades involved in this specific eosinophil-recruitment response. Among the characterized eosinophil-active and chemoattractant cytokines, we detected significant quantities of eotaxin prior to inoculation, with no changes observed in response to PVM infection; similar kinetics were observed for the chemokine RANTES (regulated on activation, normal T expressed and secreted). Lung tissue was found to be devoid of interleukin (IL)-5 throughout, and we have since demonstrated that pulmonary eosinophilia observed in response to PVM infection proceeds unabated in mice completely devoid of IL-5 (unpublished results). In contrast, the chemokine macrophage inflammatory protein-1{alpha} (MIP-1{alpha}), although undetectable at baseline, increases in concentration in lung tissue in response to virus infection. This was not surprising, because MIP-1{alpha} has been shown to be a central regulator of the inflammatory response to influenza [46 ] and cytomegalovirus [47 ] infections in mice, and we and others have documented the production and secretion of MIP-1{alpha} in response to RSV infection in respiratory epithelial cells in vitro [31 , 48 ] and in mechanically ventilated infants with RSV in vivo [31 ]. MIP-1{alpha} has also been shown to be a potent eosinophil chemoattractant in several unrelated mouse models of respiratory disease [49 50 51 ], although its role in virus-induced pulmonary eosinophilia had not been addressed specifically.

To address the role of MIP-1{alpha} in virus-induced pulmonary eosinophilia, we examined the responses of two specific strains of gene-deleted mice in our infection model with PVM [52 ]. In our first set of experiments, we found that the entire inflammatory response of MIP-1{alpha}-deficient mice was ablated nearly completely, with only 10–60 neutrophils/ml and no eosinophils detected in BAL fluid at any point in time after inoculation (down from counts on the order of 105 and 104/ml, respectively; Table 1 ), accompanied by a sixfold increase in recovery of infectious virus from lung tissue. Similar results were obtained from mice deficient in CCR1, the major MIP-1{alpha} receptor. When compared with CCR1-sufficient (+/+) mice, CCR1 -/- mice responded to PVM infection with minimal inflammatory response (including zero eosinophils), six- to eightfold increased recovery of infectious virus, and accelerated mortality. Taken together, these results suggest that the MIP-1{alpha}/CCR1-mediated acute inflammatory response protects mice by limiting virus replication and thereby attenuating the lethal sequelae of PVM infection. Although the large reduction in neutrophils precludes any strong conclusions on the role of eosinophils in antiviral host defense, it is possible that some (if not all) of the enhanced recovery of infectious virions and the accelerated demise of the CCR1 -/- mice may be attributable to the absence of eosinophils.


View this table:
[in this window]
[in a new window]
  		Table 1. Eosinophils (x103/ml BAL Fluid) Recruited in Response to PVM Infection in Wild-Type(wt) and Specific Gene-Deleted Mice

Adamko and colleagues [53 ] presented another approach to the question of eosinophils and antiviral immunity. They examined responses to infection with Parainfluenza type I (Sendai virus) in guinea pigs, with and without presensitization with intraperitoneal ovalubumin, using doses consistent with those traditionally used for generating asthmatic-type responses upon subsequent inhalation. Among other findings, Adamko and colleagues demonstrated that when challenged with infectious parainfluenza virus, sensitized animals respond with increased pulmonary eosinophil counts and reduced recovery of infectious virus, both responses inhibited by administration of antibody to IL-5. However, as discussed by the authors, the immunomodulatory effects of IL-5 are complex, and the implication that eosinophils mediate a reduction in viral titer remains to be substantiated.

Overall, the question of the role of eosinophils in antiviral host defense in vivo needs to be addressed directly with more specific eosinophil-ablating reagents. Given our findings regarding the lack of involvement of IL-5 in the primary, nonsensitized eosinophilia observed in response to PVM noted above, we are focusing on alternative strategies, including use of the anti-CCR3 antibody described by Grimaldi and colleagues [54 ] and/or anti-VLA4 [55 ]. Although the genetic complexity of mouse eosinophil-associated ribonucleases precludes a straightforward gene-deletion approach, the information available on the mouse genome sequence may present some more clever strategies. Finally, further documentation of the specific involvement of other eosinophil granule proteins might provide the impetus for evaluating the EPO- and MBP-deficient strains of mice recently described by Lee and colleagues [56 , 57 ] regarding eosinophils and their overall antiviral responses.


