SARS, Stress, and Immunity

SARS and beyond – April 27, 2003

It has been nearly 6 months since the SARS (Severe Acute Respiratory Syndrome) outbreak emerged and more than 6 weeks since the illness spread from its birthplace in southern China to put the world on alert. Yet with more than 4,800 cases in at least 26 countries to date, SARS has rocked Asian markets, ruined the tourist trade of an entire region, nearly bankrupted airlines, and spread panic through some of the world's largest cities. Hospitals and schools were shut down last week in Beijing, thousands of people were put under quarantine, and rumors flew through the capital that martial law was about to be imposed. In other countries, including the U.S. with zero SARS deaths, fear is spreading faster than SARS.

As the truth about SARS slowly emerges, it is becoming clear that government cover-ups not only damage China but also threaten the entire world. Epidemiologists have long worried about a highly contagious, fatal disease that could spread quickly around the globe, and SARS might end up confirming their worst fears.

Facing the mysterious SARS, what should we personally do to stop the spread of SARS? Should we count on a health-care system to protect us? Can we simply just wait for availability of a vaccine or remedy? Is it possible to seal off the mouths and noses of an entire nation and the world? Is it possible to turn all of the big cities like Beijing into ghost cities to halt the spread of SARS?

Can modern-day science wipe out SARS?

By remarkable international cooperation and advanced techology, scientists have already isolated the virus that causes SARS. In this amazing age of molecular genetics and medicine, can scientists stop a new viral disease that is now entering the human population? Can they erase its traces from the human race and set up a vaccine barricade it cannot breach? Dr. John R. La Montagne, Deputy Director of the National Institute of Allergy and Infectious Diseases, said, "probably NOT."

In history, smallpox may be the only infectious disease eradicated, because 1) smallpox does not have animal reservoirs, and 2) the symptoms of this disease can be easily identified. In contrast, polio is much more difficult to eradicate due to the mild symptoms that some patients may develop. It is impossible to eradicate flu because the flu virus has a variety of animal hosts, including pigs, birds, and horses. One cannot eradicate flu virus until you eradicate it in animals. The SARS virus perhaps has animal hosts so that eradication may be a problem. Most coronaviruses cannot be grown in the laboratory. However it is fortunate that SARS is different in this respect and can be isolated and grown in standard laboratory cells which may facilitate scientific research. Nonetheless, an effective vaccine or drug may not be immediately available although the entire genome of the corona virus has already been sequenced. In addition, whether the coronavirus is truly the cause of SARS remains to be determined since a Canadian virologist, Dr. Frank Plummer, announced earlier that he had found evidence of the virus in only 40 percent of patients. It was reported very recently that rapid mutation of SARS virus could complicate efforts to develop a solid diagnosis and a vaccine (Saturday, May 3, 2003, by AP).

Although vaccines may be used to protect both individuals and whole populations, vaccines may not provide full protection from disease (1). It is well known that evolution of vaccine resistance prompted by anti-growth rate and anti-toxin vaccines can substantially increase the risk for non-immune individuals (2-6). Therefore, this evolution of vaccine resistance can erode any population-wide benefits since "mutant" pathogens can escape immune recognition.

Uncertainty around SARS and unavailability of its cure may be the main source of panic sparked by the virus.

Stress and immunity

Psychological stress is known to affect immune function and to predict infectious disease susceptibility (7-10). Certainly, psychological stress can intensify a variety of health threats including SARS. Psychological factors have been repeatedly related to enumerative and functional indices of the immune system, to the common cold and wound healing rate, and the immune response of individuals to vaccinations. Psychological interventions were found to affect various immune parameters, cytokine profile, gene regulation in both innate and adaptive immune cells, and functional changes of immune cells. Both traumatic life events and psychological stress (perceptions and negative affect) are associated with increased susceptibility to a variety of diseases, including respiratory infections.

How does the brain communicate with the immune system? The brain affects immune responses via the hypothalamic-pituitary-adrenal (HPA) axis (11-13). Immune cells express receptors for the cytokines and neurotransmitters generated by the HPA axis. Immune system function modulated by the sympathetic nervous system may lead to uncontrolled inflammation via adrenergic receptors, while heightened vagal tone may suppress over-reactive inflammation via the cholinergic pathway. Stressful experiences can affect the HPA axis to promote excessive inflammation by production of sustained cytokines, suppress immune responses so that infection is prolonged, and increase morbidity and mortality in a variety of disorders.

