key: cord-0989097-ityut6bh
authors: Bower, Julienne E.; Radin, Arielle; Kuhlman, Kate R.
title: Psychoneuroimmunology in the time of COVID-19: Why neuro-immune interactions matter for mental and physical health
date: 2022-05-06
journal: Behav Res Ther
DOI: 10.1016/j.brat.2022.104104
sha: 6fc7a3a0b9695c6f2340ed1bff6c353c26fd7666
doc_id: 989097
cord_uid: ityut6bh

The brain and immune system are intricately connected, and perturbations in one system have direct effects on the other. This review focuses on these dynamic psychoneuroimmune interactions and their implications for mental and physical health in the context of the COVID-19 pandemic. In particular, we describe how psychological states influence antiviral immunity and the vaccine response, and how immune changes triggered by COVID (either via infection with SARS-CoV-2 or associated stressors) can influence the brain with effects on cognition, emotion, and behavior. We consider negative psychological states, which have been the primary focus of psychological research in the context of COVID-19 (and psychoneuroimmunology more generally). We also consider positive psychological states, including positive affect and eudaimonic well-being, given increasing evidence for their importance as modulators of immunity. We finish with a discussion of interventions that may be effective in improving immune function, the neuro-immune axis, and ultimately, mental and physical health.

psychosocial factors and immunity among individuals infected with SARS-CoV-2 are not yet available. However, there is compelling evidence that individuals with mental disorders are at increased risk for COVID-19-related hospitalization and mortality (Vai et al., 2021; Wang, Xu, & Volkow, 2021) , supporting the relevance of negative psychological states for immune response to SARS-CoV-2.

The field of PNI is founded on studies examining links between stress and the immune system. This work is particularly relevant in the context of COVID, which combines all elements of a major stressor: the pandemic is unpredictable, uncontrollable, has generated tremendous fear, loss, and grief, created social and political turmoil, and disrupted almost all aspects of daily life. The effect of stress on antiviral immunity have been elegantly demonstrated in preclinical research, including studies with rodents using restraint stress as a model (Sheridan et al., 1998) . This program of work has shown that restraint stress activates the hypothalamicpituitary-adrenal (HPA) axis and the sympathetic nervous system, leading to suppression of virus-specific T and B cell responses that ultimately result in more severe viral infection (Sheridan et al., 1998) . In nonhuman primates, stress is associated with increased sympathetic innervation of lymph nodes and accelerated progression of simian immunodeficiency virus (SIV), the primate version of HIV (Sloan et al., 2007) . In humans, stressors ranging from examination stress to caregiving for a spouse with dementia have been shown to impair aspects of the adaptive immune response relevant for viral infection (Glaser & Kiecolt-Glaser, 2005) .

Further, studies in which individuals are exposed to a cold or influenza virus have shown that those under chronic stress are more likely to develop upper respiratory infections (Cohen, 2021) .

These effects extend to vaccine response, such that stressed individuals mount a diminished antibody response to vaccination (Madison, Shrout, Renna, & Kiecolt-Glaser, 2021 ). J o u r n a l P r e -p r o o f 7 immunodeficiency virus . Similarly, socially inhibited men with HIV showed faster progression from HIV to AIDS, earlier mortality, and poorer response to antiviral medication (Cole, 2008) . Social isolation, as indicated by fewer social contacts, also increases risk for developing a cold after experimental viral exposure (Cohen, 2021) .

In addition to the absence of social contacts, social conflict is associated with alterations in immunity. Among married couples, hostile interactions are associated with negative changes in several aspects of adaptive immune function and increased systemic inflammation (Kiecolt-Glaser, 2018) . Of note, these dyadic processes may worsen during the pandemic secondary to COVID-related stress (Pietromonaco & Overall, 2021) . Conflict and mistrust in social relationships has also been associated with elevated inflammation in adolescents, indicating that immune effects of social stress (and other forms of stress) can be observed across the lifespan (Chiang et al., 2019; Miller, Rohleder, & Cole, 2009 ). Indeed, adverse childhood experiences are strongly linked to immune alterations which may persist for years and ultimately contribute to elevated morbidity and mortality (Baumeister, Akhtar, Ciufolini, Pariante, & Mondelli, 2016; Kuhlman, Horn, Chiang, & Bower, 2020; Kuhlman, Chiang, Horn, & Bower, 2017) .