arrow
EOSINOPHILS AND RESPIRATORY VIRUSES, EOSINOPHILS AND ASTHMA: THE DOUBLE-EDGED SWORD?
 
The double-edged sword, reflecting the competing beneficial and detrimental features of a given physiologic response, is a concept that has successfully taken hold in our understanding of the physiology of the neutrophil and of diseases involving dysregulation of neutrophil recruitment and activation. For example, although neutrophils are clearly effective at mediating host defense against bacterial and fungal pathogens via degranulation, phagocytosis, and production of reactive oxygen species, the dysregulation of these essential, beneficial responses can lead to reperfusion injury and adult respiratory distress syndrome (reviewed in refs 58 59 ). Perhaps the same can be said for eosinophils and the pathogenesis of reactive airways disease. Although not without controversy, there are studies that have suggested a correlation linking severe RSV infection in infancy and the development of reactive airways disease in later childhood years (most recently reviewed in ref 60 ). Even without a direct link to this specific virus infection, certainly respiratory virus infections are sufficiently commonplace so as to be considered a universal affliction of infancy and childhood. Regardless of the inciting event, once reactive airways disease is established, respiratory virus infection is certainly accepted as one of the most common causes of symptomatic events and exacerbations [61 62 63 ]. Although the circle has not yet been completed from an experimental perspective, we propose the possibility that asthma and reactive airways disease represent dysregulation of what are otherwise essential, beneficial eosinophil responses. Whatever causes this dysregulation to be established—whether it is infection with a specific respiratory virus at a specific developmental stage in a specifically genetically and/or environmentally susceptible individual or all or none of the above—it is intriguing to consider the possibility that the eosinophil responses characteristic of the asthmatic state—the over-abundant expansion, recruitment, and activation in response to (among other things) virus infection—represent the dysregulation of the responses of cells primarily directed toward a beneficial role in promoting innate antiviral host defense.


arrow
ACKNOWLEDGEMENTS
 
This work was supported by a grant from the American Heart Association to J. B. D.

We thank Cynthia A. Bonville, Kimberly D. Dyer, and Jianzhi Zhang, members of our laboratory groups who have made substantial contributions to the studies described herein. We also thank our collaborators Andrew Easton, Philip Murphy, and Jiliang Gao for contributing to the success of the mouse studies described.


arrow
REFERENCES
 
    1
  1. Foster, P. S., Mould, A. W., Yang, M., Mackenzie, J., Mattes, J., Hogan, S. P., Mahalingam, S., Mckenzie, A. N., Rothenberg, M. E., Young, I. G., Matthaei, K. I., Webb, D. C. (2001) Elemental signals regulating eosinophil accumulation in the lung Immunol. Rev. 179,173-181[Medline]
    2. 2
  2. Hamelmann, E., Gelfand, E. W. (2001) IL-5-induced airway eosinophilia—the key to asthma? Immunol. Rev. 179,182-191[Medline]
    3. 3
  3. Rothenberg, M. E., Mishra, A., Brandt, E. B., Hogan, S. P. (2001) Gastrointestinal eosinophils Immunol. Rev. 179,139-155[Medline]
    4. 4
  4. Rothenberg, M. E. (1998) Eosinophilia N. Engl. J. Med. 338,1592-1600[Free Full Text]
    5. 5
  5. Behm, C. A., Ovington, K. S. (2000) The role of eosinophils in parasitic helminth infections: insights from genetically modified mice Parasitol. Today 16,202-209[Medline]
