Emotional style, nasal cytokines, and illness expression after experimental rhinovirus exposure

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Abstract

Psychosocial factors moderate the expression of illness during upper respiratory virus infections but past attempts to define mediational pathways were not successful. Here, we used a model of experimental rhinovirus infection in humans to evaluate three proinflammatory cytokines for their potential role in mediating the previously documented association between positive emotional style and illness. After assessing emotional style in 327 healthy adults, each was exposed to one of two strains of rhinovirus and followed for 5 days in quarantine. Symptoms/signs, nasal lavage IL-1β, IL-6, and IL-8 protein, and viral shedding were assessed at baseline and on each of the 5 days after exposure. Virus-specific antibody was assessed at baseline and 28 days after challenge. An analysis of the data for 234 subjects with documented infection showed that nasal IL-1β, IL-6, and IL-8 protein levels were all associated with greater illness expression but IL-6 was by far the best predictor of nasal signs and symptoms. Lower positive emotional style was associated with greater objective and subjective markers of illness and these associations were decreased substantially by controlling for IL-6 but not for IL-1β or IL-8. These results are consistent with the hypothesis that IL-6 acts as a biological mediator in linking positive emotional style to illness expression during rhinovirus infection.

Introduction

A traditional method for studying the pathogenesis of upper respiratory diseases and their complications is the assay of local secretions and/or other recovered fluids for chemicals that are expected to participate in the immune/inflammatory process (Doyle et al., 2005). High levels of proinflammatory and anti-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8, IL-10, interferon (INF)α, INFγ, and tumor necrosis factor (TNF)α have been recovered in nasal secretions and nasal lavage fluids at the time of acute viral upper respiratory illnesses (vURIs) caused by respiratory syncytial virus, parainfluenza virus, rhinovirus (RV), influenza virus, and infections of unspecified etiology (Chen et al., 2002, Garofalo et al., 2004, Gern et al., 2002, Hornsleth et al., 2001, Kaiser et al., 2001, Noah et al., 1995, Oh et al., 2002, Sheeran et al., 1999). Assays of nasal cytokine production in adults experimentally infected with known viruses indicated similarly patterned cytokine responses that were consistent across viruses (de Kluijver et al., 2003, Doyle et al., 2005, Fritz et al., 1999, Hayden et al., 1998, Linden et al., 1995, Noah and Becker, 2000, Yoon et al., 1999, Yuta et al., 1998, Zhu et al., 1996, Zhu et al., 1997). For example, Hayden and colleagues reported increases in nasal IL-6, IL-8, TNFα, and INFα levels in persons expressing symptoms after influenza challenge (Hayden et al., 1998) and Gentile and colleagues reported increased levels of IL-1β and IL-6 in only those subjects who expressed symptoms after RV challenge (Gentile et al., 2003).

A continuing focus of our research is the psychosocial modifiers of illness expression during natural and experimental vURIs. For example, we previously reported that chronic stress, less diverse social networks, and low levels of positive emotional style (PES) all predicted an increased probability of developing a common cold in persons experimentally infected with an upper respiratory virus (e.g., Cohen et al., 1991, Cohen et al., 1997, Cohen et al., 1998, Cohen et al., 1999, Cohen et al., 2003). However, while most pathways (e.g., cortisol, epinephrine and norepinephrine, cigarettes/day, alcoholic drinks/day, zinc, and vitamin C intake) evaluated as potentially linking these psychosocial factors to illness severity were not supported, the results of one study suggested a mediating role for local IL-6 production (Cohen et al., 1999). There, the symptom/sign response and nasal IL-6 level for 55 adult subjects experimentally infected with influenza A virus were monitored and compared between groups defined by pre-exposure perceived stress. The results documented that greater stress predicted greater IL-6 production, symptoms and nasal secretions, and mediational analysis supported IL-6 production as a potential pathway linking perceived stress to illness (Cohen et al., 1999).