Why a mind/body approach for SARS?

Dr. Patrick Dixon, a specialist in predicting global trends based at London's Development Management School, warned that more than one billion people worldwide could be infected by the SARS virus within a year. If this were true, how should we prepare for SARS spread?

The physical mechanism by which SARS is spread is still unclear, while other factors, such as uncertainty and unavailability of its cure, have been greatly fueling SARS fears in the world. Obviously, SARS targets both the human body and human mind. Moreover, despite that progress, and rapid work on a diagnostic test, the only available method to combat SARS is the crudest weapon in the public-health arsenal: quarantine. Quarantine alone, may enhance stress and anxiety in humans and act to promote spread of the disease. Some scientists questioned the efficacy of quarantine (14). The lack of effective treatment strategies suggests that novel approaches to prevention be identified. In this context, it may be useful to consider an alternative holistic way-- a mind/body approach for SARS prevention.

Multi-dimensional factors have been found to play important roles in human health. These factors may function psychologically through the immune and neuroendocrine systems (15, 16). Basically, it is well known and documented that the key healthy factor is in the human mind. However, the human mind is beyond genetic material – genome, which is the fundamental base of modern-day science.

Twenty-five years ago, it was reported that the only differences which distinguish various species might be the quantitative variation in gene expression rather than structural changes in gene products (17). The genomes of all mammals are so similar that it is hard to understand how similar genetic materials can generate so many different living creatures (18). Recently, it was confirmed that mice and humans share more than 99% of their genetic material, and one of the main differences between the mouse and human genome lies in the activity of "junk" DNA sequences that are coding for proteins (19, 20). What "magic" factors could possibly be beyond the one-dimensional genome? If genes of different animals are alike, then it is possible that other factors, such as mind-mediated changes in gene regulation, might drive the differences between species. The difference in gene activity of the brain between chimps and humans indicates that human uniqueness might be all in the mind (21). A great body of knowledge regarding gene regulation by a variety of physical and pathological insults has been obtained. However, little effort has examined how the human mind affects the body biologically and pathologically.

Currently, the responses of people to SARS may be viewed as a panic reaction. The impact of SARS is spreading even faster than SARS virus itself. Although nobody knows the unknown factors that fuel SARS fears, stress-and anxiety-associated immunological changes will definitely affect the onset, spread, and development of SARS in individuals. Therefore, a new paradigm – a mind/body interactive approach – is urgently needed to cope with this aggressive infectious disease.

An interesting phenomenon regarding SARS is that though the illness has killed hundreds of people around the globe, none have been children. Children have been infected with SARS but experts found the disease was mild and the symptoms were less serious. Why is SARS virus less aggressive in children? Perhaps children are less stressed psychologically.
Molecular mechanism of Mind/body interaction

There has been increasing interest in the phenomena of mind-body relationships, a subject that has been primarily excluded from systematic scientific investigations due to its complex nature. Mind/body medicine is based on more than 2000 scientific studies that have been published in peer-reviewed journals in the past 25 years (22). In addition, ample evidence has been accumulated throughout history to support the powerful physical effects of practices that are directed towards the mind and/or spirituality. Such practices include both religious and non-religious cultivation practices. In the Western societies, religious practices are predominant, while the Eastern culture emphasizes the activation of energy systems through sets of physical and mental disciplines, such as Yoga, Qigong, Tai Qi, and most recently, the spiritual teachings of Falun Gong (FLG) (also known as Falun Dafa) (23-28). While the health benefits of Yoga, meditation, and prayer have been documented and partly recognized by the general public, the mechanisms that underlie such apparent effects are not well-understood at the physiological level. Less has been documented and systematically studied at the cellular or molecular level. On the other hand, major technological progress has been made in the area of biological research that now allows rapid and precise monitoring of many of the detailed molecular events inside of a single cell.