    6. 6
  6. Meeusen, E. N. T., Balic, A. (2000) Do eosinophils have a role in the killing of helminth parasites? Parasitol. Today 16,95-101[Medline]
    7. 7
  7. Lee, N. A., Gelfand, E. W., Lee, J. J. (2001) Pulmonary T cells and eosinophils: coconspirators or independent triggers of allergic respiratory pathology? J. Allergy Clin. Immunol. 107,945-957[Medline]
    8. 8
  8. Wardlaw, A. J., Brightling, C., Green, R., Woltmann, G., Pavord, I. (2000) Eosinophils in asthma and other allergic diseases Br. Med. Bull. 56,985-1003[Abstract/Free Full Text]
    9. 9
  9. Busse, W. W., Lemanske, R. F., Jr (2001) Asthma N. Engl. J. Med. 344,350-362[Free Full Text]
    10. 10
  10. Cappelletti, P., Doretto, P., Signori, D., Bizzaro, N. (1992) Eosinophilic peroxidase deficiency. Cytochemical and ultrastructural characterization of 21 new cases Am. J. Clin. Path. 98,615-622[Medline]
    11. 11
  11. Rosenberg, H. F., Gallin, J. I. (1993) Neutrophil specific granule deficiency includes eosinophils Blood 82,268-273[Abstract/Free Full Text]
    12. 12
  12. Lekstrom-Himes, J. A., Dorman, S. E., Kopar, P., Holland, S. M., Gallin, J. I. (1999) Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon J. Exp. Med. 189,1847-1852[Abstract/Free Full Text]
    13. 13
  13. Rosenberg, H. F. (1999) Eosinophils Gallin, J. I. Snyderman, R. eds. Inflammation: Basic Principles and Clinical Correlates 3rd ed. ,61-76 Lippincott, Williams & Wilkins Philadelphia.
    14. 14
  14. Walsh, G. M. (2001) Eosinophil granule proteins and their role in disease Curr. Opin. Hematol. 8,28-33[Medline]
    15. 15
  15. Archer, G. T., Hirsch, J. G. (1963) Isolation of granules from eosinophil leucocytes and study of their enzyme content J. Exp. Med. 118,277-284[Abstract]
    16. 16
  16. Gleich, G. J., Loegering, D. A., Bell, M. P., Checkel, J.L., Ackerman, S. J., McKean, D. J. (1986) Biochemical and functional similarities between human eosinophil-derived neurotoxin and eosinophil cationic protein: homology with ribonuclease Proc. Natl. Acad. Sci. USA 83,3146-3150[Abstract/Free Full Text]
    17. 17
  17. Slifman, N. R., Loegering, D. A., McKean, D. J., Gleich, G. J. (1986) Ribonuclease activity associated with human eosinophil-derived neurotoxin and eosinophil cationic protein J. Immunol. 137,2913-2917[Abstract]
    18. 18
  18. Gullberg, U., Widegren, B., Arivason, U., Egesten, A., Olsson, I. (1986) The cytotoxic eosinophil cationic protein (ECP) has ribonuclease activity Biochem. Biophys. Res. Commun. 139,1239-1242[Medline]
    19. 19
  19. Rosenberg, H. F. (1998) The eosinophil ribonucleases Cell. Mol. Life Sci. 54,795-803[Medline]
    20. 20
  20. Rosenberg, H. F., Domachowske, J. B. (1999) Eosinophils, ribonucleases and host defense: solving the puzzle Immunol. Res. 20,261-274[Medline]
    21. 21
  21. Molina, H. A., Kierszenbaum, F., Hamann, K. J., Gleich, G. J. (1988) Toxic effects produced or mediated by human eosinophil granule components on Trypanosoma cruzi Am. J. Trop. Med. Hyg. 38,327-334
    22. 22
  22. Rosenberg, H. F. (1995) Recombinant eosinophil cationic protein (ECP): ribonuclease activity is not essential for cytotoxicity J. Biol. Chem. 270,7876-7881[Abstract/Free Full Text]
    23. 23
  23. Durack, D. T., Ackerman, S. J., Loegering, D. A., Gleich, G. J. (1981) Purification of human eosinophil-derived neurotoxin Proc. Natl. Acad. Sci. USA 78,5165-5169[Abstract/Free Full Text]
    24. 24
  24. Newton, D. L., Walbridge, S., Mikulski, S. M., Ardelt, W., Shogen, K., Ackerman, S. J., Rybak, S. M., Youle, R. J. (1994) Toxicity of an antitumor ribonuclease to Purkinje neurons J. Neurosci. 14,538-544[Abstract]
