Does the compromised sleep and circadian disruption of night and shiftworkers make them highly vulnerable to 2019 coronavirus disease (COVID-19)?

ABSTRACT

Rotating and permanent night shiftwork schedules typically result in acute and sometimes chronic sleep deprivation plus acute and sometimes chronic disruption of the circadian time structure. Immune system processes and functionalities are organized as circadian rhythms, and they are also strongly influenced by sleep status. Sleep is a vital behavioral state of living beings and a modulator of immune function and responsiveness. Shiftworkers show increased risk for developing viral infections due to possible compromise of both innate and acquired immunity responses. Short sleep and sleep loss, common consequences of shiftwork, are associated with altered integrity of the immune system. We discuss the possible excess risk for COVID-19 infection in the context of the common conditions among shiftworkers, including nurses, doctors, and first responders, among others of high exposure to the contagion, of sleep imbalance and circadian disruption.

Abbreviations

ACE2: Angiotensin-converting enzyme 2; APC: Antigen.-presenting .cells; CCL: Chemokine (C-C motif) ligand; CD⁺: .Adhesion molecule expression; COVID-19: 2019 coronavirus disease; DCs: Dendritic cells; GH: Growth hormone; HPA: Hypothalamic-pituitary-adrenal; HSF: Heat shock factor; HSP70: Heat shock protein 70; HSP90: Heat shock protein 90; IL: Interleukin; INFγ: Interferon-gamma; LT/LB: T/B lymphocytes; MHC: Major histocompatibility complex; NK: Natural .killer; RAAS: renin–angiotensin–aldosterone system; SARS: .Severe acute respiratory syndrome; SCN: Suprachiasmatic nucleus;SD: Sleep deprivation; SNS: Sympathetic nervous system; Th1/Th2: T helper lymphocytes 1/2; TLR2/TLR4: Toll-like receptor 2/4; TNF-α: Tumor .necrosis .factor alpha; VEGF: Vascular endothelial growth factor

KEYWORDS:

• COVID-19
• shiftwork
• sleep deprivation
• immune system
• circadian disruption

COVID-19 and shiftwork

Coronaviruses are RNA viruses broadly distributed in humans and other mammals (Richman et al. 2017). Previously reported human coronaviruses, such as 229E (αHCoV229E), NL63 (HCoV-NL63), OC43 (βHCoV-OC43), and HKU1 (HCoV-HKU1), primarily affected the upper respiratory tract (Chan et al. 2012; Tang et al. 2017). The new 2019 coronavirus (COVID-19) epidemic (Wang et al. 2020), like that of the earlier 2003 severe acute respiratory syndrome (SARS) outbreak, is a beta-coronavirus that can be spread to humans through intermediate hosts such as bats (Paules et al. 2020). Human-to-human transmission has been observed via virus-laden respiratory droplets (Chen et al. 2020), and severe cases can lead to cardiac injury, respiratory failure, acute respiratory distress syndrome, and death (Holshue et al. 2020).

Viruses induce the stress–response reaction in infected cells (Cymerys et al. 2009). HSPs (Heat shock proteins) are known as stress proteins that play important roles in physiological activities and also act as molecular chaperonage that stabilizes unfolded protein during the stage of protein synthesis under the influence of stressors, thus, improving cell survival from degradation (Bolhassani and Agi 2019). HSPs, especially HSP70, are stimulated by viral infections leading to increase in viral gene expression (Kim and Oglesbee 2012). Moreover, when HSP70 is released from cells, it induces innate immune response through toll-like receptor 2/4 (TLR-2 and TLR-4) responses (Bolhassani and Agi 2019). Viruses do not inherently possess HSPs; therefore, they rely entirely on the host HSPs for viral protein folding. Thus, processes that regulate host stress proteins are likely targets of strategic manipulation by both invading viruses and already infected hosts (Lee et al. 2010).