Recently, a health phenotype-associated profiling of gene expression at the genome-wide level was investigated in a group of people with spiritual practice. Dramatic changes have been identified in neutrophil transcripts from practitioners of Falun Gong (29, 30). These biological changes are characterized by enhanced immunity, alteration of apoptotic genes in favor of a rapid resolution of inflammation, as well as down-regulation of cellular metabolism that was supported by a downsizing of the substrate-dependent protein degradation pathway, ubiquitin-dependent protein degradation pathway. The regulation of immunity and apoptosis may be a manifestation of balanced biological regulation which can function as a key element to enhance immunity without adverse effects. The lifespan of healthy cells is prolonged to reduce cell proliferation, while cell death of inflammatory and diseased cells is accelerated to protect the host.

In another preliminary study, we have found drastic gene regulation in peripheral blood mononuclear cells (PBMC) from FLG practitioners in contrast to normal healthy non-practitioners as controls. Among 22,000 probes (Human 22 K oligo Gene chip), there were about 300 genes significantly altered in FLG practitioners in contrast to normal controls. However, after one hour of meditation, there were about 1,000 genes dramatically changed in PBMC isolated from practitioners in contrast to normal controls with one hour of sham meditation. To avoid the possibility of individual variation among subjects, a longitudinal study was carried out with comparison of samples before and after one hour of meditation in the same subject. Significant changes were observed in samples before and after one hour of meditation in practitioners, but not in sham-meditation controls. The longitudinal study of gene regulation indicates that meditation can significantly alter gene regulation in as little as one hour. Among the up-regulated genes, a transcriptional factor for interferon- [interferon (IFN) regulatory factor (IRF-5)] was up-regulated 50-100 fold in PBMC from meditation practitioners after one-hour meditation. Since microarray technology cannot be used to quantitate transcriptional expression, the capability of PBMCs to produce IFN- was further confirmed by other assays (31). Transcriptional factors of the IRF family have been shown to play an essential role in the regulated expression of the type I IFN gene, IFN-stimulated genes, and other cytokines and chemokines, which are involved in host defense against bacterial and viral infection (32). Up-regulation of IFN-inducing transcriptional factor instead of IFN itself may represent a safe-mode regulation. It is well known that cytokines, chemokines, and the other growth factors can function as a double-edged sword by killing infectious agents and damaging self as well (33, 34). Increase in transcriptional factor(s) that have lower cellular toxicity may lead to rapid synthesis of cytokines when needed without self-damaging side effects. This safe-mode marked regulation may be the characteristics of mind/body approach.

Enhanced immunity was identified in the practitioners of Falun Gong. However, it is well known that immune activation could be detrimental to the host when the immune response is sustained. How can the immune cells from those subjects with enhanced immune functions reconcile with the dilemma? Recently, we presented a case of a 58-year-old woman who had progressive systemic scleroderma (PSS) with progressive cutaneous and pulmonary involvement for 8 years (manuscript in preparation). Her practice of Falun Gong has successfully improved her disease and the improvement has persisted for 5 years without relapse. Among all immunologic parameters of peripheral blood mononuclear cells (PBMC), CD4+CD25+ T regulatory cells (Treg) are significantly increased in PBMC in contrast to age-, sex-, and race-matched healthy controls, and the ratio of Treg of this subject is 58% (30% ± 10 in normal healthy controls). Recently, there was a burst of papers regarding immunosuppressive activity (35). This case suggests that a mind/body approach-mediated immune regulation not only can increase immunity via induction of cytokines but also can suppress autoimmune regulation by increase of Treg.

Our data and that of others clearly indicate that mind/body-mediated health benefit may result from lowering of metabolic rate, modulating of cell death, and enhancing of immunity and mind/body approach may represent a homeostasis-based safe-mode regulation.