    25. 25
  25. Rosenberg, H. F., Dyer, K. D., Tiffany, H. L., Gonzalez, M. (1995) Rapid evolution of a unique family of primate ribonuclease genes Nat. Genet. 10,219-223[Medline]
    26. 26
  26. Zhang, J., Rosenberg, H. F., Nei, M. (1998) Positive Darwinian selection following gene duplication in primate ribonuclease genes Proc. Natl. Acad .Sci. USA 95,3708-3713[Abstract/Free Full Text]
    27. 27
  27. Larson, K. A., Olson, E. V., Madden, B. J., Gleich, G. J., Lee, N. A., Lee, J. J. (1996) Two highly homologous ribonuclease genes expressed in mouse eosinophils identify a larger subgroup of the mammalian ribonuclease superfamily Proc. Natl. Acad. Sci. USA 29,12370-12375
    28. 28
  28. Singhania, N. A., Dyer, K. D., Zhang, J., Deming, M. S., Bonville, C. A., Domachowske, J. B., Rosenberg, H. F. (1999) Rapid evolution of the RNase A gene superfamily: adaptive expansion of independent gene clusters in rats and mice J. Mol. Evol. 49,721-728[Medline]
    29. 29
  29. Cormier, S. A., Larson, K. A., Yuan, S., Mitchell, T. L., Lindenberger, K., Carrigan, P., Lee, N. A., Lee, J. J. (2001) Mouse eosinophil-associated ribonucleases: a unique subfamily expressed during hematopoiesis Mamm. Genome 12,352-361[Medline]
    30. 30
  30. Zhang, J., Dyer, K. D., Rosenberg, H. F. (2000) Evolution of the rodent eosinophil-associated ribonuclease gene family by rapid gene sorting and positive selection Proc. Natl. Acad. Sci. USA 97,4701-4706[Abstract/Free Full Text]
    31. 31
  31. Harrison, A. M., Bonville, C. A., Rosenberg, H. F., Domachowske, J. B. (1999) Respiratory syncytial virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation Am. J. Respir. Crit. Care Med. 159,1918-1924[Abstract/Free Full Text]
    32. 32
  32. Garofalo, R., Kimpen, J. L., Welliver, R. C., Ogra, P. L. (1992) Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection J. Pediatr. 120,28-32[Medline]
    33. 33
  33. Domachowske, J. B., Rosenberg, H. F. (1999) Respiratory syncytial virus infection: immune response, immunopathogenesis and treatment Clin. Microbiol. Rev. 12,298-309[Abstract/Free Full Text]
    34. 34
  34. Fraenkel, D. J., Bardin, P. G., Sanderson, G., Lampe, F., Johnston, S. L., Holgate, S. T. (1995) Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects Am. J. Respir. Crit. Care Med. 151,879-886[Abstract]
    35. 35
  35. Domachowske, J. B., Dyer, K. D., Bonville, C. A., Rosenberg, H. F. (1998) Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus J. Infect. Dis. 177,1458-1464[Medline]
    36. 36
  36. Domachowske, J. B., Dyer, K. D., Adams, A. G., Leto, T. L., Rosenberg, H. F. (1998) Eosinophil cationic protein/RNase 3: another eosinophil ribonuclease with direct antiviral activity Nucleic Acids Res 26,3358-3363[Abstract/Free Full Text]
    37. 37
  37. Domachowske, J. B., Bonville, C. A., Dyer, K. D., Rosenberg, H. F. (1998) Evolution of antiviral activity in the Ribonuclease A gene superfamily: evidence for a specific interaction between eosinophil-derived neurotoxin (EDN/RNase 2) and respiratory syncytial virus Nucleic Acids Res 26,5327-5332[Abstract/Free Full Text]
    38. 38
  38. Lee-Huang, S., Huang, P. L., Sun, Y., Huang, P. L., Kung, H. F., Blithe, D. L., Chen, H. C. (1999) Lysozyme and RNases as anti-HIV components in beta-core preparations of human chorionic gonadotrophin Proc. Natl. Acad. Sci. USA 96,2768-2781
    39. 39
  39. Adamko, D. J., Yost, B. L., Gleich, G. J., Fryer, A. D., Jacoby, D. B. (2001) Antiviral activity of eosinophil peroxidase mediated via sodium bromide. International Meeting of the Eosinophil Society, May 3–6, 2001, Abstract #018, Banff, Alberta, Canada.
