Immunological Mechanisms of Sickness Behavior in Viral Infection

Abstract

Sickness behavior is the common denominator for a plethora of changes in normal behavioral routines and systemic metabolism during an infection. Typical symptoms include temperature, muscle weakness, and loss of appetite. Whereas we experience these changes as a pathology, in fact they are a carefully orchestrated response mediated by the immune system. Its purpose is to optimize immune cell functionality against pathogens whilst minimizing viral replication in infected cells. Sickness behavior is controlled at several levels, most notably by the central nervous system, but also by other organs that mediate systemic homeostasis, such as the liver and adipose tissue. Nevertheless, the changes mediated by these organs are ultimately initiated by immune cells, usually through local or systemic secretion of cytokines. The nature of infection determines which cytokine profile is induced by immune cells and therefore which sickness behavior ensues. In context of infection, sickness behavior is typically beneficial. However, inappropriate activation of the immune system may induce adverse aspects of sickness behavior. For example, tissue stress caused by obesity may result in chronic activation of the immune system, leading to lasting changes in systemic metabolism. Concurrently, metabolic disease prevents induction of appropriate sickness behavior following viral infection, thus impairing the normal immune response. In this article, we will revisit recent literature that elucidates both the benefits and the negative aspects of sickness behavior in context of viral infection.

Keywords: T cells; anorexia; appetite; coronavirus; cytokines; cytomegalovirus; diabetes; infection; metabolic disease; metabolism; nausea; sickness behavior.

Figure 1

Immunological mediators produced in context of viral infection induce sickness behavior by targeting various organs in our body. Prime examples are (1) the induction of fever by cytokines. TNF and IL-6, which stimulate endothelium in the brain and promote their release of prostaglandin PGE2, which directly target the thermoregulatory center in the CNS; (2) induction of anorexia by cytokines such as TNF and IL-18, which promote release of leptin and suppress appetite; and (3) induction of fatigue by Type-I interferons and IFNγ, which directly target muscle cells.

Figure 2

Sickness behavior is beneficial for immune cell activation. Fever can induce migration of cells to the lymph nodes and increase their cytotoxic activity. Loss of appetite induces the release of circulating free fatty acids (FFA) that are used as an energy source in immune cells. Muscle fatigue can be the consequence of insulin resistance (IR) and reduced glucose uptake, which increases systemic insulin levels and promotes the anti-viral T-cell response.