WARFARE ANALOGY There is no question that the medical field has for a long time recognized analogies between host-pathogen relationships and warfare, as judged by use of terminology in describing pathological interactions. Thus they speak of microbial invasion, host lines of defense, breaching defenses, counterattack, the need for surveillance, combatting disease, etc. But the important question is whether there is more than a superficial similarity between the two areas. Some medical researchers claim there is (see Playfair example below), and it is certainly common for medical practitioners to refer to infectious disease situations using such terminology. From the widespread use, it would appear that medical professionals find warfare-related analogies intuitively appealing and powerful devices for conveying knowledge in the field. Yet, it is not clear how far and in which directions the analogy can be extended. There are probably both general and specific levels at which analogies can be extended. At the most general level there is the notion of war, the concept of aggression and defense, weapons, invasion of territory, direct assaults, lines of defense, battles for resources, soldiers, forces, capture, etc. Below I have sketched out actual and potentially useful warfare or conflict terminology applied to the pathology of microbes. (The references M83, M75, etc. in the text below refer to the page numbers in Mims (1995): Pathogenesis of Infectious Disease, 4th edition where warfare terminology is applied or could apply. All of the references were gathered from pages 62-89, the section I was reading at the time of the "assignment", an indication, I believe, of the richness of this cluster of analogies.) The analogies suggested below were selected from a longer list because they either had a direct support from a specific reference (the Mims book), or seemed to apply well from my general reading of topics in the field. There are unquestionably many others. For example, just today I saw the term "hijacking" in a microbiology journal to describe the interaction of a microbial toxin with a cell membrane. Higher Level Analogies Arms Race (referring to evolution of weapons and defenses, see M85 for a reference to this that implies but does not use the term) Attack invasion counterattack overwhelming assaults (as in some cases of sepsis or immunodeficiency) breaching defenses Defense first line of defense (applied in at least three cases: 1. nonimmune defenses such as physical barriers, chemicals 2. innate immune system cf the adaptive immune system 3. with regard to sequential invasion of tissue spaces. second line of defense, etc More specific notions are: Form of attack guerrilla warfare (many cases of microbial attack can be viewed this way - not directly confrontational. hit and run (M62 in reference to respiratory/intestinal infections which do not invade epithelium of lungs/gi tract and escape before immune response can be mounted) sabotage (M73 - of host protein production by bacteria) subversion (commonly used in reference to viruses taking over host machinery) sieges (macrophages that surround and wall off bacteria (e.g., tuberculosis) without killing them. neutralization (normal term for antibody binding to microbes in the blood or extracellular fluid and blocking pathogenicity) military alliances (could apply to synergistic pathologies, where more than one pathogen act in concert) defender types special forces (could be applied to the specialization of phagocytotic and immune cells: macrophages, PMN's, cytotoxic T-cells, helper T-cells, etc) surveillance, monitoring, scouts(?) (applied to macrophages which travel through tissues looking for foreign bodies) search and destroy units (could apply to macrophages, leukocytes) scavengers (M72 applied to white blood cells policemen (M72 white blood cells) hit squads, assassins, professional killers (M76 immune phagocytes that seek out specific microbes based on antigenicity) suicide mission (cells that self-destruct to kill the intruder) suicide bags (name applied to lysosomes that break open and release their contents destroying the cell. The triggering for the reaction is by binding of microorganism products to outside, a way that the microorganism has outsmarted the cell.) "shoot me" cells (host cells which display stamp on membrane of invasion by viruses. These cells are attacked and killed by the host's own cytotoxic T-cells) evasion of defense efforts camouflage (coating on gram negative bacteria that inhibits recognition as foreign body by failing to provide earmarks of enemy) hit and run (described above under attack strategies) wolf in sheep's clothing (could be applied to viruses which have envelope made from host cell membrane) Trojan horses (bacteria which invade macrophages meant to destroy them and travel to other sites of the body protected from attack) disguise (binding to receptors on cells that are for messenger chemicals like hormones, cell-cell recognition, etc) changing identity (mutations in protein coats or envelope proteins are common for some viruses or membrane proteins for some bacteria are frequent, preventing an