Immune Systems as Parasites

Here's a think for you: does your complex adaptive intelligent immune system actually do you any good, or is it a parasite which is maintained by the very arms race with parasites that it started?

"The Acquired Immune System: A Vantage from Beneath", Hedrick 2004; excerpts:

"The immunity exhibited by plants and animals is often viewed as the evolutionary response to the problem of infectious agents. In this respect, the combination of the innate immune system and the acquired immune system has been characterized as the “optimal solution.” In this essay, I propose that there is no possibility of an optimal solution to the problem of parasitism. Regardless of the immunological mechanisms evolved, infectious agents establish a dynamic interaction with common strains of their host species, weighing virulence against transmissibility. In the endless host-parasite coevolution, the immune system can never gain an upper hand on the millions of parasitic microbes and viruses. Rather, evolution of the immune system is driven, most importantly, by the small advantages conferred as a result of host variation. By selecting for evermore-devious parasites, the immune system is the cause of its own necessity.
Introduction
Immunologists, myself included, have long thought about the immune system as if it were of crucial importance in defense against infection. The thinking is that the “immune-system genes must evolve to keep pace with increasingly sophisticated evasion by pathogens” (Trowsdale and Parham, 2004). The acquired immune system, signaled into action by the innate immune system, is seen as an optimal host defense (Janeway and Medzhitov, 2002). The proof of this is thought to be that most infections are cleared (Trowsdale and Parham, 2004). I think this is a perspective that could benefit from broader evolutionary point of view. If the vertebrate immune system has evolved to provide “optimal host defense,” then an implication is that invertebrates, lacking an acquired immune system, should be rife with pathogens and frequently succumb to infections. If the vertebrate immune system has evolved to keep pace with increasingly sophisticated mechanisms of pathogenesis, why are diseases such as cholera, measles, malaria, ancylostomiasis (hookworm), and leishmaniasis endemic in much of the world? If it is an evolutionary solution to infectious disease, why did influenza kill 40 million people in 1918? In fact, is there any evidence that vertebrates experience less morbidity and mortality due to infectious disease than invertebrates? The solution is to realize that we have an anthropocentric perspective. We (and most military planners) forget that the targeted enemy has a life or death stake in avoiding our strategies for defense. In fact, parasitic agents (meaning infectious bacteria, fungi, parasitic invertebrates, and viruses) only exist if they’ve managed to avoid their host’s immune system, at least long enough to replicate and send their next generation on to a new host.

Animals represent a wonderfully rich habitat including almost limitless energy and a stable environment for replication. Thousands of microbial agents and viruses have evolved to carve out parasitic niches; in fact, there are far more obligate parasitic species than free-living species of plants and animals (Price, 1980). If we think of a food chain or food web in terms of large organisms eating smaller ones, then the relationship between parasites and their hosts can be thought of as an inverse food web. Small organisms develop the ability to tap into the resources of larger ones—eating them from the inside out. This is a true web of interactions since vertebrates often harbor multiple parasites, the invertebrate parasites have parasites, and the parasites’ parasites have parasites. A constraint on a parasite’s strategy is that the potential host can have a strong motivation to avoid being parasitized. It can mean loss of reproductive fitness. On the other hand, an obligate parasite is under an even stronger selective pressure. It must find a host, or its lineage is history. Furthermore, a parasite can be of any biological form, from a complex animal to a virus, and its generation time is short. Bacteria can undergo 100,000 generations for each one of ours. No matter what “defense” a host can muster, there will always be a parasitic agent that can avoid it to achieve replication and transmission.

Plants and the vast majority of animals on earth have no acquired immune system; rather, they have a multiplicity of mechanisms to prevent infection that we collectively term innate immunity. I wish to emphasize that the most effective innate mechanism is the denial of access. Without barriers to infection, there are no possible cell and molecular devices that would be able to prevent rampant parasitism. In addition to barriers, the innate immune system is based on a set of rules that translate into a proscription against the display of pathogen-associated molecular patterns (PAMPs) not present within free-living multicellular organisms. These rules have evolved over hundreds of millions of years, they are passed on intact to each new generation, and they are manifest in the specificity found in receptors and mediators of the innate immune system: Toll-related receptors, mannose receptors, defensins, complement, peptidoglycan recognition proteins, the coagulation reaction, and many others, some of which have yet to be discovered (Cooper et al., 1992; Vilmos and Kurucz, 1998; Soderhall and Cerenius, 1998; Hoffmann and Reichhart, 2002; Janeway and Medzhitov, 2002; Steinert et al., 2003; Rolff and Siva-Jothy, 2003; Dziarski, 2004; Theopold et al., 2004). Cells respond to PAMPs by setting in motion a number of physiological changes designed to slow microbial growth or viral replication. Specialized cells, such as hemocytes, can be called into the fray.  Exactly how does the acquired immune system convey a selective advantage? Since an acquired immune response requires days to become effective, it is mainly directed toward combating an infectious agent that has gained purchase despite barriers and other innate mechanisms of immunity. Studies on a number of bacterial pathogens have shown that the acquired immune system is important in resolving an infection that is initially controlled by innate immunity (Nauciel, 1990; Weintraub et al., 1997). It also confers memory upon surviving individuals, such that reinfection is much less likely.