HSP synthesis is critical for pathogen survival (Goulhen et al. 2003). Some viruses can induce the overexpression of HSPs in infected cells, and intensive virus replication is associated with high expression of some HPSs, especially Hsp70 and HSP90. Furthermore, CD11b⁺ and natural killer (NK) cells, which play major roles in the elimination of infectious agents, show up-regulation of HSP70 initial stages of infection – especially at the peak of virus replication and also show up-regulation of HSP90 during later stages of infection. HSP70 has been identified as a cellular interaction partner of the influenza virus ribonucleoprotein complex (Li et al. 2011). In this regard, HSP70 and HSP90 are observed in viral pneumonia and other viral infections (Jesse and Chung 2019).

Shiftwork is defined as work done outside the normal hours of the traditional workday, as exemplified by evening, night, early morning, and rotating shift schedules (Almeida and Malheiro 2016; National Sleep Foundation, N 2016) that are common in essential services (Costa et al. 2004). Shiftwork, particularly night work, due to alteration of the sleep-wake cycle from normal plus exposure to artificial light at night, interferes with and disrupts the normal circadian time structure, giving rise to possible psycho-physiological disturbances and compromised neuroimmune-endocrine homeostasis (Akerstedt, 1990; Knutsson 2003; Reinberg and Ashkenazi 2008; Schernhammer et al. 2001). The conclusion of the night shift corresponds, in reference to circadian time, with circadian rhythm-driven immune system changes (Kobayashi et al. 1996; XU et al. 1998), specifically, reduction in NK activity, for example, as observed in nurses (Kobayashi et al. 1996).

Sleep and immunomodulatory function

Human circadian rhythms are controlled by a neurological master clock, the suprachiasmatic nucleus (SCN), and also peripheral clocks of almost every cell, including immune system cells (Arjona and Sarkar 2006; Duguay and Cermakian 2009; Haimovich et al. 2010). The SCN thus enables all tissues and cells to anticipate and promptly respond to usual and predictable-in-time cyclic environmental changes and challenges, including pathogens (Labrecque and Cermakian 2015). Cells of the innate and adaptive immune system also show circadian expression, for example, as day-night variation in blood count, functioning of peripheral lymphoid organs, lymphocytic proliferation, and blood cytokine levels (Dimitrov et al. 2009; Lange et al. 2010; Steinman 2004; Young et al. 1995). In humans adhering to a normal daytime wake and nighttime sleep schedule, the trough of the circadian rhythm in T cell count precedes the peak time (morning) of the circadian rhythm in blood cortisol, while the phase relation these two rhythms in the early evening is reversed (Dimitrov et al. 2009; Lange et al. 2010), as further described below.

In association with the circadian system, sleep is known to regulate immune functions (Segerstrom and Miller 2004; Weibel et al. 1996). Sleep deprivation (SD) is related to substantial alteration of the immune system (Axelsson et al. 2013; Born et al. 1997; Dinges et al. 1994, 1995; Fondell et al. 2011; Irwin et al. 1994, 1996; Wilder-Smith et al. 2013), in particular, increased production of pro-inflammatory cytokines (Prather et al. 2009). SD in the amount of 50–64 h is associated with temporary increase in the activity of TCD4⁺ lymphocytes, CD8⁺, and NK (Dinges et al. 1994, 1995; Wilder-Smith et al. 2013). SD also leads to decreased activity of NK cells and CD16⁺, CD56⁺, CD57⁺, and Interleukin (IL)-2 levels (Axelsson et al. 2013; Fondell et al. 2011; Irwin et al. 1994, 1996), all being important for the host defense against viruses (Biron et al. 1999).

In insomniacs, who routinely experience SD, there is a change in Th1 and Th2 immune balance favoring the Th2 response, with decrease in secretion of interferon-gamma (IFN-γ) and IFN-γ/IL-4 (Sakami et al. 2002) and reduction of TCD3⁺, TCD4⁺, plus TCD8⁺ and total lymphocytes (Savard et al. 2003). Importantly, the infectivity of rhinovirus has been shown to vary with sleep status. For example, individuals assessed by wrist actigraphy and substantiated to sleep fewer than 6 h before exposure to the contagion were found to be four times more likely to become infected than those who slept more than 7 h (Prather et al. 2015). The effect of sleep on the magnitude of the immune response to a viral antigen (Hepatitis B virus) was also evaluated, finding that fewer than 6 h of sleep per night, assessed by sleep diary and wrist actigraphy, was associated with reduction of vaccine protection from the B virus (Prather et al. 2012). Importantly, adequate sleep after immunization against the Hepatitis A virus significantly doubled the number of specific Th1 cells, due to the adjuvant effect of slow-wave sleep (Lange et al. 2011).