efficient antibody response (e.g., AIDS, influenza). monkey wrench (blocking normal killing mechanisms within killer cells, e.g., blocking fusion of endosome and lysosome (see text below)) blocking capture (inhibition of phagocytosis) turning the tables (using host's own destructive processes to your advantage, e.g., viruses which let the host degrade them partially so that their DNA/RNA can be freed for replication) Methods tracking (PMN's locate enemy by tracking chemical gradients; chemotaxis) Defense Strategies containment (M71 - restrict microbes to lymph nodes, or wall them off) running the gauntlet (M71 used to describe the carrying of the microbes via the flow of lymph through several areas where macrophages were lined up) resource deprivation scavenging/sequestering (M73 host sequesters iron which microbes need to grow) cutting supply lines (viral inhibition of host synthesis) defense structures defense post (M71 referring to lymph node) communication distress signals (chemicals released by injured and dying cells) sabotage of communications (microbes commonly bind to cell signaling receptors on surface distorting or blocking communication. false sentries (some viruses produce products which insert in the membrane as defective signalers. Many are "oncogenes" which cause cancer in the host) transport block transport (secretion of mucus) disable transporter (toxins that inhibit locomotion) weapons aggressins (M85 weapons of attack of microbes that are destructive, i.e.,(toxins) impedins (M85 weapons which impede host attack but do not injure host directly) arsenals (M89 lysosomal weaponry) armory (M83 antimicrobial armory) food poisoning (M89 phagocyte can be said to die of food poisoning) path clearers (microbes have a variety of enzymes that dissolve extracellular, membrane, or cytoskeletal network components) THE INVASION SCENARIO The basic analogy revolves around attack and defense. The host is always seen as the defender and the microorganism as the attacker. In this sense the analogy is from a subjective rather than objective viewpoint. Host aggressive responses are always viewed as self-defense. The soldiers for the two sides are the pathogens, which usually have to be in some minimal concentration to successfully invade, and the immune system cells, which engage either at close range or produce "weapons" to engage and destroy the enemy at a distance. Examples of weapons are microbial exotoxins and endotoxins, host antibodies, and host toxins. The battle is over control of resources, with the microbial organism requiring resources for growth and reproduction possessed by the host. In many cases the resources sufficient for survival can be gathered without perturbing the host sufficiently to cause disease. These silent infections are thought to represent the vast majority, and may be considered analogous to the persistence of parasites in a society, who are troublesome but not worth the effort to annihilate completely. In fact, the majority of pathogens are carried by significant fractions of the host population without causing overt disease. The reasons for this are still not completely understood, but it is thought that it is accomplished by the ability to restrict pathogen numbers or location within the host, accomplished by natural physical/chemical barriers and immune surveillance, which is normally highly efficient and effective. Pathogenicity typically is caused by unusual virulence arising from mutation or species crossover from the normal host, a decrease in normal defensive capability or barriers (immunosuppression, nutritional deficiency, wounds, genetic defects in immune system), or unusual synergies between pathogens. The considerable individual variation in susceptibility is still an issue of active investigation. An important distinction between pathogens and enemies of war is that it is not in the pathogen's interest to destroy or even harm the host. This results in evolutionary pressures for retaining the least possible virulence necessary for successful propagation. One possible analogy here is that if you are trying to control resources possessed by the enemy you should not destroy them during the assault, nor provoke the enemy to destroy them. The key to a host's defense is being able to recognize its own cells and molecules from those of the pathogen (i.e. SELF from NON-SELF). In the military context, such recognition is accomplished by wearing different uniforms. While the host situation is similar, in that all liver cells, or all heart cells, will share the same set of surface proteins, and so can be readily identified as friend, the pathogens have no need to recognize differences between themselves. For them it is much more like "every man for himself". The measures of success are very different. For the host, it is retention of control of resources and of structural integrity, for the pathogen it is access to resources and successful escape or persistence for sufficient numbers of invaders to perpetuate the species. This puts a very heavy burden on the host to find a way to destroy the invaders without causing too much destruction to its own health and survival. The