(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
* Eosinophil Biology Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
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
 |
ABSTRACT
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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
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EOSINOPHILS MISUNDERSTOOD
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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
].
|
EOSINOPHILS AND EOSINOPHIL RIBONUCLEASES
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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 (pI8), 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
].
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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
].)
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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.]
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EVOLUTION OF THE EOSINOPHIL RIBONUCLEASES
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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.
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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
].)
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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.
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THE LARGER PICTURE
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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.
|
EOSINOPHILS, EOSINOPHIL RIBONUCLEASES, AND RESPIRATORY SYNCYTIAL
VIRUS (RSV)
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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
(KdS10-14 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
].
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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
].)
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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.
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NATURE OF THE TARGET MOLECULE
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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.
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OTHER ANTIVIRAL PROTEINS FROM EOSINOPHILS
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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.
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EOSINOPHILS AND ANTIVIRAL HOST DEFENSE IN VIVO
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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
].
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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
].)
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SIGNALS ELICITING PULMONARY EOSINOPHILIA IN RESPONSE TO VIRUS
INFECTION
|
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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
(MIP-1), although
undetectable at baseline, increases in concentration in lung tissue in
response to virus infection. This was not surprising, because MIP-1
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 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 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 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-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 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/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.
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Table 1. Eosinophils (x103/ml BAL Fluid) Recruited in Response to
PVM Infection in Wild-Type(wt) and Specific Gene-Deleted Mice
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|
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.
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EOSINOPHILS AND RESPIRATORY VIRUSES, EOSINOPHILS AND ASTHMA: THE
DOUBLE-EDGED SWORD?
|
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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.
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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.
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ABSTRACT
EOSINOPHILS MISUNDERSTOOD
