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Nitric Oxide and the Common Cold

David Proud  Jan 27, 2005 Authors & Disclosures

Curr Opin Allergy Clin Immunol. 2005;5(1):37-42. © 2005 Lippincott Williams & Wilkins 
 

There is substantial evidence that Nitric Oxide possesses broad-ranging antiviral activity

 

Purpose of Review: The common cold is a clinical syndrome triggered by a variety of viral pathogens, but rhinoviruses are the most frequent cause. Complications of such infections include sinusitis, otitis media, and exacerbations of asthma and chronic obstructive lung disease. There is growing interest in host innate defence responses that may regulate the severity of viral responses. We will review recent evidence that nitric oxide is an important contributor to the host response during colds. 

Recent Findings: Infection of human airway epithelial cells with human rhinovirus has been shown to lead to the increased expression of inducible nitric oxide synthase both in vitro and in vivo. This increase in epithelial inducible nitric oxide synthase correlates with increased levels of nitric oxide in exhaled air. Importantly, nitric oxide can inhibit human rhinovirus-induced epithelial expression of several pro-inflammatory cytokines and can inhibit viral replication in epithelial cells in vitro. Moreover, nitric oxide can modulate several signal transduction pathways that are associated with cytokine generation. Nitric oxide can also nitrosylate viral proteases and can interact with the immune system. Consistent with these observations, pilot studies have indicated that the increased generation of nitric oxide during rhinovirus infections is associated with fewer symptoms and more rapid viral clearance. 

Summary: Further studies are warranted to evaluate the role of nitric oxide in colds and to determine whether the administration of nitric oxide donor compounds could be a viable therapeutic approach for viral exacerbations of airway diseases.

The common cold is the most frequently experienced acute respiratory illness in humans. Although several viral pathogens, including coronaviruses, respiratory syncytial virus (RSV), influenza, parainfluenza and adenoviruses can induce this clinical syndrome, human rhinoviruses account for approximately 50% of all colds. [1] Colds result in 25 million days lost from work each year in the United States. [2] In addition, respiratory viral infections, particularly human rhinovirus (HRV) infections, lead to substantial healthcare costs by virtue of being important precipitating factors for otitis media, [3] sinusitis, [4] and exacerbations of chronic obstructive pulmonary disease (COPD), [5*] and asthma. [6*] In addition, HRV-induced wheezing in early childhood has been associated with the development of asthma. [7*]

Despite the high incidence of colds, the mechanisms by which inciting viruses induce symptoms and exacerbations of asthma and COPD remain poorly understood. In-situ hybridization has demonstrated that the airway epithelial cell is the primary site of HRV infection in vivo, [8] and that virus can spread to, and replicate in, the lower airway epithelium. [9] In contrast to other viral types above, HRV infections result in no overt epithelial cytotoxicity, either in vivo or in vitro, [10,11] supporting the hypothesis that symptom development is induced by altering epithelial cell biology in a manner that induces, or exacerbates, airway inflammation. We will review recent evidence that the epithelial cell, particularly via the production of nitric oxide (NO), plays an important role in regulating the host inflammatory and innate immune response to viral infections.

Symptomatic colds are associated with increased airway infiltration of neutrophils and lymphocytes [12,13] and, in some atopic individuals, increased lower airway eosinophilia is seen. [14] Several recent studies have examined whether susceptibility, or responses, to viral infection are altered in allergic or asthmatic subjects. A longitudinal cohort study concluded that there was no difference in the frequency, duration or severity of rhinovirus infections between asthmatic and non-asthmatic subjects, although lower respiratory symptoms were more common in asthmatic subjects. [15] A comparison of patients who were admitted to hospital with acute exacerbations with individuals with stable asthma found that sensitization and exposure to allergens was an independent risk factor for hospitalization, suggesting that allergens and viruses act synergistically to exacerbate asthma. [16] Despite this link, studies of the interaction of experimental allergen exposure and experimental virus infection have generated mixed results.

Atopic or asthmatic individuals with colds have been shown to experience increased upper and lower airway inflammatory responses to allergen provocation. [17,18] By contrast, chronic low-dose allergen provocations had no effect on subsequent lower airway responses to viral infection, [19*] and allergen challenge delayed onset and shortened the duration of common colds in the upper airways. [20] It remains to be determined if these variable effects are caused by the relative timing and dose of allergen and viral challenges, or whether specific subgroups of individuals may show enhanced responses. For example, a recent study [21*] observed that challenge with HRV led to significantly greater symptoms and inflammation in those asthmatic subjects with high total serum IgE compared with those with lower levels of IgE.