Stress can be characterized as a state of autonomic nervous system compromise (36). Stress can either exert effects on attenuating or worsening diseases, depending on a multitude of factors (37, 38). However, clinically negative influences of stress upon health and disease processes seem to dominate. Nowadays, stress-related disorders seem to be increasingly epidemic. Chronic imbalance of the autonomic nervous system, which is composed of sympathetic and parasympathetic systems, is a prevalent and potent risk factor for a variety of disorders. Sympathetic and parasympathetic (vagus nerve) nervous systems are regulated in a reciprocal manner. It has been well documented that vagal tone is concerned with restoration and conservation of bodily energy and resting of vital organs. Any factor that leads to inappropriate activation of the sympathetic nervous system can be expected to have adverse effects on living beings, while any factor that increases vagal tone tends to improve biological systems. Currently, a great number of people experience sympathetic overdrive due to a fast-paced lifestyle, inappropriate diet, sympathomimetic medication, negative psychosocial factors, climate changes, chaotic environments, wars, infectious diseases like SARS, and so on, because those factors may specifically challenge the fight-or-flight sympathetic nervous system. Therefore, most autonomic related pathological complications are due to sympathetic dominance. These include hypertension, myocardial infarction, diabetes, autoimmune diseases, chronic infectious diseases, cancer, and neurodegerative disorders.

In general, the parasympathetic system promotes functions associated with growth, preservation, and restoration. In contrast, the sympathetic nervous system promotes increased metabolic output to deal with external challenges (from outside of body). The parasympathetic system deals primarily with anabolic activities concerned with the restoration and conservation of bodily energy and the resting of vital organs.

Meditation can be characterized as a wakeful hypometabolic state of parasympathetic dominance. Although there are some analogies between sleep, hypnosis, and hibernation, physiologic evidence shows that sleep and meditation are not the same. Meditation represents a special case of the hypometabolic response (39).

When practiced once or twice a day for just 20-30 min at a sitting, persistent effects on the metabolism that is opposite from the fight-flight reflex, can be observed. It was observed that the higher central command associated with meditation was apparently able to override a powerful adrenergic stimulus provided by the pharmacologic infusion (40). In the fight-flight reflex, catecholamine levels increase dramatically, large amounts of glucose become available for quick energy mobilization, respiratory rate increases, blood is shunted away from the viscera to oxygenate skeletal muscle, and the organism goes into a state of heightened vigilance (38). It has been documented that catecholamines can block production of nitric oxide (NO) (41), one of major relaxing factor by endothelial cells (see below), which can partially explain the impaired immune protection against viral infection in stressed animals. NO is an immune mediator that has a potent activity against viral replication (42-44), and animals lacking inducible nitric oxide synthesis are more susceptible to viral infection (45).

The endothelium, the major target of acetylcholine, is a continuous cellular monolayer lining the blood vessels and has an enormous range of important homeostatic roles. Endothelial integrity plays an important role in vascular homeostasis. The main neurotransmitter or vagus nerve, acetylcholine, can stimulate endothelium-dependent vascular relaxation via production of three major vasodilators: NO, protacyclin, and endothelium-derived hyperpolarizing factor (EDHF) (46, 47), specifically epoxyeicosatrienoic acid (EET) (48). Esch et al. found that constitutive or low-output NO production may be involved in protective effects by relaxation response (49, 50). Those endogenous vasodilators possess anti-inflammatory, anti-proliferative and anti-thrombotic properties. EETs were linked to the inhibition of the activity of pro-inflammation nuclear transcription factor B (NF-B) (51). NO can also inhibit NF-B and attenuate inflammation (52, 53). Vasodilator-mediated anti-inflammatory effects may further maintain blood flow. It was found that EET inhibited the aggregation of the most abundant inflammatory cells, neutrophils (54, 55). When the balance is disturbed, endothelial dysfunction develops and participates in many of the pathological processes seen in a variety of disorders, including inflammation and immune diseases (56).

Recently, a nervous connection in the control of inflammation was identified, indicating that inflammation is not only a local response, but is also fine-tuned and regulated precisely, because of deficiencies or excesses of the inflammatory response which cause morbidity (57, 58). The acetylcholine-mediated cholinergic pathway can efficiently modulate immune responses (59, 60). The vagus nerve plays an important role in transmitting immune information between visceral organs to brain and maintaining the immune balance of the organism.

Tracey hypothesized that meditation, hypnosis, and acupuncture may exert anti-inflammatory effects via increasing vagus nerve activity (57, 61). Scientific inquiry of alternative medicine and a mind/body approach is urgently needed to provide insights into holistic medicine in preventing and perhaps treating the mysterious and fear-inducing SARS.

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