Why, then, is innate immunity sufficient for the most abundant species on earth, but not for vertebrates? After all, even a minor congenital deficiency in vertebrate acquired immunity is often incompatible with life. It’s rarely discussed, but one idea is that long-lived, complex vertebrates require an acquired immune system (Janeway and Medzhitov, 2002). The implication is that invertebrates are simple and have short generation times relative to most vertebrates, and perhaps they can afford a high casualty rate. In case these ideas are attractive, we need to consider the existence and success of large and complex invertebrates, such as giant squids, clams, tubeworms, lobsters, oysters, sea urchins, or even insects. To take the argument to the extreme, we might consider plants, since they too have a parasitic burden. The giant sequoia can live 2000 years and the ancient bristlecone pine can live past 4000 years. If acquired immunity is defined by somatic diversification and clonal selection, then as far as we know, none of these species appears to require an acquired immune system to avoid deleterious infections.

The role of the immune system in vertebrate versus invertebrate evolution cannot be understood in the absence of virulence theory. One way to define virulence is the utilization of host resources by the parasite with the attendant costs to the host in terms of morbidity and mortality. At the two extremes, commensal organisms coexist with their hosts in a completely benign or mutually beneficial manner, whereas parasites utilize host resources, immobilize the host, and cause death in a high percentage of infections. Many fall somewhere between, exacting a price in terms of host resources without impeding host mobility. The differences seem to be tightly interwoven with mode of transmission or, alternatively, the ability to infect multiple hosts (Read, 1994; Cooper et al., 2002; Ewald, 1995; Day, 2003). For parasites that are directly and exclusively transmitted from one vertebrate to another, virulence appears to be calibrated such that the host retains mobility. Too virulent, and the parasite immobilizes or even kills the host before its progeny can be passed on. Too benign, and it is out competed by faster growing variants. An important point is that high virulence is dominant. The entire population of parasites within a host pays the price of a highly virulent variant.
How can this be reconciled with the existence of parasites that are extremely virulent? High virulence is strongly correlated with parasitic agents that can effect transmission other than by direct contact between hosts (Ewald, 1999). One effective mechanism is to utilize an intermediate vector. Agents such as flaviviruses (causing diseases like dengue fever, yellow fever, or West Nile fever) or Plasmodium falciparum (malaria) maximize replication while paying less of price for host incapacitation. In fact, an infected host lying immobilized but alive is even more susceptible to the bite of a mosquito, and the mosquito thus acts an agent for the parasite. A second mode of infection for highly virulent agents is water transmission. Microbes, such as Vibrio cholera, cause terrestrial animals to excrete copious quantities of infectious fluids, and without extraordinary precautions, they are transmitted through the water supply. Of course, the parasites of marine organisms are readily transmitted through water. A third strategy is for an agent to be highly enduring. Bacilli such as Bacillus anthracis can form spores that lie in wait for years, even under extreme conditions, and thus become transmitted through the mobility of healthy potential hosts.

Another example of high virulence can occur when an infectious agent can not only replicate in one species without extracting a high cost (low virulence), but also infect a second species where it is highly virulent. For example, Ebola virus kills a large percentage of infected patients, great apes, and monkeys, but epidemics are local and appear to expire quickly. Since it continues to crop up, we assume that it has been selected to propagate in a natural host (as yet unknown) in which it is less virulent (Leroy et al., 2004). The high virulence in humans may be, in a sense, accidental. Influenza infects wild birds without causing obvious pathology, whereas it can be highly virulent in human beings (Hilleman, 2002).

How do the principles of virulence help to explain the enigma of invertebrate immunity? One answer is that invertebrates don’t need an acquired immune system because they never had it. The parasitic agents of invertebrates have not coevolved with acquired immunity so their virulence is calibrated to the coevolved innate immune system. The proposal here is that contrary to widely held views of practicing immunologists, the immune system is not evolutionarily selected to prevent infection in an absolute sense. Rather, it is selected to make one individual slightly more resistant or at least different than others of the same or related species. The adversary of any individual is not really the world of parasites, they are truly undefeatable, it is his or her neighbor. A zebra doesn’t have to outrun the lion, just the slowest member of the herd.

