Eosinophils and Respiratory Viruses

Abstract

Eosinophils have been mainly associated with parasitic infection and pathologies such as asthma. Some patients with asthma present a high number of eosinophils in their airways. Since respiratory viruses are associated with asthma exacerbations, several studies have evaluated the role of eosinophils against respiratory viruses. Eosinophils contain and produce molecules with antiviral activity, including RNases and reactive nitrogen species. They can also participate in adaptive immunity, serving as antigen-presenting cells. Eosinophil antiviral response has been demonstrated against some respiratory viruses in vitro and in vivo, including respiratory syncytial virus and influenza. Given the implication of respiratory viruses in asthma, the eosinophil antiviral role might be an important factor to consider in this pathology.

Introduction

Eosinophils, along with neutrophils and basophils, belong to a group of leucocytes known as granulocytes. They originate from bone marrow-derived CD34⁺ cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) (77), interleukin (IL)-3, and IL-5 (15,68) regulate eosinophil development, IL-5 being the most specific for the eosinophil lineage (111). Once mature, eosinophils migrate to peripheral blood with a half-life of ∼18 h (122).

Under homeostatic conditions, low numbers of eosinophils can be detected in peripheral blood (< 450–500 eosinophils/μL) (60). They rapidly leave the bloodstream and migrate into the adipose tissue, thymus, lungs, uterus, mammary glands, and mainly the gastrointestinal tract, where they are predominantly involved in the particular physiology of each tissue or organ (62,78,136). In contrast, during allergy, asthma, and parasitic infections, eosinopoiesis is increased, resulting in up to 5% of eosinophils in circulating blood (60).

The main feature of eosinophils is their high content in granular cationic proteins, which are responsible for their reactivity to the acidic dye eosin. In specific granules, also known as secondary granules, the major basic protein (MBP)-1 and MBP-2 are found within the granule core, whereas the eosinophil cationic protein (ECP), eosinophil peroxidase (EPO/EPX), and eosinophil-derived neurotoxin (EDN) are localized in the granule matrix (106). The granules of mature eosinophils also contain preformed cytokines, chemokines, and growth factors (136). Human eosinophils constitutively store interferon (IFN)-γ, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, IL-12 (p70), and IL-13, which can be rapidly secreted in response to specific stimuli without de novo transcription (121).

Eosinophils have been preserved during evolution, being present in vertebrates (62,72). For many years, the role of eosinophil in host defense focused on their response against helminth parasites. The dogma that these cells play crucial protective roles in helminth parasite infection began in the 1970s, and this notion was reinforced in the 1980 and 1990s, as demonstrated by the fact that either rodent and human eosinophils or their granular content was able to kill helminth larvae in in vitro assays (13,16,131).

With the development of eosinophil-deficient mice, new in vivo studies showed that this paradigm is mainly sustained to secondary infections (47,57). However, in the case of some helminths, such as Strongyloides stercoralis and Schistosoma mansoni, eosinophils are dispensable in host protection both in primary and secondary infections (85,126). In other cases, they may even play a beneficial role to the parasite, as the absence of eosinophils decreased Trichinella spiralis larvae growth and survival in skeletal muscle (34,36). In contrast, eosinophil presence or their products are associated with diseases that affect the skin, airways, and gastrointestinal tract (118). From an evolutionary point of view, a cell type would not persist if most of its functions were harmful to the host; so other unknown favorable ones may sustain its presence.

In recent years, several studies have demonstrated the functions of eosinophils that change their traditional description as a classic inflammatory end-stage cell involved in host protection against parasites. Among these were their involvement in homeostasis maintenance by secreting key cytokines, such as IL-4 that sustains alternatively activated macrophages in adipose tissue (141), and APRIL (a proliferation-inducing ligand) that generates and preserves immunoglobulin (Ig)A-expressing plasma cells in the gastrointestinal tract (17). In addition, the functions of eosinophils as effector cells have been reported in cancer response (19) and in bacterial, fungal, and viral infections (98), mainly against respiratory viruses (102).

Relationship Between Asthma, Eosinophils, and Respiratory Viral Infection

Asthma is a heterogeneous disease characterized by chronic inflammation of the airways. Symptoms include wheezing, chest tightness, shortness of breath, and coughing, which vary over time and intensity (39). According to the World Health Organization, there are ∼235 million people with this disease (5).

Patients with asthma can be classified based on the presented phenotype or endotype. While a phenotype describes “observable characteristics,” an endotype refers to “a subtype of a condition defined by a distinct pathophysiological mechanism,” and it is currently considered as a more accurate manner to classify asthma patients to choose their treatments (69). T_H2-high endotype is the most prominent endotype and is mainly characterized by eosinophilic inflammation in the airways (125,137). Although it is the most studied endotype, its etiology is no clear (4).

Eosinophils release different molecules that participate in the pathogenesis of asthma. MBP has been found in sputum from patients with asthma and causes epithelial damage (37). It also induces the release of histamine from mast cells and basophils (86,94), which in turn induce bronchospasm and mucus secretion (138). Leukotrienes are potent bronchoconstrictors and cause the activation of eosinophils themselves, mast cells, basophils, monocytes, and T cells (80). Eosinophils also release cytokines that participate in asthma pathology. IL-13 induces airway hyperresponsiveness and mucus hypersecretion (40), while transforming growth factor (TGF)-β participates in tissue remodeling via fibroblast proliferation (28).

Asthma exacerbations can be triggered by environmental factors and, more frequently, by viral infections (127). Some of the viruses associated with wheezing illnesses are respiratory syncytial virus (RSV), human rhinovirus (HRV), human parainfluenza virus (PIV), influenza virus, metapneumovirus, coronavirus, bocavirus, and adenovirus (50). RSV is the main pathogen isolated from children younger than 3 years during winter months, and HRV is the most common virus during the rest of the year (46). Respiratory viruses are not only inducers of asthma exacerbations; they might also cause asthma development, at least in the case of RSV and HRV infections. Studies have shown that children with severe RSV bronchiolitis have a significantly higher risk of suffering from asthma at later ages (117). Meanwhile, others have found that wheezing illnesses caused by HRV predict asthma development in children (48,59,66).