Shiftworker’s sleep and the immune system

Sleep influences two major biological axes/systems that modulate the immune system: the hypothalamic-pituitary-adrenal (HPA) axis mediated by cortisol (D’Aurea et al. 2015; Leproult et al. 1997; Spiegel et al. 1999) and the sympathetic nervous system (SNS) mediated by catecholamines (Molina 2005). The mediators of both axes/systems cause reduction of pro-inflammatory cytokines (Barnes 1998; Hou et al. 2013) and migration and activity of immune cells (Leposavić et al. 2008; Sanders 2012). Under a night-oriented schedule similar to that of shiftworkers, cytokine release is partly altered in response to change in the sleep-wake cycle (Prather et al. 2015). Importantly, COVID-19 affected Chinese persons and revealed a history of chronic illness plus of poor sleep quality – indicated by a global PSQI (Pittsburgh Sleep Quality Index) score of 14, findings that not atypical of the Chinese workforce employed in 30 Chinese occupations (Huang et al. 2020).

It is well known that the circadian time structure substantially affects the pharmacokinetics – absortion, distribution, metabolism, and elimination – as well as the pharmacodynamics of medications according to the biological time of their administration (Smolensky et al. 2017). In the same way, the handling of and tolerance to chemical, physical, and biological agents, including infectious ones, can differ, often markedly, according to the circadian time of exposure (Smolensky et al. 2017). This can be explained by the staging of the circadian system, alone or in combination with the immune system, that based on past evolutionary determinants anticipate environmental challenges and additionally facilitate beneficial adjustment to changes associated with the pro-inflammatory state during nighttime sleep and anti-inflammatory state during daytime activity (Moldofsky 1995).

During nighttime sleep, pro-inflammatory hormones and cytokines are synchronized to facilitate the onset of adaptive immune responses, while during daytime activity, anti-inflammatory signals, hormones, and cytokines are supportive of immediate reactions to biological and other environmental challenges (Levi et al. 1991). Growth hormone (GH) and prolactin under the usual sleep-wake routine increase to highest levels during the night and decline to lowest levels during the waking state, and this temporal pattern is preserved even in the state of continuous wakefulness. However, in SD, the amplitude of these circadian rhythms is suppressed, such that peak values are attenuated. Additionally, TNF-α, IL-12, and dendritic cells (DCs) ordinarily show peak values during the night in those adhering to a normal sleep-wake routine, but also in those kept awake for 24 h, and without alteration of the period (24 h) of these rhythms. The peak time of the circadian rhythms of cortisol, epinephrine, norepinephrine, and IL10 occurs early in the morning, around the time of awakening from nighttime sleep. In situations of continuous wakefulness, epinephrine lacks a defined rhythm. The peak time of the rhythm in IL10 shifts to the nighttime. Cortisol and norepinephrine present peak value rhythms similar to sleep values, which Nadir values, for both, are higher under conditions of constant wakefulness (Lange et al. 2010).

Human beings are a diurnal active species; accordingly, the circadian time structure of humans is organized to efficiently support a routine of activity during the light phase of the day and sleep during the dark phase of the night (Skene and Arendt 2006). The circadian structure of shiftworkers when working a night shift of several days duration must be reorganized to accommodate the unnatural routine of activity during the dark phase and sleep during the light phase of the day. The necessary biological adjustments result in a transient state of circadian disturbance, i.e., circadian disruption, that can increase vulnerability to chemical and other xenobiotic stressors (Smolensky et al. 2019).

