Stress Response and Immunity: Links and Trade Offs

Life is ubiquitous on Earth wherever liquid water is present. The three domains of life Eukaryota, Bacteria, and Archaea, although very different, have a common origin. They share the basic enzymatic machinery, and they use ATP as an energy source. Every organism is adapted to a specific set of environmental conditions. Divergence from such conditions disturbs the normal functioning of the organism and generates stress - a pressure to adapt to the new conditions. Stress can be caused by many factors, from lack of nutrients to heat, cold, radiation, and toxins. Organism’s reaction to stress is called stress response. It involves modification of cellular functioning, which may include activation of specific transcriptional programs, modification of membranes and proteins, production of protective compounds, and metabolic adaptations. Every type of stress causes similar problems in all organisms; for example, heat causes protein denaturation. A universal response to this problem is the production of chaperones that help proteins to refold and of other compounds that stabilize protein structure. Accordingly, diverse organisms share many features of their stress responses.

Pathogens live inside other organisms called hosts, exploiting them and causing disease. Viruses and other mobile genetic elements such as transposons are pathogens that parasite on all life forms. They are obligate pathogens since they replicate only inside their hosts. Many bacterial pathogens are facultative since they can live outside their host. Viruses recognize host cells by specific molecules that serve as viral receptors. Only cells expressing them can be infected. Multicellular organisms host pathogenic bacteria and eukaryotic pathogens such as fungi, protozoa, and helminths in addition to viruses. Infection depends on pathogen’s ability to survive inside the host. Some pathogens quickly kill their host with large numbers of new pathogens released, whereas others establish long-lasting infection. Lytic viruses replicate and then lyse their host to get released. Other viruses do not lyse their host; instead, they establish chronic infection by replicating slowly and exiting the host cells by extrusion. Temperate viruses integrate into host DNA and stay silent for many cell divisions until the cell experiences stress. Then, the lytic program is activated, and the virus replicates and kills the cell. Similar to viruses, some intracellular bacterial pathogens are obligate and can only replicate inside their host. Pathogens differ in their host range; some can infect only a single species, while others are generalists. Hosts constantly evolve mechanisms preventing infection and destroying pathogens. In turn, pathogens evolve to overcome host defenses.

Most of the information about stress response in prokaryotes comes from studies in bacteria. Bacteria developed a set of measures to maintain homeostasis in unstable environments. In response to a particular stress, bacteria switch their transcription to an alternative mode that better serves survival in the changed environment. They do it by using alternative sigma subunits of RNA polymerase (RNAP). Some sigma factors induce a transcription switch to a particular program that adjusts bacteria to specific stress, such as heat. Other sigma factors are responsible for the general stress response that protects the bacteria from various stresses. In addition to alternative transcriptional modes, bacteria use other mechanisms to cope with stress including DNA damage stress response and programmed cell death in response to severe stress.

Many Earth habitats have an extreme cold, heat, salinity, and pressure conditions. Such places are populated by extremophiles. Thermophiles prefer environments with high temperatures. Psychrophiles live at very low temperatures. Halophiles can tolerate high salt, alkaliphiles tolerate high and acidophiles low pH. Barophiles adapt to live under high pressure. Extremophiles have permanent modifications in their membranes and in the amino acid composition of their proteins that allow them to maintain a stable internal environment under extreme conditions. Many environments have several extreme conditions, e.g. cold and high pressure on the ocean floor; such places are populated by polyextremophiles.

Prokaryotes protect themselves from viruses and mobile genetic elements at several levels. They can produce exopolysaccharide capsules around the cell or slime that covers viral receptors and prevents viral binding. Secreted extracellular enzymes can destroy pathogenic nuclear acids around the cell. After a pathogen enters the cell, it can be destroyed by sugar-nonspecific nucleases that cleave both DNA and RNA. A common defense mechanism is restriction-modification (R/M). R/M systems are based on methylation of the host DNA at specific sequences, whereas viral DNA not protected by methylation is quickly degraded by restriction endonucleases. R/M systems differ in the type of enzymes and recognition principles. Most archaea and half of the bacteria have the prokaryotic adaptive immune system CRISPR-Cas. This system consists of CRISPR (clustered regularly interspersed short palindromic repeats) and CRISPR-associated (Cas) proteins. Other defenses include Argonaute-based systems that utilize both DNA and RNA guides to destroy foreign nucleic acids and abortive infection (Abi), which is a measure of last resort, such that death of the infected cells prevents spread of infection.

In prokaryote cells, stress response interacts with immune response. Stress caused by diverse factors from DNA damage to heat, low pH, heavy metals, antibiotics, and toxins leads to the induction of proviruses and movement of mobile genetic elements. This can lead to horizontal gene transfer of immune mechanisms encoded by such elements and stimulate the evolution of bacterial immune defenses. The viral infection is associated with changes in host membranes and metabolism, which can be sensed as stress. Such stress then affects immune mechanisms. Stress can activate CRISPR-Cas systems preventively before they encounter an intruder. During DNA damage and associated DNA repair, unmodified R/M recognition sites may appear in the prokaryotic genome. To avoid targeting such sites by R/M systems, their activity is downregulated during stress.