Secondarily, there are multiple factors that may affect the evolution of different forms of defense in species that are physiologically and ecologically disparate. There is a high cost to developing and utilizing even the innate immune system (Moret and Schmid-Hempel, 2000), and the adaptive immune system, with its surfeit of cellular production, is likely to be even more resource intensive. This does not explain how most animals are successful

without an adaptive immune system, but it argues that invertebrates could probably not afford the energy expenditure it would require. The field of ecological immunology has emerged to study just this problem (Rolff and Siva-Jothy, 2003). The problem for biologists is to understand how substantially different strategies of defense can be equally successful in host-parasite evolution.
But We Seem to Be Protected?
The immune system was not evolved to protect us? This seems counterintuitive. We see that the immune system is absolutely essential to survival in a world of infectious agents, and we conclude that it was selected to prevent disease. The problem is it doesn’t prevent disease. Once infected, are we really protected from influenza, tuberculosis, coccidioidomycosis, or toxoplasmosis? In the match-up between host immunity and parasitic selection, there’s no contest. Like Alice pacing the Red Queen, we never get anywhere (evolutionarily) even though we continue to run as fast as we can (Figure 1). Once the acquired immune response was invented, of course, there was no going back. Any individual with a defective acquired response would be quickly eliminated by a parasite expecting a full armament. Even commensal flora could become pathogenic. Regardless that infection of such a host might be a dead end for the parasite, an immune compromised individual would immediately succumb to a pathogen that would appear overly virulent. Moreover, pushed by parasitic selection, the acquired immune system has continued to find novel ways of conferring host advantage; not host immunity, host advantage.
The Success of Invertebrates
If the proposal is that the outcome of parasitism is predominantly determined by the parasite and not by the intricacy, strength, or elasticity of the immune system, then, when compared with vertebrates, invertebrates in their native ecosystem should not exhibit a mortality rate that is predominantly determined by infection and pathogenesis. Free-living invertebrates and their parasites should exhibit the same types of relationships that we find for vertebrates—a dynamic interaction in which parasites weigh the use of resources (virulence) against transmission. There should be benign parasites that minimally affect host behavior as well as highly virulent parasites that utilize multiple hosts or exhibit other characteristics that ensure their transmission. The longevity of invertebrates in the wild will undoubtedly be influenced by infectious agents, as it is in vertebrates, but a prediction is that it is not primarily limited by the absence of an acquired immune system.

Lifespan. As already noted above, the first issue may be addressed by considering the observed life span of invertebrates, and there is no doubt that complex invertebrates can be extremely long lived. There exist representations from the phyla of arthropods (lobsters, spiders, insects) (Ennis et al., 1986), mollusks (clams, squid) (Ropes, 1999; Cargnelli et al., 1999), and echinoderms (sea urchins) (Ebert and Southon, 2003) with life spans as long or longer than vertebrates. For example, red sea urchins (Strongylocentrotus franciscanus) and ocean quahogs (Arctica islandica) can live to be more than 200 years of age. Lobsters (Homarus Americanus) are known to live to be at least 30 years of age (Herrick, 1977; Campbell, 1983)...More convincingly, the analyses of invertebrate life tables show that mortality rate is not necessarily different in vertebrates and invertebrates (Carey, 2001). This is a vast topic that I can’t consider in detail here, but I’d like to list two examples. A species of subsocial dung beetles (Passalidae) has an average lifespan of greater than 2 years in the wild (hardly a clean environment!), and approximately 5 years in captivity (Cambefort and Hanski, 1991). This is not so different from our favorite species for studying acquired immunity, the house mouse, mus musculus, which has an average lifespan in the wild of approximately 1 year and a lifespan in captivity of 2–5 years. A second example is the lobster (Homarus americanus), which has been studied extensively due to its commercial importance. Lobsters reach sexual maturity at 5-8 years. Including predation, disease, and storm damage, the natural mortality rate of juveniles and adults (excluding human harvesting) is very low with estimates ranging from 2%–8% per year (Thomas, 1973; Ennis et al., 1986; Fogarty, 1995). Adult lobsters in the wild are relatively free of disease (pathogenic protozoans, fungi, and metazoan parasites) (Fisher et al., 1978), as many diners can attest, although bacterial and parasitic infections have been detected when lobsters are subjected to suboptimal culture conditions, e.g., poor water quality, low oxygen tension, or overcrowding.