host is often far from successful in this; in fact in a significant fraction of cases the pathology and lethality of the infectious disease is the direct result of severe over-reactions on the part of the host that are provoked, to be sure, by the pathogen. This includes the widespread destruction of healthy tissue in attempts to destroy the foreign invaders, fatal disturbances in electrolyte imbalances (as in anaphylactic shock caused, e.g., by severe allergic response to bee stings, etc.), and reactions against self-tissue that shares similarity with a pathogen which persists long after the original pathogen has been cleared out (auto-immunity). Perhaps in auto-immunity there is an analogy with the police state, where all suspected enemies are destroyed, including many innocent victims. The recent assault on Grozny (which had a large population of ethnic Russians) by the Russians, and even some of the NATO bombing incidents in the Kosovo conflict may have analogies to destruction of friend in efforts to destroy the foe. The case of anaphylactic shock does not bring any analogy to mind at the moment. This problem of detecting the enemy and reacting to it appropriately has led in mammals to an adaptive immune system of remarkable specificity, sophistication and complexity. The heart of this immune system is the ability to recognize certain features on invading cells or their molecular products as foreign. To do this, the agents of recognition (T-cells, monocytes) produce detection devices (surface membrane receptors) for specific parts of microbial membrane surface protein or carbohydrate components (or protein coats in the case of viruses). Perhaps this is a bit like the training for detection of enemy planes during World War II according to certain features, like tail shape, etc. No T-cell receptor recognizes a whole molecule, but rather just a part of it, called an epitope. It's a bit like the blind men identifying the elephant, each feeling a different part. During development, over 90% of the T-cell trainees are thought to be eliminated, either because they never become effective identifiers, or because the component they have learned to identify is a fragment of a self component. Those who pass muster are divided into two groups, the assassins composing hit squads (cytotoxic T-cells), whose job is to search out and destroy any cell, particle, or molecule bearing a foreign stamp, and the commanders of artillery, (helper T-cells) who direct the production and release of neutralizing weapons by the B-cells (the circulating antibodies). In the case of viral infections of cells, some of the invaders are destroyed and their recognition stamps (viral fragments) posted on the surface of the cell ("shoot me" gambit). When the T-cell search and destroy group detects these stamps on host cell membranes, the infected cell is attacked and destroyed. Perhaps there are partial analogies here to hostages that manage to get word to the enemy of their capture, and who are killed in the assault, or even more appropriately those who sacrificed themselves in desperate situations in Viet Nam by calling for artillery or aerial bombardment on their own positions when they were hopelessly surrounded by enemy troops. The pathogen, too, has its own strategies for attack and defense. It must first overcome the host's physical defenses by locating or creating a portal of entry. Many enter by natural portals, like the nose and mouth, or by openings created by injury or bites, while a few may succeed in creating their own openings. Opportunism is an important capability of most pathogens, who, as I have mentioned, are often innocuous residents on or in the host until an opportunity for proliferation presents itself. Failure to penetrate the first line of defense may be due to lack of sustainable resources, as for instance on dry areas of the skin, host chemical toxicity caused by acidity or secretion of degradative enzymes, physical barriers such as compacted tissue (the outer layer of dead skin, the extracellular connective tissue matrices) or mucous secretions that impede mobility (respiratory and intestinal systems), and active removal mechanisms such as violent expulsion (sneezing, nose-blowing, coughing, vomiting), sweeping away (upward beating cilia in the respiratory tract), and flushing out (tearing and diarrhea). Physical barriers have direct analogies with warfare in walls, roadblocks, etc. The chemical defenses also have their obvious counterparts, although chemical warfare has not been a common component of warfare to date. The best analogy I can think of at the moment to violent expulsion is a water cannon (:>). Release of water from dams has sometimes been used as a defensive measure, but the flushing analogy seems uncommon. Successful pathogens have a host of strategies for overcoming host defenses. These include opportunism, barrier removal, overcoming barriers, stealing the password, and friendly disguise. Waiting ("Lie and wait" gambit) for a temporary lapse in host defenses is very common, as I have mentioned. Wounds, stress, and nutritional deficiencies can lead to breakdowns in barriers. Others