Asthmatic individuals have a reduced innate immunity against respiratory viruses compared with non-asthmatics (30,49). The main difference between asthmatic patients and control subjects seems to be the impaired production of type I IFNs (IFN-α, IFN-β) (12,133) and type III IFNs (IFN-λ) (18) detected in asthmatics, which might be caused by eosinophil TGF-β production (71). However, more studies are needed because there are many reports that have failed to show differences in IFN production between these two groups; there is a general lack of data on asthma phenotypes analyzed in these studies; and most of them have focused on HRV (30).

Eosinophils are present in the airways in homeostatic conditions, so during viral infection with respiratory viruses, both elements may be in contact. In contrast, eosinophilic asthma is the predominant endotype of the disease (4); therefore, it is possible that eosinophils interact with respiratory viruses in this specific scenario. In fact, the involvement of respiratory viral infections in asthma exacerbations is widely accepted. In this review we summarize the eosinophil antiviral arsenal and analyze the in vitro and in vivo studies that support the eosinophil role against respiratory viruses, specifying when the antiviral eosinophil response is analyzed under an asthmatic condition.

Eosinophil Antiviral Arsenal

Eosinophils contain a group of receptors that allow the detection and response to viruses. They are also capable of developing different antiviral mechanisms and even participating in the initiation of adaptive T cell response (Fig. 1).

FIG. 1.

Eosinophil antiviral content. Eosinophils possess different molecules and mechanisms with potential antiviral activity, including TLRs, RLRs, preformed and inducible cytokines, antigen presentation molecules, EETs, and oxygen and nitrogen reactive species. ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EET, eosinophil extracellular trap; EPO, eosinophil peroxidase; MBP, major basic protein; NO, nitric oxide; RLR, RIG-I-like receptor; ROS, reactive oxygen species; TLR, toll-like receptor.

Viral recognition

Eosinophils express a large variety of toll-like receptors (TLRs) at the mRNA and protein levels, including those that participate in viral recognition such as TLR-3 (79,93), TLR-7, and TLR-9 (140). TLR-7, which recognizes single-stranded RNA (ssRNA) (23), stands out because its expression in eosinophils is higher compared with neutrophils (82,93). It has been shown previously that R-848 (Resiquimod), a TLR-7 synthetic ligand, prolonged survival and induced superoxide generation in eosinophils (82), suggesting the possible antiviral activity of this cell against ssRNA viruses.

Retinoic acid-inducible gene I (RIG-I) expression (mRNA and protein) has been found in eosinophils (61), which is a RIG-I-like receptor (RLR) that recognizes RNA sequences marked with 5′ triphosphorylated ends (67). However, RIG-I expression is low in eosinophils, especially when compared with neutrophils (61), and there are no studies that demonstrate its activity in eosinophils yet.

Antiviral immune response

Eosinophils possess and produce different molecules and develop several mechanisms with potential antiviral activity. ECP not only possesses antibacterial (14,65) and antiparasitic activities (14,41), it is also a member of the ribonuclease A superfamily along with EDN (38). It has been demonstrated that both proteins have RNase activity (101,119), so they could have activity against ssRNA viruses.

Eosinophils are also capable of producing oxidizing species by EPO, which uses hydrogen peroxide as a substrate to produce hypohalous acids (2,134). They also produce NO by inducible NO synthase (21), a molecule that inhibits viral replication by multiple mechanisms (1), and which is effective against several viruses, including influenza virus (99).

Even though eosinophils are frequently associated with T_H2 responses, they are able to produce T_H1, proinflammatory, and anti-inflammatory cytokines (115,121). Eosinophil granules contain preformed IL-2, IL-12, and IFN-γ (20,121), which are typical T_H1 cytokines involved in antiviral responses (58,114).

Similar to neutrophils, eosinophils are able to produce extracellular traps (ETs) (142). Currently, there are no studies that demonstrate the antiviral activity of eosinophil ETs (EETs), but the antiviral effects of neutrophil ETs have been previously reported (112). Similar antiviral effect may be found in EETs.

Eosinophils as antigen presenting cells

Finally, although resting eosinophils do not express major histocompatibility complex (MHC) class II molecules, they could be induced in vitro by GM-CSF (70,95,132), IL-4, and IFN-γ (135). Moreover, eosinophils express co-stimulatory molecules such as CD80 (132), CD86 (132,139), CD28 (139), and CD40 (87,132). This is clinically relevant, since eosinophils recovered from bronchoalveolar lavage (BAL) of atopic patients after an allergen challenge (75,113) and from sputum of asthmatic patients (43) were found to express MHC II molecules.

Furthermore, it has been demonstrated that eosinophil acts as an antigen presenting cell (APC) in response to different antigens (95,132), including viral antigens (42,109), and is capable of inducing cytokine secretion by T cells (42,89,95,109,132). Additionally, eosinophils are able to migrate to lymph nodes, sites where they can present antigens to T cells (109,116,132).

In the next section we summarize and discuss the known antiviral activities of eosinophils against the main respiratory viruses in different models (Fig. 2).

FIG. 2.

Eosinophil response against respiratory viruses. (A) RSV infects eosinophils and induces an overexpression of CD11b, degranulation, and IL-6 release. RSV is recognized by eosinophil TLR-7, which responds with RNase activity and potentially NO production. (B) Human rhinovirus binds to eosinophil ICAM-1 and induces antigen-specific T CD4⁺ proliferation and IFN-γ release. (C) Influenza virus is able to replicate in eosinophils, although the replication is abortive. It induces piecemeal degranulation, expression of viral proteins NP and PB1 on eosinophils, and overexpression of MHC I and CD86. Eosinophils pulsed with influenza peptides are able to activate antigen-specific T CD8⁺ cells, inducing the release of IFN-γ and TNF-α. (D) Parainfluenza virus replication in eosinophils is abortive, and NO is the main eosinophil antiviral response, which is mediated by TLR-7. This response increases with IFN-γ pre-incubation. ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; NP, nucleoprotein; PB1, polymerase basic protein 1; RSV, respiratory syncytial virus; TNF, tumor necrosis factor.

Respiratory Syncytial Virus

RSV is an enveloped virus that contains a non-segmented, negative-sense ssRNA that belongs to the Paramyxoviridae family. RSV is one of the most important pathogens that causes airway infections during childhood (9). Approximately 50% of pneumonia cases and up to 90% of bronchiolitis cases during childhood are caused by this virus (26).