The pandemic has brought racial and socioeconomic inequities into sharp relief, with higher rates of COVID among communities of color and those of lower SES. These effects can also be observed at the level of the immune system. There is a robust association between SES and inflammation, with those of lower SES showing higher levels of circulating and genomic markers of inflammation (Muscatell, Brosso, & Humphreys, 2020) . Low SES has also been associated with decreases in antiviral immunity (Levine et al., 2017) , and increases the likelihood of developing a cold after viral exposure (Cohen, 2021) .

Experiences of discrimination are also linked to elevated inflammatory activity across the J o u r n a l P r e -p r o o f lifespan and may account in part for elevated levels of inflammation observed in Black individuals (Beatty Moody, Brown, Matthews, & Bromberger, 2014; Lewis, Aiello, Leurgans, Kelly, & Barnes, 2010; Thames, Irwin, Breen, & Cole, 2019) .

Although research in PNI has primarily focused on stress and other negative psychological states, there is growing recognition that positive psychological states may also modulate the immune system and neuro-immune interactions (Bower, Kuhlman, Haydon, Boyle, & Radin, 2019) . Here, we consider how positive psychological states, including positive affect, eudaimonic well-being, and social connection/support, are linked with antiviral immunity and inflammation.

Perhaps surprisingly, many individuals are able to maintain relatively high levels of PA during stressful experiences. Indeed, longitudinal studies have shown no change or even increases in PA during the pandemic (Barcellos, Jacobson, & Stone, 2021; Ebert, Bernstein, Carney, & Patrick, 2020) . PA has been linked with both mental and physical health, and there is compelling evidence that PA is associated with enhanced antiviral immunity (Pressman, Jenkins, & Moskowitz, 2019) . For example, dispositional PA predicted a stronger antibody response to hepatitis B vaccination, lower risk of developing an upper respiratory infection following infection a cold or influenza virus, and lower risk of AIDS-related mortality (Cohen, Alper, Doyle, Treanor, & Turner, 2006; Marsland, Cohen, Rabin, & Manuck, 2006; Moskowitz, 2003) . PA is also associated with lower levels of circulating inflammatory markers, lower production of proinflammatory cytokines by immune cells (a measure of inflammatory potential), and reduced inflammatory activity in the laboratory and in daily life . Importantly, associations between PA and immunity are maintained in J o u r n a l P r e -p r o o f analyses controlling for negative affect, demonstrating that PA has a unique link with the immune system.

Unlike stress, there are no validated methods for assessing or eliciting PA in preclinical models. However, investigators have manipulated activity in reward-related neural regions and examined effects on immunity. In one report, activation of dopaminergic neurons in the ventral tegmental area using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) led to increased innate and adaptive immune responses to bacterial infection (Ben-Shaanan et al., 2016) . These findings are consistent with a recent study showing links between activation of reward-related neural regions and changes in inflammatory markers in breast cancer survivors (Dutcher, Boyle, Eisenberger, Cole, & Bower, 2021) .

Despite (or perhaps because of) the life disruption and distress that accompanies stressful life events, many individuals are able to find positive meaning or benefit from these experiences (Stanton, Bower, & Low, 2006; Tedeschi & Calhoun, 2004) . These benefits include enhanced interpersonal relationships, greater appreciation for life, a sense of increased personal strength, greater spirituality, and valued change in life priorities or goals. Initial reports suggest that many individuals report positive benefits from living during the COVID-19 pandemic. For example, in a sample of 1175 individuals in New Zealand, two-thirds reported finding a "silver lining" from the pandemic (Jenkins et al., 2021) .

Finding meaning or benefit following stress is thought to promote psychological adjustment (Taylor, 1983; Tedeschi & Calhoun, 2004) , and has also been linked with antiviral immunity. In an early study of men who were HIV+ and had lost a close friend or partner to AIDS, those who reported finding meaning from the loss showed elevated T cell levels and J o u r n a l P r e -p r o o f lower AIDS-related mortality (Bower, Kemeny, Taylor, & Fahey, 1998) . A recent report also found that meaning in life predicted greater survival in a diverse sample of individuals with HIV (Ironson, Verhagen, da Rosa, & Hylton, 2021) . Further, among women who had lost their mothers to breast cancer, those who rated meaning-related goals as more important had higher levels of natural killer (NK) cell activity; these cells are an important component of the immune system's defense against viruses (Bower, Kemeny, Taylor, & Fahey, 2003) .