circumvent host removal strategies by developing tenacious mechanisms for binding to host tissues (e.g., pili), as do many respiratory bacteria that must penetrate mucous layers. Once they have gained a foothold they are then able to penetrate the endothelial cells of gut or respiratory tract. It is a bit like scaling a cliff to get into enemy territory. Still others secrete corrosive enzymes that dissolve barriers, such as the skin outer layers, cell membranes, or the extracellular fibrous matrix. I suppose artillery and bombing perform this role of knocking down barriers in warfare, although it is a physical rather than chemical effect. Once securely inside the first line of defense, most pathogens spend a period of growth and proliferation just within the portal of entry. From there they disseminate to other tissues. Most have specific target tissues or cells that they aim for. At the tissue level they face the next line of defense consisting of tissue fluids containing antimicrobial substances, local macrophages which devour and destroy foreign bodies, a hydrated gel matrix which is difficult to move in, and a lymph system which conveys them to the lymph nodes where a battery of immune defenses await. To successfully replicate, bacteria must resist all of these lines of defense. Many have enzymes capable of breaking down the gel matrix. Others have ways to defeat the antimicrobial substances either by destroying them by proteolytic secretions, blocking their entry through the membrane, or destroying them intracellularly. Many bacteria resist phagocytosis by macrophages by secreting a capsule which masks membrane proteins, and may even be toxic in itself (e.g., lipopolysaccharides, "camouflage gambit"). A few bacteria survive phagocytosis to take up residence inside the very host immune cells that are supposed to kill them, where they are protected from further attack ("Trojan horse" gambit). This Trojan Horse scenario applies to Staphylococcus aureus and a few other bacteria capable on intracellular seclusion, as well possibly to many of the viruses who can persist for long periods within their immune system target cells (e.g., AIDS in helper T-cells). While bacteria normally proliferate in the extracellular spaces, viruses must enter cells to get access to the host's replication machinery. Free viruses consist of nothing more than DNA or RNA surrounded by a protective protein coat and sometimes an outer membranous envelope made from one of the host cell membranes. Outside the cell they are inert, and the covering must protect them from physical and chemical destruction until they can invade their target cells and replicate. Most bacteria are capable of living free in the environment, and choose the host simply because it provides a more generous resource environment. Once in the host, they normally remain in the extra-cellular spaces. Viruses on the other hand must take advantage of host cell replication machinery or host cell infrastructure for propagation, and so are obligate intracellular parasites. Once in the vicinity of the target cells viruses have specific cell receptor targets, which have been identified for most of the major viruses. The most common types of receptors chosen by viruses are signaling pathway receptors (for hormones, neurotransmitters, etc), immunoglobulins (cell recognition and immune defense), or cell adhesion receptors (cell-extracellular matrix adhesion, cell-cell adhesion in tissues). The virus utilizes these receptors for its own purposes by posing as the legitimate ligand ("disguise" gambit). Once attached, the virus, or at least its DNA, must get through the membrane. Viruses have several methods for doing this. Those without envelopes (naked viruses) can either inject the DNA through the membrane, or trigger the process of endocytosis, by which means they are taken into the cell wrapped in a piece of the cell membrane that has been pinched off. Enveloped viruses may use this same method of endocytosis, or they may fuse their envelope with the cell membrane, liberating the unenveloped virus particle into the cytoplasm. These steps are like commandeering the enemy's transport network to advance your own troops. However, the case for the virus which is taken up by endocytosis is more difficult. Receptor-mediated endocytosis is used for several purposes by the cell, but it normally involves the destruction of the ligand which binds to the receptor and the recycling of receptors as a regulatory mechanism. As mentioned earlier, sometimes the ligand is a hormone, and the cell uses the removal of the hormone as a way to prevent continual signaling of the hormone. Therefore the virus allows itself to be captured ("surrender" gambit) in order to use the transport system to get into the cell interior, but it must avoid being destroyed. After uptake by endocytosis into these pinched-off membrane vesicles called endosomes, the endosome normally fuses with acidic degradation vesicles called lysosomes. The high acidity of lysosomes and the abundance of proteolytic enzymes leads to rapid degradation of the contents of the fused vesicles. The virus must escape the vesicle