The first connection between RSV and eosinophils occurred in the late 1960s during trials of a formalin-inactivated RSV (FI-RSV) vaccine, which caused the death of two children after being exposed to wild-type (WT) RSV infection. Notably, this vaccine did not induce the production of protective antibodies (56). According to published histopathological findings, the fatal cases presented “peribronchiolar monocytic infiltration with some excess in eosinophils” (56,97). However, this histologic description was not accurate, as neutrophils and mononuclear cells were the most prominent infiltrating cells, as originally described in the autopsy and was also confirmed in another analysis of the original postmortem tissue (9,97). This inaccurate description caused researchers to conclude that eosinophils were responsible for the observed phenomenon (97).

Additionally, some reports have shown the presence of ECP and/or EDN in lung (44) and nasopharyngeal secretions (35) of children with severe RSV infection. These observations should be taken carefully, since none of these proteins are specific to eosinophils, as they can also be found in smaller amounts in other leukocytes such as neutrophils (124). Moreover, in BAL of RSV-infected individuals, neutrophils are the predominant cell type, and eosinophils constitute <1% of the cell population (33,74). A possible mechanism of eosinophil recruitment to the site of RSV infection is through Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) (54,105), which has been detected in the supernatant of human bronchial epithelial cells infected by RSV (7).

Controversies in these observations led some researchers to evaluate the eosinophil antiviral role against RSV. The fact that ssRNA is capable of inducing eosinophil degranulation and EPO release suggests its participation in RSV response (93). Some in vitro studies have demonstrated that lung epithelial cells infected by RSV trigger the release of ECP by eosinophils (88), which together with EDN have antiviral activity against RSV-B due to their RNase activity (24). Furthermore, when eosinophils are exposed to RSV-infected epithelial cells or to TLR-7 ligands, they overexpress CD11b (82,88,93), a surface molecule that has been reported as an activation marker in eosinophils (52,55), so they could be responding to viral infection.

The eosinophil antiviral activity against RSV has been also evaluated in in vivo models. Phipps et al. used IL-5 transgenic mice (IL-5Tg) (93), which are characterized by systemic eosinophilia (22), and WT mice. In these experiments an accelerated viral clearance was observed in mice with a higher number of eosinophils. In contrast, infected ΔdblGATA-1 mice (eosinophil-deficient mice (143)) had a lower viral clearance compared with WT controls (93). In the same study, the authors performed an eosinophil adoptive transfer from MyD88-deficient mice to WT mice. The mice that received MyD88-deficient eosinophils had a higher viral titer compared with those that received WT eosinophils. These results suggest that the observed antiviral effect depends on MyD88 signaling, probably initiated by TLR-7 (93).

Su et al. used eotaxin and IL-5 double-knockout (EotIL-5^−/−) mice, which are characterized by undetectable eosinophils in blood and lungs (123). EotIL-5^−/− mice that were immunized or not with FI-RSV presented a higher viral titer after RSV challenge compared with the controls. The adoptive transfer of eosinophils from IL-5Tg to FI-RSV-immunized and RSV-infected EotIL-5^−/− mice led to a reduced viral titer and an increment in IFN-β production, compared with animals without eosinophil transfer (123). Notably, when a NO inhibitor was used, the effect of eosinophils against RSV was reversed (123), an event that has also been observed in IL-5Tg mice infected with RSV (93). These findings demonstrated the importance of NO in the observed antiviral effect, suggesting that it may be the main mechanism by which eosinophils reduce the viral titer (123).

Eotaxin-2/IL-5 double transgenic mice have been also used to study eosinophil antiviral activity against RSV (91). Besides systemic eosinophilia, these mice developed significant airway eosinophilia, and pulmonary pathologies representative of severe asthma, and presented eosinophils undergoing extensive degranulation (84). When eotaxin-2/IL-5 and WT mice were infected with pneumonia virus of mice (PVM—a severe RSV infection model in mice (100)), eotaxin-2/IL-5 mice presented a reduction in the virus recovered from lungs compared with the control strain, and they were also protected from a lethal inoculum of PVM (91).

In another assay, WT mice were sensitized and challenged with an extract of Aspergillus fumigatus and then infected with PVM. In the lungs of these mice, high levels of EPX and RNase activity, and degranulating eosinophils possibly by piecemeal degranulation, were found. These mice were also completely protected from a lethal inoculum of PVM, suggesting that, although activated eosinophils in the airways are considered detrimental to the host, they might promote the antiviral host defense (91).

Dyer et al. reported for the first time that mouse and human eosinophils can be infected by PVM and RSV, respectively. RSV infection induces the release of IL-6 by human eosinophils, while mouse bone marrow-derived eosinophils (bmdEos) infected with PVM release IL-6, IFN-γ-induced protein 10 (IP-10/CXCL10), monocyte chemoattractant protein 1 (MCP1/CCL2), and macrophage inflammatory protein 1-α (MIP-1α/CCL3). Interestingly, MyD88^−/− bmEos presented an accelerated PVM replication and a decrease in IL-6 release, while the addition of exogenous IL-6 suppressed viral replication (29) (Fig. 2A).

Human Rhinovirus

HRVs are positive-sense ssRNA viruses, members of the Picornaviridae family. They are the most frequent cause of upper respiratory tract infection (51), being also the main viral pathogen isolated from patients with acute asthmatic exacerbations (53,120).

It has been reported that eosinophils bound to HRV 16 by intercellular adhesion molecule (ICAM)-1 in vitro (42), which was overexpressed in BAL eosinophils from allergic asthma patients (75). The incubation of peripheral blood eosinophils with HRV 16 demonstrated, for the first time, the capacity of these cells to act as an APC in response to viral antigens, inducing the proliferation of T CD4⁺ cells and the release of IFN-γ (42). In this context, IFN-γ might be increasing the expression of TLR-7 and TLR-8 on eosinophils (82), suggesting a cooperation between eosinophils and T cells (Fig. 2B).

In a recent publication, patients with mild asthma were treated with Mepolizumab (a humanized monoclonal antibody anti-IL-5) and challenged with HRV 16, which resulted in decreased but not abolished eosinophil count. This treatment did not prevent eosinophil activation upon HRV 16 challenge, and patients showed a higher viral load compared with those that received placebo (108), indicating a possible antiviral role of eosinophils.