The American Academy of Sleep Medicine proclaims SD has a negative impact on the overall health of the population (Dregan and Armstrong 2011), and that shiftworkers are certainly some of the most affected (Dregan and Armstrong 2011; Kessler et al. 2011; Loef et al. 2019). Because immune responsiveness is controlled by circadian processes, they are likely to be affected by shiftwork-schedule-induced disruption (Labrecque and Cermakian 2015). Shiftwork can induce progressive SD, stress, and alteration of the natural circadian pattern that as a consequence can compromise immune responsiveness (Mohren et al. 2002; Nagai et al. 2011; Nakano et al. 1982). It is known that shiftworkers show reduction of T lymphocytes (LT), especially in those working fixed night shifts (Axelsson et al. 2013; Dinges et al. 1994, 1995; Irwin et al. 1994, 1996; Nakano et al. 1982; Savard et al. 2003; Wilder-Smith et al. 2013). It is also well known that IL-1β and TNF-α are associated with sleep quality, which for shiftworkers is depressed because of the requirement to sleep during the daytime light phase, the biological time of greatest alertness for the human species (Dijk D-J 1999; Drake et al. 2004). Therefore, shiftworkers are often chronically sleep deprived (Honn et al. 2016; Smith et al. 2009), giving rise to increased risk for diminished health and work accidents (Laugsand et al. 2014).

The period of sleep serves to renew functions related to wakefulness and processes controlling the immunological response to infections (Motivala and Irwin 2007; Opp and Krueger 2015). The loss of sleep in modern society, as observed among shiftworkers, is associated with increased susceptibility to developing infectious diseases, including the flu (Cohen et al. 2009; Patel et al. 2012) and other upper airway infections (Prather et al. 2015). Thus, the matter of shiftwork-associated SD is of major economic and public health policy interest (Irwin 2012).

Chronic stress is correlated with suppression of cellular and humoral immunity (Segerstrom and Miller 2004; Tsigos and Chrousos 2002). The immune response to shiftwork is highly variable and depends on several factors, in particular, job-related stress that can make one’s job intolerable (Barnes-Farrell et al. 2008; Tamagawa et al. 2007). In the long term, rotating shiftwork may give rise to chronic adaptive stress, and as shown in Figure 1, with possible repercussions on the neuroendocrine-immune system (Shields 2002) that results in attenuation of immune responsiveness (Amati et al. 2007; Boscolo et al. 2009; De Gucht et al. 1999; Endresen et al. 1987; Okamoto et al. 2008), evident by increased CD3⁺ CD16, CD56⁺ cell numbers, increased IL-6 plasma levels, reduced CD57⁺, CD8⁺, CD11b⁺ cell numbers, reduced LT function (Curti et al. 1982; Nakano et al. 1982), and attenuated NK activity (Magrini et al. 2006; Morikawa et al. 2005; XU et al. 1998). Accordingly, SD in combination with altered circadian time structure may result in increased vulnerability during night shift not only to industrial contaminants but contagions, such as viruses (Smolensky et al. 2019).

Figure 1. Illustrative image of the role of sleep in immunological memory. (Orange triangles) represents the migration of T/B lymphocytes from systemic circulation IL, Interleukin; APC, antigen-presenting cells; Th1/Th2, T helper lymphocytes 1/2; DCs, dendritic cells.

Importantly, a study of Japanese emergency department physicians demonstrated immune changes at the start of the night shift (Okamoto et al. 2008), with the interaction between sleep and immune system adaptive memory (Lange et al. 2011; Prather et al. 2012). Shiftworkers, especially those working the night shift, experienced a greater number of upper respiratory infections – colds and flu – compared to those working daytime only shifts (Nagai et al. 2011). Moreover, the shiftwork schedule of these Japanese emergency department physicians was also associated with depression of the innate immune response, i.e., decreased NK cell activity that was associated with increased fatigue. Reduced sleep (<5 h), as well as poor sleep quality or excessive sleep (>9 h), are linked with risk for pneumonia (Patel et al. 2012). In China, COVID-19 positive persons showed leukopenia and lymphopenia, with several or all of the following immune biomarker concentrations being elevated: IL1β, IL7, IL8, IL9, IL10, IL5, IL12p70, IL15, IFNγ, CCL2, CCL3, CCL4, TNF-α, and VEGF (World Health Organization, W 2003; Zaki et al. 2012), and in association with pulmonary inflammation and extensive lung damage, as also found those affected by the past infectious diseases of SARS and MERS-CoV, and often in conjunction with increased IFNγ, TNF-α, and IL1 (de Groot et al. 2013; Mahallawi et al. 2018).