Eukaryotic stress response involves changes in transcription, translation, and proteostasis. Some changes are similar across many stress responses. Stressors such as misfolded proteins, oxidative stress, viral RNAs, heme deficiency, heat shock, amino acid shortage, and others activate the integrated stress response (ISR) kinases PERK, PKR, HRI, and GCN2; they phosphorylate eIF2α inducing global inhibition of translation. Some stresses, e.g. oxidative and osmotic can activate several kinases. Transcriptional response to stress involves the suppression of genes functioning in energy-consuming processes such as protein biosynthesis and activation of genes that mitigate damage caused by stress. Many stresses interfere with the synthesis and folding of proteins. When unfolded protein level exceeds folding and clearance capacity of the cell, the unfolded protein response is triggered, which increases that capacity by producing more chaperones and proteases. Autophagy is another common response to stress that helps to cleanse the cell of aggregated proteins and dysfunctional organelles and replenish the supply of biosynthetic precursors and energy. There are also responses specific to heat, cold, osmotic, pH, oxidative, and mitochondrial stress. They involve activation of programs that mediate adjustment to specific stress.

p53 is the most important tumor suppressor. It arrests cell cycle in response to stress, stimulates DNA repair, and induces senescence or apoptosis of cells that have unrepairable damage. p53 level and activity are kept low by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 targeting it for proteasomal degradation. Additional post-translational modifications of p53 such as phosphorylation, methylation, acetylation, and others, signal the cell’s internal condition to p53 and modulate its activity.

Autonomous immunity is a set of immune mechanisms present in practically every cell of a multicellular organism. They include immune mechanisms based on nuclear acids, such as RNA interference (RNAi). Small RNAs generated from pathogen dsRNAs guide nucleases to the pathogenic nucleic acids. In addition, RNAi restricts the expression of transposable elements by establishing transcriptionrepressing chromatin over DNA regions that encode such elements. Other autonomous mechanisms prevent the entry of viruses into cells, detect and destroy non-self nucleic acids, restrict pathogen growth and replication, prevent pathogen release, and induce regulated cell death if the infection cannot be suppressed. Infected cells release interferons and other cytokines that alert neighboring cells and preventively induce defensive mechanisms in them. Pathogens express pathogen-associated molecular patterns (PAMPs), which are recognized by pattern-recognition receptors (PRRs). These receptors also recognize damaged “self” molecules expressing damageassociated molecular patterns. Infection can also be sensed indirectly through changes in the functioning of some key cellular molecules. Stress and infection can lead to the formation of inflammasomes triggering production and secretion of pro-inflammatory cytokines.

Stress response contributes to autonomous immune responses. Many stresses including infection induce integrated stress response (ISR). ISR is mediated by a set of kinases PKR, PERK, HRI, and GCN2. Viral dsRNA activates PKR. Viral proteins are produced in the endoplasmic reticulum and may cause ER stress, which activates PERK. Infection also can cause iron deficiency sensed by HRI kinase and amino acid shortage sensed by GCN2. The arrest of translation caused by ISR inhibits viral replication and activates NFkB, a major regulator of immunity. Therefore, ISR acts as an immunodefense mechanism. Other stress responses that contribute to immune defense include unfolded protein response (UPR). UPR activates degradation of ERassociated mRNAs and proteins including viral ones. DNA damage response leads to NFkB activation, and so does oxidative stress through various mechanisms. The major stress response factor p53 has anti-viral activity. Autophagy activated by many stresses also plays a role in immunodefense by degrading intracellular pathogens.

Specialized immune systems of animals include innate and adaptive immune cells and humoral factors. Inflammation is also a specialized systemic immune response. Innate immune cells include professional phagocytes such as macrophages, dendritic cells, and neutrophils, as well as natural killer (NK) cells. Adaptive immune cells are T and B lymphocytes. Immune cells work in cooperation with humoral factors such as the complement system, secreted pattern-recognition receptors, and antibodies. Inflammation activates immune cells and generates fever. Acute inflammation is beneficial, whereas chronic inflammation may lead to pathology including atherosclerosis, type 2 diabetes, and autoimmune diseases. Recognition of pathogenassociated molecular patterns (PAMPs) by phagocytes leads to their activation, phagocytosis, respiratory burst producing reactive oxygen (ROS) and nitrogen (RNS) species, and secretion of antimicrobial peptides and pro-inflammatory cytokines. NK cells function on a different recognition principle. They express a variety of activating receptors to endogenous molecules expressed on distressed but not healthy cells. Engagement of these receptors triggers cytotoxic activity. NK cells also express inhibitory receptors that bind “self” markers such as MHCI molecules, which are expressed on all healthy cells. The balance between the engagement of activating and inhibitory receptors determines cell fate. Complement is a humoral cascade of enzymes that promotes chemotaxis, inflammation, and phagocytosis, as well as kills pathogens and infected or stressed cells. The evolutionary youngest specialized adaptive immune system consists of T and B cells, which express rearranging receptors both membrane and secreted.

Brain coordinates physiological, immunological, and behavioral responses to stress. A typical stress response is “freeze, fight or flight”. It involves the release of catecholamines by the sympathoadrenal system and activation of the hypothalamopituitary- adrenal (HPA) axis to produce various hormones that prepare the organism for a particular response. Stress generally leads to a strong suppression of the adaptive immune system and a partial suppression of the innate immune system. The brain controls the immune organs through hormones produced by the HPA axis and through direct control by neurotransmitters. In turn, immune mechanisms affect behavior and brain development. Brain microglia support developing neurons, phagocyte dead and inactive cells, and participate in the formation of connections between neurons through synaptic pruning. Peripheral immune cells regulate neurons through neurotransmitters and inflammatory mediators such as IL6, TNF, PGE2, histamine, and others. These mediators induce sickness behavior during illness. They also alter the developing brain during maternal stress, maternal immune activation, and early life stress predisposing the brain to a mental illness. Immune mechanisms contribute to psychiatric and neurodegenerative disorders.