Human Parainfluenza Virus

Human PIV is an enveloped, negative-sense, single-stranded, non-segmented RNA virus that belongs to the Paramyxoviridae family (11). They are major causes of lower respiratory infections in infants, immunocompromised patients, and elderly people (45), and have been detected in children with acute asthmatic exacerbations (53).

Adamko et al. used ovalbumin (OVA)-sensitized guinea pigs that were infected by PIV. Sensitized animals showed a ∼80% reduction in the viral content of lungs compared with non-sensitized guinea pigs. This effect was reverted by using anti-IL-5 antibodies, suggesting that the observed effect originated by the recruitment of eosinophils to the lungs (3).

Drake et al. used mouse models to evaluate the antiviral role of eosinophils against PIV. Similar to OVA-sensitized guinea pigs, C57BL/6 mice that were sensitized and challenged with OVA had a ∼90% reduction of viral RNA in the lungs 4 days post-infection (27). Because OVA sensitization and challenge also induces the recruitment of neutrophils and macrophages, authors infected NJ.1726 mice, which are characterized by a local accumulation of peribronchial eosinophils (64). The NJ.1726 mice also presented a viral RNA reduction compared with WT controls. Importantly, mice that constitutively expressed IL-5 but had eosinophil deficiency (NJ.1726-PHIL) behaved like the control mice after infection, suggesting that the antiviral effect was not due to IL-5. Furthermore, using EPX^−/− mice, authors demonstrated that the antiviral effect was not caused by EPO (27).

The same group reported that human peripheral blood eosinophils isolated from healthy volunteers are susceptible to PIV infection. However, the viral progeny was not infectious, suggesting that the infection was abortive (27). Abortive infection has been also suggested in eosinophils infected with influenza virus (109), and it has been proposed as a passive mechanism by which eosinophils limit viral infection (27).

In the same study was also demonstrated that human eosinophils have antiviral activity to PIV in vitro, and this activity increased when eosinophils were pre-incubated with IFN-γ. This antiviral effect was mainly induced by NO production through TLR-7 (27). Although a NO-mediated antiviral effect of eosinophils against RSV was previously suggested by in vivo assays (93,123), this study demonstrated, for the first time, that NO production by eosinophils was indeed responsible for the decreased viral titer, at least against PIV. Besides, no RNase activity of eosinophil ECP and EDN was detected (27), which contrasts with a previous study reporting that RNase activity participated in the antiviral activity against parainfluenza (25). Contradictory results might be due to the different methodologies used (Fig. 2D).

Influenza Virus

Influenza viruses are enveloped, negative-sense, single-stranded, segmented RNA viruses that belong to the Orthomyxoviridae family (92,128). They are common causes of human respiratory infections, inducing high morbidity and mortality (128). Influenza virus induces acute asthma exacerbations in children and adults, especially during annual seasons (90). Interestingly, among patients hospitalized during the 2009 influenza pandemic, patients with asthma had less severe outcomes related to viral infection compared with non-asthmatics (10,31,73,81,83), although the asthma phenotype of these patients was not reported (130).

Samarasinghe et al. developed murine models of comorbidity by combining allergic asthma models (acute and chronic) with a model of influenza A virus (IAV) infection. In the acute asthma model, infected mice presented higher numbers of eosinophils in the airways and an accelerated virus clearance compared with infected mice with chronic asthma. Moreover, those mice with acute asthma presented higher numbers of CD8⁺ T cells and less epithelial damage compared with the chronic asthma model (110).

The same group evaluated the role of eosinophils against IAV by performing an adoptive transfer of eosinophils from A. fumigatus antigen-sensitized mice to the airways of IAV-infected mice. They observed a decrease in viral titer and an increase in virus-specific CD8⁺ T cells in recipient mice compared with non-transferred mice. Opposite results were obtained using infected ΔdblGATA-1 mice, supporting the role of eosinophils against IAV (109).

In the same study, through an in vitro model, it has been demonstrated that mouse eosinophils are susceptible to IAV infection, which triggers eosinophil piecemeal degranulation and an overexpression of MHC I and CD86 (109). Mouse eosinophils pulsed with viral peptides were able to induce IFN-γ and TNF-α release by CD8⁺ T cells obtained from IAV-infected mice, and to promote their proliferation (109). TLR-3, which was found to be elevated in the IAV model, might be recognizing the virus, although experiments have to be performed to demonstrate this. Authors suggest that a higher number of eosinophils in the airways of IAV-infected mice could induce better cellular immunity, considering that eosinophils have the capacity to prime CD8⁺ T cells, as well as to serve as APCs and also as a source of cytokines in the lung microenvironment (109) (Fig. 2C).

Perspectives

Recently a different population of eosinophils has been identified in the lungs of mice. This previously undescribed population, known as lung-resident eosinophils, differ from traditional eosinophils in their phenotype, function, and localization, being capable of inhibiting T_H2 responses against inhaled allergens (76). It would be interesting to evaluate if the response against respiratory viruses from lung-resident eosinophils is similar to traditional eosinophils. In contrast, despite differences between eosinophils from healthy and asthmatic donors reported (6,52), the differences in antiviral responses from these cells have not been addressed.

The relationship between asthma and respiratory virus infection is not fully understood. Even though several studies have demonstrated the interaction between eosinophils and respiratory viruses using in vitro and in vivo models, knowledge about the exact mechanisms of eosinophil participation in the innate and adaptive immune response is lacking. For example, are eosinophils able to degranulate in response to PIV and RV as they do in response to influenza virus and RSV? Which granule proteins are released? Do they possess antiviral properties?

So far, the RNase activity of EDN and ECP has been observed only against RSV, failing to promote antiviral activity against PIV (27) or HRV (71). In contrast, EPO release has been observed when eosinophils are incubated with ssRNA, but its antiviral role has not been demonstrated against any virus yet. The clear lack of data is more evident in HRV infection, which is the main virus that induces exacerbations in asthmatics. Information is also needed to identify the relationship between specific allergens and the antiviral response, since it is known that in some models the antiviral response is allergen-dependent (91). Furthermore, most of the findings discussed above result from studies performed in mice. Although human and mouse eosinophils share many characteristics (63), they also possess differences (104), and the results should be carefully analyzed.