A sense of meaning and purpose in life is one component of eudaimonic well-being, a broader construct that also includes self-acceptance, mastery, autonomy, positive relationships, and the potential for personal growth as well as social coherence, acceptance, and contribution (Keyes, 2002; Ryff, 2014) . Eudaimonic well-being is associated with lower CTRA gene expression in middle-aged and older adults in the US and other countries, even after controlling for positive affect and measures of distress (Cole, Levine, et al., 2015; Fredrickson et al., 2015 Fredrickson et al., , 2013 Kitayama, Akutsu, Uchida, & Cole, 2016) .

There is a large literature demonstrating beneficial effects of social relationships on mental and physical health, including measures of immunity. Of potential relevance for COVID, early studies found that social support was associated with enhanced NK cell activity and lymphocyte proliferation to mitogens (a measure of the ability of B and T cells to make more of themselves after stimulation) (Baron, Cutrona, Hicklin, Russell, & Lubaroff, 1990; Esterling, Kiecolt-Glaser, & Glaser, 1996; Uchino, Cacioppo, & Kiecolt-Glaser, 1996) . A larger body of research has documented links between social support, social integration, and lower levels of inflammation (Kiecolt- Glaser, Gouin, & Hantsoo, 2010; Uchino et al., 2018) . Social support is also associated with stronger immune response to hepatitis B J o u r n a l P r e -p r o o f vaccination in medical students, although the broader literature on social support and response to vaccination is more mixed (Glaser et al., 1992; Uchino, Landvatter, Zee, & Bolger, 2020) .

In addition to these direct links with immunity, social support may buffer the negative effects of stress on the immune system. For example, in a study of adolescents, social support buffered the detrimental effect of examination stress on NK cell activity (Kang, Coe, Karaszewski, & McCarthy, 1998) . Further, social support buffered the negative effect of caregiver stress on measures of cellular immunity in older adults (Kiecolt-Glaser, Dura, Speicher, Trask, & Glaser, 1991) . Social relationships may also buffer effects of lower social status; indeed, maternal warmth buffered the association between childhood SES and adult inflammation, and positive relationships with parents buffered the association between childhood SES and development of a cold after viral infection in adulthood (Chen, Miller, Kobor, & Cole, 2010; Cohen, Chiang, Janicki-Deverts, & Miller, 2020) .

One recent study used a nonhuman primate model to examine the immune effects of "shelter in place" (SIP) policies, which have been widespread during the pandemic, and how social interaction may ameliorate these effects . Adult male rhesus macaques were moved from communal field cage communities to individual indoor shelters for two weeks, which led to pronounced decreases in Type I interferon gene expression. After a recovery period, the same animals were subject to a second period of SIP; however, this time each animal was co-housed with a novel juvenile macaque. Co-habituation reversed the detrimental effects of SIP on gene expression, demonstrating the promise of prosocial approaches for enhancing antiviral immunity. Of note, the adult macaques spent only 23% of their time directly interacting with juveniles (in grooming or play); the other 51% was spent in the same cage, and 26% was spent apart from the juvenile (in their adjacent shelters). This situation is quite different from J o u r n a l P r e -p r o o f the demands of parenting young children experienced by many during pandemic lockdowns and periods of virtual schooling.