A role for IL-6 in mediating the association between psychosocial factors and illness is supported by the results of past studies. Basal serum levels of IL-6 are higher in subjects reporting negative psychological traits and behaviors, and lower in those reporting positive ones. For example, serum levels of IL-6 were higher in those who reported high levels of hostility (Suarez, 2003) and anger (Lutgendorf et al., 1999), and lower in cancer patients seeking social support (Lutgendorf et al., 2000) and in individuals who reported frequent church attendance (Koenig et al., 1997). Moreover, in an animal model, the release of IL-1, TNFα, and IL-6 during infection was reported to be modulated by glucocorticoids, thus providing a hypothetical pathway by which psychosocial factors (via their influence on glucocorticoid production) could control cytokine production (Dobbs et al., 1996, Konstantinos and Sheridan, 2001).

PES is a measure of dispositional positive affect and low levels of PES have been implicated as contributing to greater mortality among community-dwelling elderly, higher morbidity for several diseases, and greater reports of unfounded pains and symptoms (review in Pressman and Cohen, in press). We previously reported a protective effect of high PES on cold incidence in a large cohort of adult subjects experimentally infected with RV39 or RV23 (Cohen et al., 2003) and more recently assayed archived, serial nasal lavage samples collected from these subjects for IL-1β, IL-6, and IL-8 protein levels. This panel of cytokines was chosen for assay because its members are locally produced during the ill period of a vURI (Gentile et al., 2003, Hayden et al., 1998); were suggested to directly mediate symptom/sign expression (Cohen et al., 1999, Doyle et al., 2005), and their serum levels have been related to a wide range of psychosocial factors such as depression (Kubera et al., 2000), hostility (Suarez, 2003), and church attendance (Koenig et al., 1997).

In this report, we evaluated the hypothesis, developed from our study of IL-6 production in influenza infected subjects, that PES modulates illness during RV infection via an intermediate effect on local IL-6 production. By using three distinct symptom clusters and two objective signs of illness as outcomes, we also tested if each of the assayed cytokines—IL-1β, IL-6, and IL-8—mediates a specific domain of symptoms/signs and if the effects of PES on illness are specific to a symptom/sign domain. Because the majority of outcomes are self-reported symptoms, we included a group of control symptoms (not characteristic of a vURI) that are expected to be subject to reporting bias but not influenced by experimental conditions.

Section snippets

Materials and methods

Adult subjects (>18 years) were recruited by advertisements from the metropolitan Pittsburgh, PA area. On presentation for screening, the design and obligations of study participation were explained and informed consent was obtained from those interested in participating. All consented volunteers underwent medical screenings by history and physical, supplied demographic information and had blood taken for assay of pre-exposure RV-specific neutralizing antibodies. Subjects were excluded on

Results

Because we were interested in symptom/sign expression among infected subjects, the analyses were limited to subjects who were infected by the standard clinical criteria—either shed virus or seroconverted (Gwaltney et al., 1989). Overall, 209 of 334 (63%) subjects shed virus and, of 209 subjects with pre-exposure antibody titers <8, 106 (51%) evidenced seroconversion (fourfold antibody increase). This resulted in 234 (70%) subjects classified as infected. The population demographics were 115

Discussion

In an earlier article, we reported that greater levels of PES predicted a lesser risk for objectively defined colds in persons experimentally infected with RV. While PES could promote resistance to illness by encouraging health-enhancing behaviors, building resources to cope with stress and enhancing regulation of emotion-sensitive biological systems (Fredrickson, 2004, Pressman and Cohen, in press), none of these pathways examined at that time explained the observed relationship (Cohen et al.,

Acknowledgments

Supported by grants from the US National Institute of Mental Health (MH50429) and by a supplemental grant from the John D. and Catherine T. MacArthur Foundation Network on Socioeconomic Status and Health. The collaboration was facilitated by the Pittsburgh NIH Mind-Body Center (HL65111 and HL65112). We are indebted to Dr. Ronald Turner of the Department of Pediatrics, University of Virginia, for performing the serological and viral assays, Drs. Cuneyt Alper and David Skoner for performing the

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