before destruction. It is very clever in how it does this. Partial degradation of the protein coat or viral envelope exposes hydrophobic residues ("concealed weapon" gambit) which then interact with the hydrophobic lipid membrane, and either disrupt the vesicle membrane, break it open, or in the case of enveloped viruses, fuse with it, liberating the virus particle into the cytoplasm. Analogies here are difficult as well. Perhaps it is like surrendering, being put on a prison train, and then breaking away just before reaching the prison. The other element here is disguise, since the virus is treated just like the normal ligand, and processed accordingly. At this point the virus is within the cell, either in the cytoplasm or the nucleus, and is ready to replicate. This phase of the invasion could be considered to be the subversion and sabotage phase. The virus subverts all or part of the host replication machinery in order to replicate. This involves commandeering the necessary scaffolding, replication enzymes, and nutrients. Many viruses also produce substances that sabotage host replication and protein production by disrupting the DNA, restricting access to crucial DNA replication or RNA transcription sites on the DNA, or blocking the translation of RNA into protein at the ribosome. The ways in which different viruses have found to subvert and sabotage the host apparatus are remarkable for their breadth, ingenuity, and diversity. So what can the host do to stop these guys? The physical and chemical first lines of defense outlined above apply as well to viruses. Once past these lines of defense viruses encounter the nonspecific or innate immune system, which responds most effectively by producing interferons, a group of molecules that can direct the disruption of the virus invasion and reproduction cycle at many different points. The classic interferon requires the presence of double-stranded RNA, which is produced by all RNA viruses and some DNA viruses. Thus it has to wait until the virus is uncoated before it is able to recognize it as foreign. Individual virus species are not uniquely recognized by this system. The second line of immune defense is provided by the adaptive immune system. This system operates in two major ways - by neutralizing the virus before entry into the cell with antibodies, and by the "shoot me" defense mechanism alluded to above, where infected cells display fragments of viral proteins on their surface which are recognized by killer T-cells. This mechanism is normally highly effective, but viral counter-strategies are possible. Probably the most common one is mutation in the protein coat or envelope proteins (e.g. influenza, AIDS, "change disguise" gambit). This allows the virus to escape antibody neutralization and destruction. Once inside the cell and uncoated, however, the "shoot me" gambit still applies. Thus the virus must be quick to reach the point of assembling infectious particles before cell destruction. There is much more, of course, to the process of host defense. The immune system is amazingly sophisticated in mammals. Still, the continual struggle between microbe and host means that the system, as complicated as it has become, is far from perfect. It is still the case that the defense must damage itself to varying degrees in order to employ the highly toxic defensive substances it uses, and it can go badly wrong, as in the cases of autoimmunity and even unintentional "suicide". WARFARE ANALOGIES: FROM TEXTS (from Playfair: Infection and Immunity, p21) "We turn now to a consideration of the host and how it can defend itself against disease induced by parasites (art: used in broad sense by Playfair to designate any infectious agent). The problem is very analogous to that faced by a country at war, namely how to avoid damage by enemy agents, and in fact the solutions arrived at by nature and by governments are remarkably similar. Nature's method operates at three levels: 1. keep them out by setting up effective external defense. 2. if they get in, catch and dispose of them rapidly, using an always ready and available army of cells and molecules - the natural immune system; 3. if they elude capture, devote a specialized set of cells to each parasite, able to identify it, mark it for disposal, and retain memory of the details for the future - the adaptive immune system. (from Playfair: Infection and Immunity, p35) "Pursuing the analogy with the army (or police), one can imagine that a parasite could be recognized simply because it "looks unusual", or because it is clearly "foreign", or because it corresponds to a precisely known face" in some central filing system. At the same time, care must be taken not to mis-recognize and dispose of one of our own men. In immunological jargon, "our own men" are referred to as self, (e.g. self molecules, self cells, etc), and foreigners as non-self. Recognition is thus essentially a problem of distinguishing self from non-self. Recognition molecules that simply detect a vague 'non-selfness' are referred to as nonspecific, while those that can unerringly pick out one foreign invader from thousands of others are called specific."