Communication between the brain and the immune system is a two-way street; just as psychological states can influence the immune response, so too can activation of the immune system influence the brain and behavior. These bi-directional interactions are highly relevant in the context of COVID, as both infection with SARS-CoV-2 and pandemic-related stress may stimulate the immune system, leading to alterations in mood, cognition, and behavior. These effects may be subtle or more pronounced, depending on the nature of the immune stimulation and characteristics of the host that modulate the neuro-immune network. In this section, we review evidence for immune effects on psychological states and behavior, focusing on emerging research on long COVID. Inflammation and "sickness behavior": When exposed to pathogens or other immune triggers, cells of the innate immune system release inflammatory and antiviral cytokines. In addition to effects on the local environment, inflammatory cytokines signal the central nervous system where they lead to a variety of behavioral changes called "sickness behavior." These changes have been well-characterized in animal models and include decreased motor activity, social withdrawal, reduced food and water intake, and increased slow wave sleep (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008) . Sick animals also exhibit depressive-like behaviors, including increased immobility in the forced swim and tail suspension tests, reduced preference for saccharin solutions (indicating anhedonia), and reduced incentive motivation (Lasselin, Lekander, Benson, Schedlowski, & Engler, 2021) . In humans, studies using endotoxin and other immune stimulants to trigger an inflammatory response have documented similar J o u r n a l P r e -p r o o f Elevated inflammation has also been observed among individuals with other psychiatric disorders (anxiety, schizophrenia) as well as those with other disease-related symptoms (e.g., cancer-related fatigue), demonstrating the transdiagnostic relevance of inflammatory activity (Bower, 2019; .

Infection with SARS-CoV-2 directly activates the innate immune system, leading to release of proinflammatory cytokines that may propagate to the brain to induce "sickness behavior", including profound fatigue. For many individuals, these effects are limited to the acute stage of infection and immune response and subside within 4 weeks after symptom onset.

However, some individuals experience more persistent symptoms, referred to as "post acute COVID syndrome", "long haul COVID", or simply "long COVID", the term we use here.

Symptoms of long COVID are observed across physiological systems and include disturbances in respiratory, cardiovascular, and psychiatric/behavioral function (Nalbandian et al., 2021) . The prevalence of long COVID varies across reports depending on the nature of the sample, assessment approach, and symptom of interest. Studies conducted with individuals who were hospitalized for COVID and those recruited from long COVID clinics have generally yielded higher prevalence estimates than those conducted with community-based samples of individuals with confirmed SARS-CoV-2 infection. For example, 87% of patients attending a post-acute COVID clinic in Italy reported at least one symptom two months after hospital discharge (Carfi et al., 2020) , whereas 3-11% of previously-infected individuals involved in a population-based registry in the United Kingdom reported at least one symptom three months after diagnosis (Office for National Statistics, United Kingdom, 2021). Notably, although illness severity is associated with long COVID, individuals with milder cases of COVID may also experience persistent symptoms (Yong, 2021) . There is growing evidence that host factors, including demographic factors (age, sex) but also psychiatric history, may influence the emergence and duration of these symptoms (Nalbandian et al., 2021) .

Long COVID symptoms are hypothesized to stem in part from unresolved peripheral inflammation following infection (Yong, 2021) . Here, we focus on three key symptoms that have been shown to be affected by inflammationdepressed mood, fatigue, and cognitive dysfunction and review emerging studies that have examined links with inflammation in the context of COVID-19. We also consider stress as a risk factor, both as an elicitor of the inflammatory response (introducing a "double hit" of psychological and viral challenge) and as a moderator of the association between inflammation and behavior.

survey study of US adults, 52% of those with previous COVID infection met criteria for moderate depression on the PHQ-9 (Perlis et al., 2021) . Early studies with hospitalized COVID patients in Italy suggest that inflammation may contribute to post-COVID depressive symptoms; inflammation during hospitalization for COVID predicted depressive symptoms one month (Mazza et al., 2020) and three months after discharge (Benedetti et al., 2021a; Mazza et al., 2021) with corresponding alterations in brain structure and connectivity (Benedetti et al., 2021b) .

Further, patients who received medications that block the effect of proinflammatory cytokines IL-6 and IL-1β (tocilizumab and anakinra, respectively) exhibited fewer depressive symptoms following hospitalization (Benedetti et al., 2021a) .

One of the most common and persistent long COVID symptoms is fatigue. A recent meta-analysis of 68 studies found that 27-37% of patients previously infected with SARS-CoV-2 report fatigue at least three months after diagnosis (Ceban et al., 2021) . Prevalence J o u r n a l P r e -p r o o f estimates are even higher among previously hospitalized patients; for example, 63% of previously hospitalized COVID patients in China reported fatigue 6 months after discharge (Huang et al., 2021) . Another meta-analysis examining duration of long COVID symptoms found that fatigue continues to be a problem for more than 12 months post-infection (Alkodaymi et al., 2022) . In terms of associations with inflammation, an initial study of 128 patients seen at an outpatient post-COVID clinic found no association between fatigue and inflammatory markers, including CRP and IL-6 (Townsend et al., 2020) . However, fatigue is associated with elevated inflammatory markers in the context of other disorders (Bower, 2019) , and additional work is needed to further interrogate this association in the context of COVID-19.