    40. 40
  40. Graham, B. S., Johnson, T. R., Peebles, R. S. (2000) Immune-mediated disease pathogenesis in respiratory syncytial virus infection Immunopharmacology 25,237-247
    41. 41
  41. Chambers, P., Barr, J., Pringle, C. R., Easton, A. J. (1990) Molecular cloning of pneumonia virus of mice J. Virol. 64,1869-1872[Abstract/Free Full Text]
    42. 42
  42. Chambers, P., Matthews, D. A., Pringle, C. R., Easton, A. J. (1991) The nucleotide sequences of intergenic regions between nine genes of pneumonia virus of mice establish the physical order of these genes in the viral genome Virus Res 18,263-270[Medline]
    43. 43
  43. Barr, J., Chambers, P., Pringle, C. R., Easton, A. J. (1991) Sequence of the major nucleocapsid protein gene of pneumonia virus of mice: sequence comparisons suggest structural homology between nucleocapside proteins of pneumoviruses, paramyxoviruses, rhabodviruses and filoviruses J. Gen. Virol. 72,677-685[Abstract/Free Full Text]
    44. 44
  44. Chambers, P., Pringle, C. R., Easton, A. J. (1992) Sequence analysis of the gene encoding the fusion glycoprotein of pneumonia virus of mice suggests possible conserved secondary structure elements in paramyxovirus fusion glycoproteins J. Gen. Virol. 73,1717-1724[Abstract/Free Full Text]
    45. 45
  45. Domachowske, J. B., Bonville, C. A., Dyer, K. D., Easton, A. J., Rosenberg, H. F. (2000) Pulmonary eosinophilia and production of MIP-1{alpha} are prominent responses to infection with pneumonia virus of mice Cell. Immunol. 200,98-104[Medline]
    46. 46
  46. Cook, D. N., Beck, M. A., Coffman, T. M., Kirby, S. L., Sheridan, J. F., Pragnell, I. B., Smithies, O. (1995) Requirment of MIP-1{alpha} for an inflammatory response to viral infection Science 269,1583-1585[Abstract/Free Full Text]
    47. 47
  47. Salazar-Mather, T. P., Orange, J. S., Biron, C. A. (1998) Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways J. Exp. Med. 187,1-14[Abstract/Free Full Text]
    48. 48
  48. Olszewska-Pazdrak, B., Casola, A., Saito, T., Alam, R., Crowe, S. E., Mei, F., Ogra, P. L., Garofalo, R. P. (1998) Cell-specific expression of RANTES, MCP-1, and MIP-1alpha by lower airway epithelial cells and eosinophils infected with respiratory syncytial virus J. Virol. 72,4756-4764[Abstract/Free Full Text]
    49. 49
  49. Campbell, E. M., Kunkel, S. L., Streieter, R. M., Lukacs, N. W. (1998) Temporal role of chemokines in a murine model of cockroach allergen-induced airway hyperreactivity and eosinophilia J. Immunol 161,7047-7053[Abstract/Free Full Text]
    50. 50
  50. Teixeira, M. M. (1998) Eosinophil-active chemokines: assessment of in vivo activity Braz. J. Med. Biol. Res. 31,19-24[Medline]
    51. 51
  51. Lukacs, N. W., Strieter, R. M., Warmington, K., Lincoln, P., Chensue, S. W., Kunkel, S. L. (1997) Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation J. Immunol. 158,4398-4404[Abstract]
    52. 52
  52. Domachowske, J. B., Bonville, C. A., Gao, J-L., Murphy, P. M., Easton, A. J., Rosenberg, H. F. (2000) The chemokine MIP-1{alpha} and its receptor CCR1 control pulmonary inflammation and anti-viral host defense in paramyxovirus infection J. Immunol. 165,2677-2682[Abstract/Free Full Text]
    53. 53
  53. Adamko, D. J., Yost, B. L., Gleich, G. J., Fryer, A. D., Jacoby, D. B. (1999) Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, m(2) muscarinic receptor dysfunction, and antiviral effects J. Exp. Med. 190,1465-1478[Abstract/Free Full Text]
    54. 54
  54. Grimaldi, J. C., Yu, N. X., Grunig, G., Seymour, B. W., Cottrez, F., Robinson, D. S., Hosken, N., Ferling, W. G., Wu, X., Soto, H., O’Garra, A., Howard, M. D., Coffman, R. L. (1999) Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3) J. Leukoc. Biol. 65,846-853[Abstract]