There are some reports that suggest the response and antiviral activity of eosinophils against viruses other than respiratory viruses, such as HIV (32,107), which requires further investigation. Likewise, the eosinophil antiviral activity against other respiratory viruses related to asthmatic exacerbations, including DNA viruses, has not been evaluated yet.

Although previously discussed studies clearly demonstrate the antiviral effects of eosinophils, whether eosinophils are necessary during viral infections in humans and their clinical significance remains unclear. Patients with asthma and chronic obstructive pulmonary disease (COPD) with high blood eosinophil counts have an increased risk of disease exacerbation (96,129). In fact, T_H2-high asthma patients might have specifically an increased risk of virus-induced asthma exacerbations (8). Moreover, there is an increasing list of studies that demonstrate a reduced innate response against respiratory viruses in asthmatic patients (30).

The use of anti-T_H2 approaches, for example, anti-IL-5, anti-IL-4, and anti-IgE biologics, has shown overall good results, reducing exacerbations in patients with eosinophilic asthma (30). It is plausible that their use could help to restore the defective innate immunity in these patients, but it needs to be demonstrated. Nevertheless, the antiviral role of human eosinophils should not be ruled out. Recent findings demonstrated that patients treated with anti-IL-5 presented a higher HRV load compared with the placebo group. These data suggest an important role of eosinophils in the control of viral infections (108).

As suggested by Rosenberg et al. (103), eosinophils might promote an antiviral response against respiratory viruses during specific scenarios, causing, however, a hyper-response attempting to eliminate the virus, leading to host damage (a double-edged sword). Further studies have to be performed to fully understand the relationship between eosinophils and respiratory viruses during certain conditions, such as asthma; this in turn will lead to a better understanding of eosinophil biology.

Footnotes

Acknowledgments

A.S.F.T. received a PhD scholarship from Consejo Nacional de Ciencia y Tecnología. We thank Sergio Lozano-Rodriguez, MD (“Dr. Jose Eleuterio Gonzalez,” Hospital Universitario, Monterrey, Mexico) for his review.

Author Disclosure Statement

No competing financial interests exist.

References

Abdul-Cader

, Amarasinghe

, and Abdul-Careem

. Activation of toll-like receptor signaling pathways leading to nitric oxide-mediated antiviral responses. Arch Virol, 2016; 161:2075–2086.

Acharya

, and Ackerman

. Eosinophil granule proteins: form and function. J Biol Chem, 2014; 289:17406–17415.

Adamko

, Yost

, Gleich

, et al. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection: eosinophils mediate airway hyperresponsiveness, M₂ muscarinic receptor dysfunction, and antiviral effects. J Exp Med, 1999; 190:1465–1478.

Aleman

, Lim

, and Nair

. Eosinophilic endotype of asthma. Immunol Allergy Clin North Am, 2016; 36:559–568.

Asthma Fact Sheet. World Health Organization, 2017. Available from: https://www.who.int/news-room/fact-sheets/detail/asthma (accessed November 2018 ).

Barnig

, Alsaleh

, Jung

, et al. Circulating human eosinophils share a similar transcriptional profile in asthma and other hypereosinophilic disorders. PLoS One, 2015; 2;10:e0141740.

Becker

, Reed

, Henderson

, et al. RSV infection of human airway epithelial cells causes production of the beta-chemokine RANTES. Am Physiol Soc, 1997; 272:L512–L520.

Bjerregaard

, Laing

, Backer

, et al. High fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations: a prospective cohort study. Clin Exp Allergy, 2017; 47:1007–1013.

Borchers

, Chang

, Gershwin

, et al. Respiratory syncytial virus—a comprehensive review. Clin Rev Allergy Immunol, 2013; 45:331–379.

10.

Bramley

, Dasgupta

, Skarbinski

, et al. Intensive care unit patients with 2009 pandemic influenza A (H1N1pdm09) virus infection–United States, 2009. Influenza Other Respir Viruses, 2012; 6:e134–e142.

11.

Branche

, and Falsey

. Parainfluenza virus infection. Semin Respir Crit Care Med, 2016; 37:538–554.

12.

Bufe

, Gehlhar

, Grage-Griebenow

, et al. Atopic phenotype in children is associated with decreased virus-induced interferon-α release. Int Arch Allergy Immunol, 2002; 127:82–88.

13.

Buys

, Wever

, van Stigt

, et al. The killing of newborn larvae of Trichinella spiralis by eosinophil peroxidase in vitro . Eur J Immunol, 1981; 11:843–845.

14.

Bystrom

, Amin

, and Bishop-Bailey

. Analysing the eosinophil cationic protein—a clue to the function of the eosinophil granulocyte. Respir Res, 2011; 12:10.

15.

Campbell

, Tucker

, Hort

, et al. Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc Natl Acad Sci U S A, 1987; 84:6629–6633.

16.

Capron

, Torpier

, and Capron

. In vitro killing of S. mansoni schistosomula by eosinophils from infected rats: role of cytophilic antibodies. J Immunol, 1979; 123:2220–2230.

17.

Chu

, Beller

, Rausch

, et al. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity, 2014; 17;40:582–593.

18.

Contoli

, Message

, Laza-Stanca

, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med, 2006; 12:1023–1026.

19.

Davis

, and Rothenberg

. Eosinophils and cancer. Cancer Immunol Res, 2014; 2:1–8.

20.

Davoine

, and Lacy

. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol, 2014; 5:570.

21.

del Pozo

, de Arruda-Chaves

, de Andrés

, et al. Eosinophils transcribe and translate messenger RNA for inducible nitric oxide synthase. J Immunol, 1997; 158:859–864.

22.

Dent

, Strath

, Mellor

, et al. Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med, 1990; 172:1425–1431.

23.

Diebold

, Kaisho

, Hemmi

, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 2004; 303:1529–1531.

24.

Domachowske

, Dyer

, Adams

, et al. Eosinophil cationic protein/RNase 3 is another RNase A-family ribonuclease with direct antiviral activity. Nucleic Acids Res, 1998; 26:3358–3363.

25.

Domachowske

, Dyer

, Bonville

, et al. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis, 1998; 177:1458–1464.