Described as "COVID brain fog" by patients, cognitive dysfunction is another common symptom of long COVID. A recent meta-analysis of 43 studies found that 17-28% of patients either report or exhibit cognitive impairment at least three months following COVID diagnosis (Ceban et al., 2021) . Studies using objective neuropsychological assessment show deficits in processing speed and executive functioning, verbal fluency, and memory encoding and recall (Becker et al., 2021) , with some evidence of corresponding neural alterations (Hellgren et al., 2021) . Initial studies have found that performance on neuropsychological tests is linked with inflammation among individuals with long COVID, such that those who perform more poorly have elevated inflammatory markers Zhou et al., 2020) . To our knowledge, there has yet to be a study examining associations between inflammatory markers and subjective cognitive problems in long COVID.

Given that stress activates the inflammatory response, long COVID might be conceptualized as the result of a "double hit" (psychological plus viral inflammatory stimuli). Indeed, there is evidence demonstrating the synergistic effects of psychological stress and infection on inflammation in the context of vaccination ). In addition to direct effects on inflammation, stress may heighten the association between inflammation and behavioral symptoms. For example, among women recovering from breast cancer, those who reported higher levels of stress showed increased sensitivity to inflammationrelated depressive symptoms in two independent cohorts . Similar effects have been observed in the context of endotoxin administration and vaccination Lasselin et al., 2021) . These effects may be due to stress-related alterations in the blood-brain interface or increased activation of microglia, both of which can increase sensitivity to peripheral inflammation . Of note, psychosocial resilience factors (e.g., positive affect, social connection, mindfulness) may buffer these effects (Manigault, Kuhlman, et al., in press) and can be cultivated by psychological interventions, considered in the next section. Even in the absence of viral infection, low-grade inflammation stemming from pandemic stress may increase depressed and anxious mood, and may also heighten affective reactivity to daily stressors (Sin, Graham-Engeland, Ong, & Almeida, 2015) and interfere with pursuit of rewarding activities (including social interactions) and positive health behaviors (exercise, sleep), creating a downward spiral that leads to further mood disturbance.

Demand for mental health services has soared during the pandemic as people struggle to cope with the fear, loss, uncertainty, loneliness, and life disruption caused by COVID.

Importantly, psychosocial interventions designed to improve mental health may also enhance immune status. A recent meta-analysis of 56 randomized controlled trials showed a beneficial effect of psychosocial interventions on immune outcomes, including increased activity of NK J o u r n a l P r e -p r o o f cells, increased ability of B and T cells to proliferate after stimulation, and decreases in markers of inflammation, all of which are relevant for antiviral defense (Shields, Spahr, & Slavich, 2020) .

Below we highlight work on specific interventions that have demonstrated links with immunity.

We focus here on psychosocial interventions but note that interventions targeting physical activity and sleep disturbance can also influence the immune system and neuro-immune network . (Antoni, 2003) . Similar benefits of CBSM have been demonstrated among women with HIV (Lopez et al., 2013) . These investigators have also examined CBSM effects among women with breast cancer and found increases in Type I interferon gene expression and decreases in inflammation-related genes, as well as decreases in depression and anxiety (Antoni et al., 2012) . Of note, these effects have persisted for up to a year post-intervention, suggesting enduring effects on mood and immunity (Carrico et al., 2005) .

Chi, Qi Gong, meditation, and yoga have considerable promise for improving mental and physical health, including immunity. Indeed, a meta-analysis of 34 trials of mind-body interventions showed beneficial effects on immune response to vaccination and markers of inflammation (Morgan, Irwin, Chung, & Wang, 2014) . Other reviews focusing specifically on inflammation have also documented beneficial effects of mind-body approaches, particularly on measures of inflammatory gene expression (Bower & Irwin, 2016) . The relevance of these findings for antiviral immunity was clearly demonstrated in a study of older adults, in which Tai Chi led to increases in immunity specifically to the varicella zoster virus (VZV) and augmented the antiviral response to VZV vaccination (Irwin, Olmstead, & Oxman, 2007) . Tai Chi has also been shown to reduce production of proinflammatory cytokines and proinflammatory gene expression in trials with older adults and breast cancer survivors with insomnia (Irwin et al., 2015; Irwin et al., 2014) .