    55. 55
  55. Miyake, K., Weissman, I. L., Greenberger, J. S., Kincade, P. W. (1991) Evidence for a role of the integrin VLA-4 in lympho-hemopoiesis J. Exp. Med. 173,599-607[Abstract/Free Full Text]
    56. 56
  56. Denzler, K. L., Borchers, M. T., Crosby, J. R., Cieslewicz, G., Hines, E. M., Justice, J. P., Cormier, S. A., Lindenberger, K. A., Song, W., Wu, W., Hazen, S. L., Gleich, G. J., Lee, J. J., Lee, N. A. (2001) Extensive eosinophil degranulation and peroxidase-mediated oxidation of airway proteins do not occur in a mouse ovalbumin-challenge model of pulmonary inflammation J. Immunol. 167,1672-1682[Abstract/Free Full Text]
    57. 57
  57. Denzler, K. L., Farmer, S. C., Crosby, J. R., Borchers, M., Cieslewicz, G., Larson, K. A., Cormier-Regard, S., Lee, N. A., Lee, J. J. (2000) Eosinophil major basic protein-1 does not contribute to allergen-induced airway pathologies in mouse models of asthma J. Immunol. 165,5509-5517[Abstract/Free Full Text]
    58. 58
  58. Babior, B. M. (2000) Phagocytes and oxidative stress Am. J. Med. 109,33-44[Medline]
    59. 59
  59. Svanborg, C., Godaly, G., Hedlund, M. (1999) Cytokine responses during mucosal infections: role in disease pathogenesis and host defense Curr. Opin. Microbiol. 2,99-105[Medline]
    60. 60
  60. Kimpen, J. L. L., Simoes, E. A. F. (2001) Respiratory syncytial virus and reactive airway disease: new developments prompt a new review Am. J. Respir. Crit. Care Med. 163,S1-S6[Free Full Text]
    61. 61
  61. Gern, J. E., Busse, W. W. (2000) The role of viral infections in the natural history of asthma J. Allergy Clin. Immunol. 106,201-212[Medline]
    62. 62
  62. Kimpen, J. L. (2000) Viral infections and childhood asthma Am. J. Respir. Crit. Care Med. 162,S108-S112[Free Full Text]
    63. 63
  63. Tuffaha, A., Gern, J. E., Lemanske, R. F., Jr (2000) The role of respiratory viruses in acute and chronic asthma Clin. Chest Med. 21,289-300[Medline]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
C. M. Percopo, Z. Qiu, S. Phipps, P. S. Foster, J. B. Domachowske, and H. F. Rosenberg
Pulmonary Eosinophils and Their Role in Immunopathologic Responses to Formalin-Inactivated Pneumonia Virus of Mice
J. Immunol., July 1, 2009; 183(1): 604 - 612.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
V. Steenwinckel, J. Louahed, M. M. Lemaire, C. Sommereyns, G. Warnier, A. McKenzie, F. Brombacher, J. Van Snick, and J.-C. Renauld
IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa
J. Immunol., April 15, 2009; 182(8): 4737 - 4743.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. L. Radke, L. E. Reynolds, R. C. N. Melo, A. M. Dvorak, P. F. Weller, and L. A. Spencer
Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation
Blood, March 26, 2009; 113(13): 3092 - 3101.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. D. Dyer, J. M. Moser, M. Czapiga, S. J. Siegel, C. M. Percopo, and H. F. Rosenberg
Functionally Competent Eosinophils Differentiated Ex Vivo in High Purity from Normal Mouse Bone Marrow
J. Immunol., September 15, 2008; 181(6): 4004 - 4009.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
T. R. Johnson, M. E. Rothenberg, and B. S. Graham
Pulmonary eosinophilia requires interleukin-5, eotaxin-1, and CD4+ T cells in mice immunized with respiratory syncytial virus G glycoprotein
J. Leukoc. Biol., September 1, 2008; 84(3): 748 - 759.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Yoon, J. U. Ponikau, C. B. Lawrence, and H. Kita
Innate Antifungal Immunity of Human Eosinophils Mediated by a {beta}2 Integrin, CD11b