Can sleep debt make shiftworkers more vulnerable to the COVID-19?

As discussed above, RNA from viruses is released by stressed or injured cells, as are HPSs (Bianchi 2007; Chu and Mazmanian 2013; Matzinger 2007) and mediators that activate inflammatory signaling pathways like NF-κB. This is followed by the release of acute-phase cytokines, such as IL-1β, TNF, and INFs, with anti-viral activity of vasoactive mediators like prostaglandins (PGs). When a virus evades this first line of defense, the adaptive immune system, consisting of T and B cells, can provide tailored, specific responses that are initiated by CD8⁺ T cells that recognize the major histocompatibility complex (MHC) and kill the target cell. Depending on the type of infection, antigen-presenting cells (APCs) release certain cytokines, thereby increasing CD4⁺ and eventually IFNs, IL-12, and Th1 (Iwasaki and Medzhitov 2015; Matzinger 2007; Vidarsson et al. 2014). After elimination of the pathogen in the effector phase, most activated antigen-specific B and T cells die, but some persist as memory cells for the contagion that make possible more efficient response thereafter with renewed exposure (Farber et al. 2016; Mueller et al. 2013; Weisel and Shlomchik 2017).

SD increases the risk of airways’ infection, especially from viruses (Patel et al. 2012; Prather et al. 2015). As discussed previously, it impairs innate immunity, expressed by reduction of the activity of NK cells and decrease of the Th1 effector cellular response, important for the activation of TCD4⁺ (Axelsson et al. 2013; Fondell et al. 2011; Irwin et al. 1994, 1996; Sakami et al. 2002; Savard et al. 2003). People positive for CODIV-19 present with higher concentrations of ligand T-cell chemokine-3 (CCL3) and also TNF-α, suggesting the observed cytokine storm of patients severely affected with this virus is responsible for such disease severity. However, COVID-19 also initiates increased secretion of Th2, IL4, and IL10 that suppresses inflammation, which differentiates COVID-19 from SARS-CoV infection (Wong et al. 2004).

Because shiftwork can present increased vulnerability to infectious diseases (Adams et al. 1984), and adaptive and innate immune system display circadian rhythms, disruption of immune responsiveness is likely to enhance susceptibility to infection (Ananthakrishnan 2015; Anderson et al. 2017). Shiftworkers, who typically are sleep deprived, report higher incidence and severity of respiratory infections (Archer and Oster 2015; Archer et al. 2018), and these observations suggest they, incontrast to non-shiftworkers, may be more susceptible to COVID-19. The higher incidence and severity to respiratory and conceivably other infections may be associated with SD, i.e., associated decreased slow-wave NREM sleep, when there is increase of IL-12 and DCs, the main precursors of APCs. Concomitant reduction of IL-10 and IL-4 levels facilitates the Th1/Th2 balance in favor of the Th1 response (Dimitrov et al. 2004; Lange et al. 2006).

Production of IL-12 by APCs is essential for the activation of Th cells (Abbas et al. 1994). The pro-inflammatory pattern during the early portion of sleep is balanced by Th2 response during the final portion of sleep when REM sleep tends to be most prevalent (Dimitrov et al. 2004). The induction of Th1 cells and the migration of immune cells from the systemic circulation to the secondary lymphoid organs during sleep may increase the interaction between the APCs and naïve T cells and B lymphocytes, like a immunological synapse, and these could be mechanisms through which sleep would collaborate on a more efficient immunological memory (Bollinger et al. 2010; Born et al. 1997; Dimitrov et al. 2004; Reis et al. 2011) as illustrated in Figure 1.

We postulate that these mechanisms of immunological memory may not be efficient in shiftworkers. Furthermore, considering that the HSP70 and HSP90 elevation is responsible for modulating the level of pathology and cell death (Morimoto 1998), it is possible that shiftworkers, who are constantly under stress and sleep deprived, may have attenuated expression of HSPs due lower production of heat shock transcription factor (HSF) and suppressed induction of NK and DCs (Bolhassani and Agi 2019). Consequently, in shiftworkers who are also highly to be likely acutely or chronically circadian disrupted, MHC-antigen processing and presentation (Call and Wucherpfennig 2005) and toll-like receptors (TLRs) processes may not be efficiently synchronized in time upon exposure to viral antigens (Vyas et al. 2008) and thus inefficient in activating potent immune response (Bolhassani and Agi 2019), thereby increasing susceptibility to COVID-19 (Figure 2).