Causes of Death. The most direct method to address the role of infection in invertebrate lifespan is to determine the proximal causes of invertebrate mortality. For insects these include predators, parsitoid insects, and nematodes, and infectious agents including fungi, protists, bacteria, and viruses. An analysis of the published life tables for 78 herbivorous insect species was carried out (Hawkins et al., 1997), and death was classified by enemy type: parasitoids; predators; and pathogens. A conclusion of the study was that herbivores examined through the pupa stage suffer little or no mortality from pathogens. Considering that sick individuals may be more susceptible to predation, even the combination of infectious agents and predation contributed relatively little to mortality. The overwhelming cause of mortality was found to be due to parasitoid insects and nematodes. Is this mortality due to the lack of an acquired immune system? Realizing that most parasitoid species do not invade adults and embryos would not be expected to have an organized immune system, this seems unlikely. In addition, the acquired immune system is notoriously poor in ridding the body of parasitic nematodes.

Versatile Infectious Agents. How does infection, such as viral infection, affect vertebrates versus invertebrates? One interesting example comes from the flaviviruses that need to replicate in both invertebrate and vertebrate hosts (Gould et al., 2003). They are the etiological agents of dengue fever, yellow fever, Japanese encephalitis, tick-born encephalitis, and the West Nile encephalitis...Some of these viral infections cause a high mortality rate in humans (yellow fever, ⬎20%), whereas others are often, but not always, cleared with little associated pathology (West Nile Virus). Those neurotropic viruses that are not cleared end up in the brain, and this might be benign were it not for the immune response to this invasion resulting in lethal encephalitis. On the other hand, the arthropod vectors appear to maintain a lifelong infection that otherwise has no known effect.

The life cycle of trypansomes, such as Trypanosoma brucei, provides another illustration of the way in which a parasite can adapt to the immune systems of both invertebrate and a vertebrate hosts. Trypanosomes are most famous for their ability to express a single variant surface glycoprotein (VSG) and then switch to a completely different VSG at a rate of 10 ⫺ 2 to 10 ⫺ 7 switches per doubling time (Turner and Barry, 1989). Importantly, this only occurs during the life-cycle phase in which the trypanosome is in the mammalian bloodstream and subject to antibody-mediated inhibition; high-frequency antigenic variation does not occur in the tsetse fly (Donelson, 2003).

A Moment of Evolutionary Ecstasy Bought Us 400 Million Years of Misery
Evolution has no foresight. A biological invention that confers an advantage gets propagated whether or not it may eventually lead to trouble or even species extinction. If the vertebrate acquired immune system is not necessary for evolutionary survival, we might even be so bold as to ask whether it was an evolutionary misstep. As discussed above, it must have provided a potent selective advantage, and it may even have contributed importantly to the success and rapid diversification of vertebrates. However, it also came with attendant costs...For example, bacterial enterotoxins cause an immune holocaust that results in the excretion of copious quantities of infectious fluids. Retroviral gene products cause the activation and cell division of a large percentage of T cells, a requirement for viral replication. Because immunopathology is perhaps the most common adverse outcome of viral infections, I suspect there are thousands of viral and microbial strategies aimed at subverting the acquired immune system. As an aside, I think a comparison of vertebrate and invertebrate viruses would be revealing, and an obvious prediction is that viruses that exclusively infect invertebrates are simpler and focused on evading innate immunity...
So being in possession of an acquired immune system, vertebrates pay a high price in terms of immunopathology, but that is hardly the only cost. Immune hypersensitivity, including allergy and asthma, affects a large segment of the human population in the Western World. And of course the most dreaded of reactions mediated by the acquired immune system is horror autoxicus (Erlich, 1906), commonly known as autoimmunity. More than 3% of people in the United States experience a form of autoimmune disease (Jacobson et al., 1997; Cooper and Stroehla, 2003) that can be debilitating or even life threatening. This is not limited to humans, although we are the most comprehensively studied species. Several strains of mouse and rat have been found to have a high incidence of autoimmune disease, and this may represent an exaggeration of traits that exist in naturally breeding populations. Domestic dogs have been found to have many different autoimmune diseases such as rheumatoid arthritis, lupus, and diseases of the skin (Fleeman and Rand, 2001; Hansson, 1999; Olivry and Jackson, 2001). On the other hand, excepting cancer, who ever heard of neutrophils raging out of control? Where is there evidence that flies can be struck down by overzealous hemocytes?
Was the acquired immune system an evolutionary misstep? It is pure speculation, but I believe that vertebrates would have evolved quite differently or even not at all had the progenitor lineage not happened upon RAG-mediated gene rearrangements or at least some method of generating a somatically diversified, clonally expressed recognition system. Over hundreds of millions of years of host-parasite interactions, even an incremental advantage would be expected to completely alter the evolutionary outcome. So to say that the acquired immune system is an evolutionary mistake is nonsensical. But, the acquired immune system came with attendant costs that have become evident in the fullness of time as the immune system and parasites engaged in runaway “Red Queen” coevolution. Rather than celebrate the acquired immune system as an optimal solution, we might see it as an appendage that generates its own necessity."

#evolution #biology #immunesystem