J. Immunol., August 15, 2008; 181(4): 2907 - 2915.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
H. F. Rosenberg
RNase A ribonucleases and host defense: an evolving story
J. Leukoc. Biol., May 1, 2008; 83(5): 1079 - 1087.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Gaudreault and J. Gosselin
Leukotriene B4 Induces Release of Antimicrobial Peptides in Lungs of Virally Infected Mice
J. Immunol., May 1, 2008; 180(9): 6211 - 6221.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
D. Yang, Q. Chen, S. B. Su, P. Zhang, K. Kurosaka, R. R. Caspi, S. M. Michalek, H. F. Rosenberg, N. Zhang, and J. J. Oppenheim
Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses
J. Exp. Med., January 21, 2008; 205(1): 79 - 90.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Y. Liu, M. E. Bates, N. N. Jarjour, W. W. Busse, P. J. Bertics, and E. A. B. Kelly
Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-{alpha}
J. Immunol., October 1, 2007; 179(7): 4840 - 4848.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Phipps, C. E. Lam, S. Mahalingam, M. Newhouse, R. Ramirez, H. F. Rosenberg, P. S. Foster, and K. I. Matthaei
Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus
Blood, September 1, 2007; 110(5): 1578 - 1586.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Monteseirin, A. Vega, P. Chacon, M. J. Camacho, R. El Bekay, J. A. Asturias, A. Martinez, P. Guardia, R. Perez-Cano, and J. Conde
Neutrophils as a Novel Source of Eosinophil Cationic Protein in IgE-Mediated Processes
J. Immunol., August 15, 2007; 179(4): 2634 - 2641.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
D. J. Tumes, J. Cormie, M. G. Calvert, K. Stewart, C. Nassenstein, A. Braun, P. S. Foster, and L. A. Dent
Strain-dependent resistance to allergen-induced lung pathophysiology in mice correlates with rate of apoptosis of lung-derived eosinophils
J. Leukoc. Biol., June 1, 2007; 81(6): 1362 - 1373.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Nitto, K. D. Dyer, M. Czapiga, and H. F. Rosenberg
Evolution and Function of Leukocyte RNase A Ribonucleases of the Avian Species, Gallus gallus
J. Biol. Chem., September 1, 2006; 281(35): 25622 - 25634.
[Abstract] [Full Text] [PDF]

Home page
 J. Gen. Virol.Home page
J.-F. Valarcher, J. Furze, S. G. Wyld, R. Cook, G. Zimmer, G. Herrler, and G. Taylor
Bovine respiratory syncytial virus lacking the virokinin or with a mutation in furin cleavage site RA(R/K)R109 induces less pulmonary inflammation without impeding the induction of protective immunity in calves
J. Gen. Virol., June 1, 2006; 87(6): 1659 - 1667.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
U.-B. Jonsson, J. Bystrom, G. Stalenheim, and P. Venge
A (G->C) transversion in the 3' UTR of the human ECP (eosinophil cationic protein) gene correlates to the cellular content of ECP
J. Leukoc. Biol., April 1, 2006; 79(4): 846 - 851.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. A. W. Claassen, P. A. A. van der Kant, Z. S. Rychnavska, G. M. van Bleek, A. J. Easton, and R. G. van der Most
Activation and Inactivation of Antiviral CD8 T Cell Responses during Murine Pneumovirus Infection
J. Immunol., November 15, 2005; 175(10): 6597 - 6604.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
K. D. Dyer and H. F. Rosenberg
The mouse RNase 4 and RNase 5/ang 1 locus utilizes dual promoters for tissue-specific expression
Nucleic Acids Res., February 18, 2005; 33(3): 1077 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. Yang, Q. Chen, H. F. Rosenberg, S. M. Rybak, D. L. Newton, Z. Y. Wang, Q. Fu, V. T. Tchernev, M. Wang, B. Schweitzer, et al.
Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation
J. Immunol., November 15, 2004; 173(10): 6134 - 6142.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
O. Levy
Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes
J. Leukoc. Biol., November 1, 2004; 76(5): 909 - 925.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J. M. Swartz, J. Bystrom, K. D. Dyer, T. Nitto, T. A. Wynn, and H. F. Rosenberg
Plasminogen activator inhibitor-2 (PAI-2) in eosinophilic leukocytes
J. Leukoc. Biol., October 1, 2004; 76(4): 812 - 819.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
C. Feistritzer, N. C. Kaneider, D. H. Sturn, B. A. Mosheimer, C. M. Kahler, and C. J. Wiedermann
Expression and Function of the Vascular Endothelial Growth Factor Receptor FLT-1 in Human Eosinophils
Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 729 - 735.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Kariko, H. Ni, J. Capodici, M. Lamphier, and D. Weissman
mRNA Is an Endogenous Ligand for Toll-like Receptor 3
J. Biol. Chem., March 26, 2004; 279(13): 12542 - 12550.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
D. Yang, H. F. Rosenberg, Q. Chen, K. D. Dyer, K. Kurosaka, and J. J. Oppenheim
Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells
Blood, November 1, 2003; 102(9): 3396 - 3403.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Espert, G. Degols, C. Gongora, D. Blondel, B. R. Williams, R. H. Silverman, and N. Mechti
ISG20, a New Interferon-induced RNase Specific for Single-stranded RNA, Defines an Alternative Antiviral Pathway against RNA Genomic Viruses
J. Biol. Chem., April 25, 2003; 278(18): 16151 - 16158.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham
IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge
J. Immunol., February 15, 2003; 170(4): 2037 - 2045.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. J. Adamko, A. D. Fryer, B. S. Bochner, and D. B. Jacoby
CD8+ T Lymphocytes in Viral Hyperreactivity and M2 Muscarinic Receptor Dysfunction
Am. J. Respir. Crit. Care Med., February 15, 2003; 167(4): 550 - 556.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. Zhang, K. D. Dyer, and H. F. Rosenberg
Human RNase 7: a new cationic ribonuclease of the RNase A superfamily
Nucleic Acids Res., January 15, 2003; 31(2): 602 - 607.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J. B. Domachowske, C. A. Bonville, A. J. Easton, and H. F. Rosenberg
Pulmonary eosinophilia in mice devoid of interleukin-5
J. Leukoc. Biol., June 1, 2002; 71(6): 966 - 972.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. A. Benner
The past as the key to the present: Resurrection of ancient proteins from eosinophils
PNAS, April 16, 2002; 99(8): 4760 - 4761.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Zhang and H. F. Rosenberg
From the Cover: Complementary advantageous substitutions in the evolution of an antiviral RNase of higher primates
PNAS, April 16, 2002; 99(8): 5486 - 5491.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. Zhang, K. D. Dyer, and H. F. Rosenberg
RNase 8, a novel RNase A superfamily ribonuclease expressed uniquely in placenta
Nucleic Acids Res., March 1, 2002; 30(5): 1169 - 1175.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Zhang and H. F. Rosenberg
From the Cover: Complementary advantageous substitutions in the evolution of an antiviral RNase of higher primates
PNAS, April 16, 2002; 99(8): 5486 - 5491.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rosenberg, H. F.
Right arrow Articles by Domachowske, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rosenberg, H. F.
Right arrow Articles by Domachowske, J. B.