Viral infection of airway epithelial cells induces the generation of a variety of cytokines and chemokines that would be fully expected to exacerbate airway inflammation. As recently reviewed, these include chemokines, such as growth regulated oncogene alpha (CXCL1), IL-8 (CXCL8), epithelial-derived neutrophil-activating peptide-78 (CXCL5), macrophage-inflammatory protein-1 a (CCL3), regulated upon activation, normal T-cell expressed and secreted (CCL5), and eotaxin (CCL11), as well as pleiotropic cytokines and growth factors, including IL-1, IL-6, IL-11 and granulocyte macrophage colony-stimulating factor. [22*] Many of these proteins are also detected in airway secretions during in-vivo viral infections. [23-25] Although these cytokines play a significant role in host defence, excessive production could account for the overexuberant recruitment and activation of neutrophils, lymphocytes, monocytes and eosinophils, and could contribute to symptoms.

 Although HRV infections elicit antigen-specific humoral and cellular immune responses, these are usually not detectable until after the majority of cold symptoms have resolved. [26] Therefore, antigen-specific adaptive immunity may play a role in final viral clearance and protection from re-infection, but the innate immune response provides the primary means of limiting symptoms. It is now recognized that the epithelium contributes to host defence, [22*,27*] and recent evidence supports the fact that the epithelium also plays a role in coordinating the innate immune response to viruses.

 

In addition to the generation of cytokines, the infection of epithelial cells with HRV induces the production of human beta-defensin-2 (HBD-2), both in vitro and in vivo. [28*] HBD-2 has no direct antiviral activity towards HRV, [28*] but the levels of HBD-2 produced in vivo are well within the range that are chemotactic for immature dendritic cells and memory T cells. [29] The viral generation of HBD-2 could thus provide an important link between the innate and adaptive immune responses. By contrast, epithelial cell production of NO appears to be directly involved in the innate antiviral response against HRV infection.

 

Nitric Oxide is produced from L-arginine by any of three isoforms of the enzyme nitric oxide synthase (NOS).

Type I and III NOS are constitutively expressed, calcium activated, and produce short bursts of NO at relatively low concentrations. In contrast, type II NOS is often absent in resting cells, but is inducible by several cytokines and microbial products, is calcium independent, and generates substantially larger amounts of NO for sustained periods. Epithelial cells express all three isoforms of NOS, [30] but the inducible enzyme, inducible nitric oxide synthase (iNOS), is the predominant form, and its expression is not inhibited by glucocorticoids. [31]

Recent studies have shown that respiratory viruses can increase epithelial iNOS expression. HRV infection increased the expression of iNOS messenger RNA and protein in human airway epithelial cells in a manner that was dependent upon viral replication. Importantly, increased epithelial iNOS gene expression was also detected in airway epithelial scrapings during symptomatic HRV infections. [32] Similarly, RSV infection induced iNOS expression in an alveolar epithelial cell line, and this induction was accompanied by increased nitrite levels in cell supernatants. [33] Influenza A infection also increases epithelial iNOS expression. [34] It remains unclear whether each of these viruses induce iNOS expression by identical mechanisms, but it is of interest that double-stranded RNA is formed during the replication of all of these viruses, and synthetic dsRNA is a potent stimulus for iNOS gene induction. [34]

Despite increased epithelial iNOS expression in response to viral infection, data supporting increased levels of NO in exhaled air during colds have been more inconsistent. Levels of exhaled NO from the lower airways increase during natural viral infections of unknown etiology, [35] as well as during experimental infections with either HRV or influenza. [36,37] In contrast, no increases in either nasal or lower airway NO were detected during experimental RSV infections in adults. [38] Similarly, nasal levels of exhaled NO were found not to be increased during either HRV or influenza infections when assayed either by the 'off-line' measurement of NO or by the assessment of nitrite. [37,39]

These variations could suggest that epithelial iNOS expression is not a major contributor to nasal exhaled NO, or simply may reflect technical issues in measuring exhaled NO. In a more recent study in which both nasal and lower airway exhaled NO were assessed at multiple exhaled flow rates, [40**] significant increases in both nasal and lower airway exhaled NO were observed during symptomatic HRV infections, and these two indices were positively correlated. Increased nasal exhaled NO levels were also associated with increased nasal epithelial iNOS mRNA expression, a finding recently confirmed by others. [41*] Symptom scores were inversely correlated with increases in nasal NO. [40**] Moreover, those subjects with the largest nasal NO increases cleared virus more quickly. [40**] It will be important to confirm these observations using larger numbers of subjects.

 There is substantial evidence that NO possesses broad-ranging antiviral activity. In several animal cell lines, the antiviral actions of IFN-γ are mediated through the increased expression of iNOS and enhanced production of NO, [42] and mice engineered to be deficient in iNOS are more susceptible to viral infection. [43] In terms of the common cold, NO at levels comparable with those detected during in-vivo infections markedly inhibits the replication of HRV in epithelial cells. [40**,44] Similarly, the replication of influenza in epithelial cells is inhibited by NO. [45] More recently, it has been demonstrated that cells constitutively generating NO as a result of transfection with a retroviral construct containing iNOS could be infected with RSV, but viral replication inversely correlated with the level of NO generated, an effect that could be reversed in the presence of a NOS inhibitor. [46**]