26.

Domachowske

, and Rosenberg

. Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment. Clin Microbiol Rev, 1999; 12:298–309.

27.

Drake

, Bivins-smith

, Proskocil

, et al. Human and mouse eosinophils have antiviral activity against parainfluenza virus. Am J Respir Cell Mol Biol, 2016; 55:387–394.

28.

Duvernelle

, Freund

, and Frossard

. Transforming growth factor-β and its role in asthma. Pulm Pharmacol Ther, 2003; 16:181–196.

29.

Dyer

, Percopo

, Fischer

, et al. Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6. Blood, 2009; 114:2649–2656.

30.

Edwards

, Strong

, Cameron

, et al. Viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness. J Allergy Clin Immunol, 2017; 140:909–920.

31.

Eriksson

, Graham

, Uyeki

, et al. Risk factors for mechanical ventilation in U.S. children hospitalized with seasonal influenza and 2009 pandemic influenza A. Pediatr Crit Care Med, 2012; 13:625–631.

32.

Espíndola

, Soares

, Galvão-Lima

, et al. HIV infection: focus on the innate immune cells. Immunol Res, 2016; 64:1118–1132.

33.

Everard

, Swarbrick

, Wrightham

, et al. Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. Arch Dis Child, 1994; 71:428–432.

34.

Fabre

, Beiting

, Bliss

, et al. Eosinophil deficiency compromises parasite survival in chronic nematode infection. J Immunol, 2009; 182:1577–1583.

35.

Garofalo

, Kimpen

, Welliver

, et al. Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. Pediatr Res, 1992; 120:29–32.

36.

Gebreselassie

, Moorhead

, Fabre

, et al. Eosinophils preserve parasitic nematode larvae by regulating local immunity. J Immunol, 2012; 188:417–425.

37.

Gleich

, Flavahan

, Fujisawa

, et al. The eosinophil as a mediator of damage to respiratory epithelium: a model for bronchial hyperreactivity. J Allergy Clin Immunol, 1988; 81:776–781.

38.

Gleich

, Loegering

, Bell

, et al. Biochemical and functional similarities between human eosinophil-derived neurotoxin and eosinophil cationic protein: homology with ribonuclease. Proc Natl Acad Sci U S A, 1986; 83:3146–3150.

39.

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available from: www.ginasthma.org (accessed November 2018 ).

40.

Grünig

, Warnock

, Wakil

, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science, 1998; 282:2261–2263.

41.

Hamann

, Gleich

, Checkel

, et al. In vitro killing of microfilariae of Brugia pahangi and Brugia malayi by eosinophil granule proteins. J Immunol, 1990; 144:3166–3173.

42.

Handzel

, Busse

, Sedgwick

, et al. Eosinophils bind rhinovirus and activate virus-specific T cells. J Immunol, 1998; 160:1279–1284.

43.

Hansel

, Braunstein

, Walker

, et al. Sputum eosinophils from asthmatics express ICAM-1 and HLA-DR. Clin Exp Immunol, 1991; 86:261–267.

44.

Harrison

, Bonville

, Rosenberg

, et al. Respiratory syncytical virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation. Am J Respir Crit Care Med, 1999; 159:1918–1924.

45.

Henrickson

. Parainfluenza viruses. Clin Microbiol Rev, 2003; 16:242–264.

46.

Heymann

, Carper

, Murphy

, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol, 2004; 114:239–247.

47.

Huang

, Gebreselassie

, Gagliardo

, et al. Eosinophils mediate protective immunity against secondary nematode infection. J Immunol, 2015; 194:283–290.

48.

Jackson

, Gangnon

, Evans

, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med, 2008; 178:667–672.

49.

Jackson

, and Johnston

. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol, 2010; 125:1178–1187.

50.

Jackson

, and Lemanske

. The role of respiratory virus infections in childhood asthma inception. Immunol Allergy Clin North Am, 2010; 30:513–522.

51.

Jacobs

, Lamson

, Kirsten

, et al. Human rhinoviruses. Clin Microbiol Rev, 2013; 26:135–162.

52.

Johansson

. Activation states of blood eosinophils in asthma. Clin Exp Allergy, 2014; 44:482–498.

53.

Johnston

, Pattemore

, Sanderson

, et al. Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. BMJ, 1995; 310:1225–1229.

54.

Kameyoshi

, Dorschner

, Mallet

, et al. Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med, 1992; 176:587–592.

55.

Kato

, Abraham

, Okada

, et al. Ligation of the beta2 integrin triggers activation and degranulation of human eosinophils. Am J Respir Cell Mol Biol, 1998; 18:675–686.

56.

Kim

, Canchola

, Brandt

, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol, 1969; 89:422–434.

57.

Knott

, Matthaei

, Giacomin

, et al. Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis. Int J Parasitol, 2007; 37:1367–1378.

58.

Komastu

, Ireland

DDC

, and Reiss

. IL-12 and viral infections. Cytokine Growth Factor Rev, 1998; 9:277–285.

59.

Kotaniemi-Syrjänen

, Vainionpää

, Reijonen

, et al. Rhinovirus-induced wheezing in infancy—the first sign of childhood asthma?. J Allergy Clin Immunol, 2003; 111:66–71.

60.

Kovalszki

, and Weller

. Eosinophilia. Prim Care, 2016; 43:607–617.

61.

Kvarnhammar

, Petterson

, and Cardell

. NOD-like receptors and RIG-I-like receptors in human eosinophils: activation by NOD1 and NOD2 agonists. Immunology, 2011; 134:314–325.

62.

Lee

, Jacobsen

, McGarry

, et al. Eosinophils in health and disease: the LIAR hypothesis. Clin Exp Allergy, 2010; 40:563–575.

63.

Lee

, Jacobsen

, Ochkur

, et al. Human vs. mouse eosinophils: “that which we call an eosinophil, by any other name would stain as red”. J Allergy Clin Immunol, 2012; 130:572–584.

64.

Lee

, Mcgarry

, Farmer

, et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med, 1997; 185:2143–2156.

65.

Lehrer

, Szklarek

, Barton

, et al. Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J Immunol, 1989; 142:4428–4434.

66.

Lemanske

, Jackson

, Gangnon

, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol, 2005; 116:571–577.

67.