Figure 2. Illustrative scheme of the relationship between immune response, shiftwork, sleep debt, airway infections, and COVID-19. (Orange arrow) Virus induces stress responses mediated by inflammatory markers, leading to airway infections. (Blue arrows) Shifworkers who are sleep deprived, experience frequent airway infections, and are more susceptible to show failure of immune response against COVID-19 and other viruses than those working the normal daytime schedule. (Green arrows) Sleep deprivation induces airway infection to viruses by contributing to immune response failure. (Pink arrows) Infected cells of shiftworkers may fail to produce HSP70 and HSP90 efficiently, which may potentiate risk for airway infection, impact negatively on anti-viral defense by reduction of DCs, APCs, NK, TLRs and MHC. IL, interleukin; CCL, CCL motif chemokine ligand; INFγ, interferon-gamma; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; CD⁺, adhesion molecule expression; LT/LB, T/B lymphocytes; MHC, major histocompatibility complex; APC, antigen-presenting cells; NK, natural killer; Th1/Th2, T helper lymphocytes 1/2; DCs, dendritic cells; TLR2/TLR4, toll-like receptor 2/4; HSP70, heat shock protein 70; HSP90, heat shock protein 90; HSF: heat shock factor.

Evidence of the importance of HSPs is supported by the findings that HSP90 is involved in other human respiratory diseases of vial origin, e.g., the 2013 Caprine Parainfluenza Virus Type 3 Infection that affected goats in China (Zhong et al. 2019), and that HSP70 is associated with suppression of the avian infectious bronchitis virus (IBV) (Zhang et al. 2017). Thus, given the extensive knowledge of the disruptive and potentially compromising effects of shiftwork with regards to circadian rhythms in the vulnerability to viral contagions, which may be further exacerbated by SD plus associated disruption of the immune and neuroendocrine among other processes and systems, mandates greater research into both the more complete understanding of the postulated potential for elevated risk for COVID-19 infection in permanent nightshift and rotating shiftworkers as well as preventative strategies, including ones linked to circadian (predictable-in-time) vulnerabilities as so-called chronopreventation interventions.

Another area of requiring future exploration regarding risk for COVID-19 virus infection and severity of infection is the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) and its constituents. COVID-19 virus invades human alveolar epithelial cells mainly through ACE2 (angiotensin-converting enzyme 2) (Liu et al. 2014). Several approaches address ACE2-mediated COVID-19, such as spike protein-based vaccine (ACE2 as a COVID-19 receptor), inhibition of transmembrane protease activity (essential for entry through interaction with ACE2 receptor), blocking ACE2 receptor, and delivering the soluble form of ACE2. The RAAS predictably activates during nighttime sleep in those routinely adhering to the normal daytime activity/nighttime sleep pattern; however, it is instable in SD individuals (Stumpe et al. 1976) and most likely permanent night and rotating shiftworkers. The peak of the 24 h temporal pattern in angiotensin 2, peaks toward the end of sleep (Hermida et al. 2011, 2007). The role of this rhythm and its interruption due to shiftwork in affecting the risk of developing more severe symptoms of diseases is unknown and deserves investigation.

Because of the dysfunction of the renin-angiotensin system seen in COVID-19 patients, there is great interest in the therapeutic potential against COVID-19 involving medications that target ACE2 (Tikellis et al. 2011; Zhong et al. 2010). Although there is clinical evidence demonstrating that RAS inhibitors improve the clinical outcomes of COVID-19 patients with hypertension (Meng et al. 2020), it is important to consider that various circadian rhythms are involved in the regulation of blood pressure during the 24 h (Portaluppi 2000). Similarly, several endogenous circadian rhythms affect the pharmacokinetics and pharmacodynamics of antihypertensive treatments (Hermida and Smolensky 2004), and the role of circadian time on the efficacy of prophylactic medications against viruses and also therapies to manage infection is also unknown and worthy of study.