Mindfulness meditation has emerged as an effective intervention for reducing depression, anxiety, and loneliness, and also increases positive affect and meaning/purpose in life (Bower et al., 2015; Garland, Farb, Goldin, & Fredrickson, 2015; Goldberg et al., 2018; Goyal et al., 2014; Wielgosz, Goldberg, Kral, Dunne, & Davidson, 2019) . A growing number of studies have examined effects of mindfulness interventions on immunity. An early study found that an 8week mindfulness-based stress reduction (MBSR) program led to reductions in anxiety and increases in antibody response to influenza vaccination among healthy employees (Davidson et al., 2003) . Of note, the intervention also led to significant increases in left-sided anterior activation as measured by EEG, a neural pattern associated with positive affect, which predicted the magnitude of change in antibody response. MBSR showed beneficial effects on antiviral immunity in a trial conducted with HIV+ men, buffering the decline in CD4 T cells (which are infected by the HIV virus) observed in the control group (Creswell, Myers, Cole, & Irwin, 2009) .

With respect to inflammation, there is evidence that mindfulness interventions lead to decreases in inflammatory gene expression and in some studies, circulating inflammatory markers (Bower & Irwin, 2016) . In research with breast cancer survivors, we have shown that a J o u r n a l P r e -p r o o f 6-week mindfulness program (Mindful Awareness Practices) leads to decreases in stress and depression, increases in well-being, and changes in immune-related gene expression (including decreases in proinflammatory gene expression and increases in Type I interferon responses) (Bower et al., 2015; Boyle, Cole, Dutcher, Eisenberger, & Bower, 2019) . Of note, changes in expression of immune-related genes were correlated with increases in well-being, but not with decreases in distress, following the MAPs intervention . We also examined intervention-related changes in neural activity and links with immunity, focusing on activity in threat and reward-related neural regions given their relevance for downstream immune processes (Eisenberger & Cole, 2012) . Results showed increases in ventral striatum (VS) activity in response to viewing positive images and decreases in amygdala activity to viewing threatening faces from pre-to post-intervention. However, only increases in VS activity were correlated with changes in immune markers; women who showed a greater increase in VS activity to the positive images showed a significantly greater reduction in circulating levels of IL-6. These effects highlight the role of positive psychological processes, and underlying neural activity, in structuring the immune response to mindfulness meditation.

Given links between well-being, social integration, and immune function, interventions that specifically target these states may also influence immune outcomes.

Investigators have been particularly interested in prosocial interventions designed to increase a sense of social connection and contribution. In one trial, healthy adults randomized to perform prosocial activities ("acts of kindness") showed decreases in CTRA gene expression, including decreases in inflammation-related and increases in antiviral genes (Nelson-Coffey, Fritz, were mediated by increases in eudaimonic well-being (Seeman, Merkin, Goldwater, & Cole, 2020) . Further, adolescents who participated in a volunteering intervention showed decreases in IL-6 (Schreier, Schonert-Reichl, & Chen, 2013) .

The COVID-19 pandemic poses tremendous challenges to mental and physical health, which have typically been considered separately in prevention and treatment efforts. However, decades of research in psychoneuroimmunology has revealed intimate connections between the mind and the immune system that support the use of an integrated approach to prevention, intervention, and policy. Many of the psychological states exacerbated by the pandemic (stress, social isolation, social conflict) can undermine aspects of the immune system that protect against viral infection. In particular, stress can suppress the innate antiviral response (important for early control of the virus), decrease the function of T and B cells (critical for neutralizing the virus and killing virally infected cells), and increase inflammation (leading to greater tissue pathology and long-term behavioral symptoms). In contrast, social support and connection are associated with enhanced T and B cell activity and lower inflammation and may buffer the negative impact of stress on the immune response. Further, growing evidence suggests that positive affect and eudaimonic well-being also have beneficial immune effects relevant for viral illness.