Loo

, and Gale

. Immune signaling by RIG-I-like receptors. Immunity, 2011; 34:680–692.

68.

Lopez

, Begley

, Williamson

, et al. Murine eosinophil differentiation factor an eosinophil-specific colony-stimulating factor with activity for human cells. J Exp Med, 1986; 163:1085–1099.

69.

Lötvall

, Akdis

, Bacharier

, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol, 2011; 127:355–360.

70.

Lucey

, Nicholson-Weller

, and Weller

. Mature human eosinophils have the capacity to express HLA-DR. Proc Natl Acad Sci, 1989; 86:1348–1351.

71.

Mathur

, Fichtinger

, Kelly

, et al. Interaction between allergy and innate immunity: model for eosinophil regulation of epithelial cell interferon expression. Ann Allergy Asthma Immunol, 2013; 111:25–31.

72.

McGarry

. The evolutionary origins and presence of eosinophils in extant species. In: Lee JJ, Rosenberg HF, (eds.), Eosinophils in Health and Disease. Elsevier, Amsterdam,, 2013:13–18.

73.

McKenna

, Bramley

, Skarbinski

, et al. Asthma in patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection-United States, 2009. BMC Infect Dis, 2013; 13:57.

74.

McNamara

, Ritson

, Selby

, et al. Bronchoalveolar lavage cellularity in infants with severe respiratory syncytial virus bronchiolitis. Arch Dis Child, 2003; 88:922–926.

75.

Mengelers

, Maikoe

, Brinkman

, et al. Immunophenotyping of eosinophils recovered from blood and BAL of allergic asthmatics. Am J Respir Crit Care Med, 1994; 149:345–351.

76.

Mesnil

, Raulier

, Paulissen

, et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest, 2016; 126:3279–3295.

77.

Metcalf

, Burgess

, Johnson

, et al. In vitro actions on hemopoietic cells of recombinant murine GM-CSF purified after production in Escherichia coli: comparison with purified native GM-CSF. J Cell Physiol, 1986; 128:421–431.

78.

Mishra

, Hogan

, Lee

, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest, 1999; 103:1719–1727.

79.

Mnsson

, Fransson

, Adner

, et al. TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis. Int Arch Allergy Immunol, 2010; 151:118–128.

80.

Montuschi

. Role of leukotrienes and leukotriene modifiers in asthma. Pharmaceuticals, 2010; 3:1792–1811.

81.

Myles

, Nguyen-Van-Tam

, Semple

, et al. Differences between asthmatics and nonasthmatics hospitalised with influenza A infection. Eur Respir J, 2013; 41:824–831.

82.

Nagase

, Okugawa

, Ota

, et al. Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol, 2003; 171:3977–3982.

83.

Nguyen-Van-Tam

, Openshaw

, Hashim

, et al. Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009). Thorax, 2010; 65:645–651.

84.

Ochkur

, Jacobsen

, Protheroe

, et al. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J Immunol, 2007; 178:7879–7889.

85.

O'Connell

, Hess

, Santiago

, et al. Major basic protein from eosinophils and myeloperoxidase from neutrophils are required for protective immunity to Strongyloides stercoralis in mice. Infect Immun, 2011; 79:2770–2778.

86.

O'Donnell

, Ackerman

, Gleich

, et al. Activation of basophil and mast cell histamine release by eosinophil granule major basic protein. J Exp Med, 1983; 157:1981–1991.

87.

Ohkawara

, Lim

, Xing

, et al. CD40 expression by human peripheral blood eosinophils. J Clin Invest, 1996; 97:1761–1766.

88.

Olszewska-Pazdrak

, Pazdrak

, Ogra

, et al. Respiratory syncytial virus-infected pulmonary epithelial cells induce eosinophil degranulation by a CD18-mediated mechanism. J Immunol, 1998; 160:4889–4895.

89.

Padigel

, Lee

, Nolan

, et al. Eosinophils can function as antigen-presenting cells to induce primary and secondary immune responses to Strongyloides stercoralis . Infect Immun, 2006; 74:3232–3238.

90.

Papadopoulos

, Christodoulou

, Rohde

, et al. Viruses and bacteria in acute asthma exacerbations—a GA 2LEN-DARE* systematic review. Allergy Eur J Allergy Clin Immunol, 2011; 66:458–468.

91.

Percopo

, Dyer

, Ochkur

, et al. Activated mouse eosinophils protect against lethal respiratory virus infection. Blood, 2014; 123:743–752.

92.

Petrova

, and Russell

. The evolution of seasonal influenza viruses. Nat Rev Microbiol, 2017; 16:47–60.

93.

Phipps

, Lam

, Mahalingam

, et al. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood, 2007; 110:1578–1586.

94.

Piliponsky

, Gleich

, Nagler

, et al. Non-IgE-dependent activation of human lung- and cord blood-derived mast cells is induced by eosinophil major basic protein and modulated by the membrane form of stem cell factor. Blood, 2003; 101:1898–1904.

95.

Pozo

, de Andrés

, Martín

, et al. Eosinophil as antigen-presenting cell: activation of T cell clones and T cell hybridoma by eosinophils after antigen processing. Eur J Immunol, 1992; 22:1919–1925.

96.

Price

, Rigazio

, Campbell

, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med, 2015; 3:849–858.

97.

Prince

, Curtis

, Yim

, et al. Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J Gen Virol, 2001; 82:2881–2888.

98.

Ravin

, and Loy

. The eosinophil in infection. Clin Rev Allergy Immunol, 2015; 50:214–227.

99.

Rimmelzwaan

, Baars

, Fouchier

RAM

, et al. Inhibition of influenza virus replication by nitric oxide. Int Congr Ser, 2001; 1219:551–555.

100.

Rosenberg

, Bonville

, Easton

, et al. The pneumonia virus of mice infection model for severe respiratory syncytial virus infection: identifying novel targets for therapeutic intervention. Pharmacol Ther, 2005; 105:1–6.

101.

Rosenberg

, and Domachowske

. Eosinophils, ribonucleases and host defense: solving the puzzle. Immunol Res, 1999; 20:261–274.

102.

Rosenberg

, Dyer

, and Domachowske

. Eosinophils and their interactions with respiratory virus pathogens. Immunol Res, 2009; 43:128–137.