Similarly, it has been shown that the increased replication of parainfluenza virus that occurs in epithelial cells from patients with cystic fibrosis is caused by an inability of cystic fibrosis cells to produce iNOS, and that the overexpression of iNOS or the addition of a NO donor provides protection against increased viral replication. [47**]

The basis of the antiviral actions of NO is poorly understood and may vary with viral type. There have been no detailed evaluations of the interaction of NO with host antiviral pathways, but several studies have indicated that viral thiol proteases may be one important target for NO. Several respiratory viruses, including HRV, contain thiol proteases as part of their genome. These proteases are important for cleavage of the viral polyprotein, suppression of host cell transcription and translation, and cleavage of certain transcription factors. [48*] It is clear that S-nitrosylation, the covalent addition of a NO moiety to cysteine residues, is an important mode of action of NO. [49] Consistent with this, it has been shown that NO can nitrosylate, and inhibit, the 2A and 3C proteases of coxsackievirus [50,51*] and the adenovirus thiol protease. [52*] In each case, protease inhibition reduced virus replication and infectivity.

 

Early considerations of the role of Nitric Oxide in the airways focused on its potential to enhance inflammation, particularly via the generation of peroxynitrite.

We now recognize that the actions of NO are more complex, and increased production of NO can regulate the inflammatory and immune response during colds. For example, lower airway NO appears to be protective during viral infections in asthmatic patients, as individuals with the largest increases in exhaled NO had the smallest increases in airways responsiveness. [36]

In addition to affecting viral replication, NO also suppresses virally induced cytokine generation. Inhibition of the HRV-induced epithelial production of IL-8 and IL-6 by NO occurs predominantly at the level of posttranscriptional regulation, [44] whereas the HRV-induced generation of other cytokines may be mediated at the level of transcription. [53] These effects are not all secondary to effects on viral replication. Some cytokines, such as IL-8 and IL-6, are induced early after infection and are also induced by ultraviolet-treated HRV that cannot replicate. Even for cytokines that require viral replication for induction, there is evidence for effects of NO that are independent of the replication cycle. Both a plasmid encoding the HRV 3C protease, [54*] and dsRNA [55*] can mimic the induction of specific cytokines, and the dsRNA-induced production of cytokines can also be inhibited by NO (R. Koetzler, D. Proud, unpublished data).

Moreover, NO is known to modulate several key signaling pathways that have been implicated in cytokine induction. These include members of the mitogen-activated protein kinase family that have been implicated in both the transcriptional and posttranscriptional regulation of virally induced cytokines, as well as members of the Janus family of kinases. [56] NO can nitrosylate a variety of transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein-1, which contain cysteine residues close to their DNA binding regions, as well as transcription factors, such as Sp1 and early growth response protein-1, which contain Cys 2His 2 zinc finger type DNA-binding motifs. [57] The case of NF-κB, however, illustrates the complexity of interpreting the outcome of S-nitrosylation by NO. [58**]

 

In addition to the ability of NO to S-nitrosylate the Cys-62 residue in the DNA-binding domain of the p50 component of NF-κB, thereby inhibiting gene activation, it has also recently been shown that NO can block the pathway further upstream via S-nitrosylation and the inhibition of inhibitory kappa B kinase. [59**] In contrast, NO also can S-nitrosylate and activate the small G protein p21 ras, which activates downstream effectors including NF-κB. [58**] It is also likely that some of these effects will depend on the specific cell context, as the acute activation of NF-κB in HRV-infected epithelial cells was not inhibited by NO. [60]

Finally, NO may modulate adaptive immune responses during viral infections but, again, the potential effects are diverse and complex, and may depend upon the concentration and cell of origin.

In murine models of autoimmune disease, iNOS knockout mice show more severe disease, suggesting an immunosuppressive function of NO. It has also been reported that NO inhibits both T helper types 1 and 2 cell proliferation in mice without altering cytokine production, [61] but the studies focused on antigen presenting cells as the source of NO. The effects of NO on human T-cell function have been less well studied. Interestingly, NO stimulates the proteasomal degradation of indoleamine 2,3-dioxygenase in a human epithelial line. [62**] Given that the indoleamine 2,3-dioxygenase pathway can suppress T-cell responses and that kynurenine, a metabolite of this pathway, can induce T-cell apoptosis, [63*,64*] NO-mediated suppression of this pathway may be expected to lead to enhanced T-cell responses. By contrast, the inhibition of the indoleamine 2,3-dioxygenase pathway reportedly leads to reduced natural killer cell activity in mice. [65]

There is now compelling evidence that NO plays a role in the host response during the common cold and its complications. Further studies are clearly needed, however, to define fully the antiviral actions of NO and to delineate the molecular mechanisms by which NO inhibits virally induced cytokine and chemokine production. The complex contributions of NO to the innate and specific immune response must also be more fully defined. Despite these issues, the evaluation of NO donor compounds as potential therapeutic agents to treat viral exacerbations of asthma and COPD remains an intriguing approach.

 

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