Infection with SARS-CoV-2 and pandemic-related stressors can also influence mental health through activation of the proinflammatory cytokine network. Proinflammatory cytokines released in response to infection or injury signal the brain and lead to changes in mood and behavior, many of which are seen in the context of long COVID. Indeed, preliminary studies suggests a role for inflammation in COVID-related depression and cognitive disturbance.

Intriguing evidence from experimental and observational studies suggests that stress (and other J o u r n a l P r e -p r o o f psychological factors) may increase sensitivity to inflammation-related behavioral symptoms outside of the context of COVID; this work should inform the investigation of risk factors for persistent post-COVID neuropsychiatric symptoms.

There is compelling evidence that behavioral interventions can increase adaptive immunity and decrease inflammation, and may thus enhance the immune response to SARS-CoV-2. In particular, cognitive behavioral therapy, mind-body approaches (mindfulness, Tai Chi, yoga), and prosocial interventions have all shown promise as modulators of virus-related immunity, although effects specifically against SARS-CoV-2 have not been assessed.

Psychosocial interventions could potentially be utilized preventatively to bolster antiviral immunity, including the immune response to vaccination. For example, a study with older adults found that a 16-week Tai Chi intervention administered prior to VZV vaccination produced a substantially higher level of anti-VZV immunity than vaccine alone (Irwin et al., 2007) . These approaches might also be effective for reducing post-COVID symptoms and underlying immune dysregulation, as we have shown among cancer survivors with persistent fatigue, sleep disturbance, and depression (Bower et al., 2015; Bower et al., 2014; Irwin et al., 2014) . A key advantage of psychosocial and behavioral interventions in the context of COVID is their ability to improve mental, physical, and (in the case of prosocial interventions) social and community well-being. Leveraging these behavioral and psychosocial factors through public health policy and interventions will be essential for promoting resilience as the repercussions of the COVID-19 pandemic are realized in the months and year ahead.

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The role of inflammation in depression: From evolutionary imperative to modern treatment target

Chronic interpersonal stress predicts activation of pro-and anti-inflammatory signaling pathways 6 months later

The effects of mind-body therapies on the immune system: meta-analysis

Positive affect predicts lower risk of AIDS mortality

Socioeconomic status and inflammation: a meta-analysis

Post-acute COVID-19 syndrome

Kindness in the blood: A randomized controlled trial of the gene regulatory impact of prosocial behavior

Technical article: Updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK

Impact of the COVID-19 Pandemic on Loneliness and Social Isolation: A Multi-Country Study

Association of Acute Symptoms of COVID-19 and Symptoms of Depression in Adults

Applying relationship science to evaluate how the COVID-19 pandemic may impact couples' relationships

Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis

Positive Affect and Health: What Do We Know and Where Next Should We Go?

Loneliness, social network size, and immune response to influenza vaccination in college freshmen

Psychological well-being revisited: advances in the science and practice of eudaimonia

Persistent Symptoms in Patients After Acute COVID-19

Effect of volunteering on risk factors for cardiovascular disease in adolescents: a randomized controlled trial

Intergenerational mentoring, eudaimonic well-being and gene regulation in older adults: A pilot study

Adaptive immunity to SARS-CoV-2 and COVID-19

Stress-Induced Neuroendocrine Modulation of Viral Pathogenesis and Immunitya

Psychosocial Interventions and Immune System Function: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Affective Reactivity to Daily Stressors Is Associated With Elevated Inflammation

Social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis

The association between loneliness, social isolation and inflammation: A systematic review and meta-analysis

Posttraumatic growth after cancer

Attributes and predictors of long COVID

Adjustment to threatening events: A theory of cognitive adaptation

Posttraumatic Growth: Conceptual Foundations and Empirical Evidence

Experienced discrimination and racial differences in leukocyte gene expression

Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

The relationship between social support and physiological processes: a review with emphasis on underlying mechanisms and implications for health

Social support, social integration, and inflammatory cytokines: A meta-analysis

Social Support and Antibody Responses to Vaccination: A Meta-Analysis

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis. The Lancet Psychiatry

Mild cognitive impairment in COVID-19 survivors: Measuring the brain fog

Increased risk of COVID-19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States

Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments

The landscape of cognitive function in recovered COVID-19 patients