103.

Rosenberg

, Dyer

, and Domachowske

. Respiratory viruses and eosinophils: exploring the connections. Antiviral Res, 2009; 83:1–9.

104.

Rosenberg

, Phipps

Sand

, and Foster

. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol, 2007; 119:1303–1310.

105.

Rot

, Krieger

, Brunner

, et al. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med, 1992; 176:1489–1495.

106.

Rothenberg

, and Hogan

. The eosinophil. Annu Rev Immunol, 2006; 24:147–174.

107.

Rugeles

, Trubey

, Bedoya

, et al. Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by HLA alloantigen recognition. AIDS, 2003; 17:481–486.

108.

Sabogal Piñeros

, Bal

, van de Pol

, et al. Anti-IL-5 in mild asthma alters rhinovirus-induced macrophage, B cell and neutrophil responses (MATERIAL): a placebo-controlled, double-blind study. Am J Respir Crit Care Med, 2019; 199:508–517.

109.

Samarasinghe

, Melo

, Duan

, et al. Eosinophils promote antiviral immunity in mice infected with influenza A virus. J Immunol, 2017; 198:3214–3226.

110.

Samarasinghe

, Woolard

, Boyd

, et al. The immune profile associated with acute allergic asthma accelerates clearance of influenza virus. Immunol Cell Biol, 2014; 92:449–459.

111.

Sanderson

. Interleukin-5, eosinophils, and disease. Blood, 1992; 79:3101–3109.

112.

Schönrich

, and Raftery

. Neutrophil extracellular traps go viral. Front Immunol, 2016; 7:366.

113.

Sedgwick

, Calhoun

, Vrtis

, et al. Comparison of airway and blood eosinophil function after in vivo antigen challenge. J Immunol, 1992; 149:3710–3718.

114.

Sen

. Viruses and interferons. Ann Rev Microbiol, 2001; 55:255–281.

115.

Shamri

, Xenakis

, and Spencer

. Eosinophils in innate immunity: an evolving story. Cell Tissue Res, 2011; 343:57–83.

116.

Shi

, Humbles

, Gerard

, et al. Lymph node trafficking and antigen presentation by endobronchial eosinophils. J Clin Invest, 2000; 105:945–953.

117.

Sigurs

, Gustafsson

, Bjarnason

, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med, 2005; 171:137–141.

118.

Simon

, Wardlaw

, and Rothenberg

. Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract. J Allergy Clin Immunol, 2010; 126:3–13.

119.

Slifman

, Loegering

, McKean

, et al. Ribonuclease activity associated with human eosinophil-derived neurotoxin and eosinophil cationic protein. J Immunol, 1986; 137:2913–2917.

120.

Song

. Rhinovirus and childhood asthma: an update. Korean J Pediatr, 2016; 59:432–439.

121.

Spencer

, Szela

, Perez

SAC

, et al. Human eosinophils constitutively express multiple Th1, Th2, and immunoregulatory cytokines that are secreted rapidly and differentially. J Leukoc Biol, 2008; 85:117–123.

122.

Steinbach

, Schick

, Trepel

, et al. Estimation of kinetic parameters of neutrophilic, eosinophilic, and basophilic granulocytes in human blood. Blut, 1979; 39:27–38.

123.

Y-C

, Townsend

, Herrero

, et al. Dual proinflammatory and antiviral properties of pulmonary eosinophils in respiratory syncytial virus vaccine-enhanced disease. J Virol, 2015; 89:1564–1578.

124.

Sur

, Glitz

, Kita

, et al. Localization of eosinophil-derived neurotoxin and eosinophil cationic protein in neutrophilic leukocytes. J Leukoc Biol, 1998; 63:715–722.

125.

Svenningsen

, and Nair

. Asthma endotypes and an overview of targeted therapy for asthma. Front Med, 2017; 4:158.

126.

Swartz

, Dyer

, Cheever

, et al. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood, 2006; 108:2420–2427.

127.

Sykes

, and Johnston

. Etiology of asthma exacerbations. J Allergy Clin Immunol, 2008; 122:685–688.

128.

Taubenberger

, and Kash

. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe, 2010; 7:440–451.

129.

Vedel-Krogh

, Nielsen

, Lange

, et al. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease: the copenhagen general population study. Am J Respir Crit Care Med, 2016; 193:965–974.

130.

Veerapandian

, Snyder

, and Samarasinghe

. Influenza in asthmatics: for better or for worse?. Front Immunol, 2018; 9:1843.

131.

Venturiello

, Giambartolomei

, and Constantino

. Immune cytotoxic activity of human eosinophils against Trichinella spiralis newborn larvae. Parasite Immunol, 1995; 17:555–559.

132.

Wang

H-B

, Ghiran

, Matthaei

, et al. Airway eosinophils: allergic inflammation recruited professional antigen-presenting cells. J Immunol, 2007; 179:7585–7592.

133.

Wark

PAB

, Johnston

, Bucchieri

, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med, 2005; 201:937–947.

134.

Weiss

, Test

, Eckmann

, et al. Brominating oxidants generated by human eosinophils. Science, 1986; 234:200–203.

135.

Weller

, Rand

, Barrett

, et al. Accessory cell function of human eosinophils. HLA-DR-dependent, MHC-restricted antigen-presentation and IL-1 alpha expression. J Immunol, 1993; 150:2554–2562.

136.

Weller

, and Spencer

. Functions of tissue-resident eosinophils. Nat Rev Immunol, 2017; 17:746–760.

137.

Wenzel

, Schwartz

, Langmack

, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med, 1999; 160:1001–1008.

138.

White

. The role of histamine in allergic diseases. J Allergy Clin Immunol, 1990; 86:599–605.

139.

Woerly

, Roger

, Loiseau

, et al. Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon gamma): inhibition by immunoglobulin a complexes. J Exp Med, 1999; 190:487–495.

140.

Wong

, Cheung

PFY

, Ip

, et al. Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. Am J Respir Cell Mol Biol, 2007; 37:85–96.

141.

, Molofsky

, Liang

, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science, 2011; 332:243–247.

142.

Yousefi

, Gold

, Andina

, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med, 2008; 14:949–953.

143.

, Cantor

, Yang

, et al. targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo . J Exp Med, 2002; 195:1387–1395.