The Acquired Immune System: A Vantage from Beneath

Abstract

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. 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 2004Trowsdale J. Parham P. Mini-review defense strategies and immunity-related genes.Eur. J. Immunol. 2004; 34: 7-17Crossref PubMed Scopus (148) Google Scholar). The acquired immune system, signaled into action by the innate immune system, is seen as an optimal host defense (Janeway and Medzhitov 2002Janeway C.A.J. Medzhitov R. Innate immune recognition.Annu. Rev. Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6152) Google Scholar). The proof of this is thought to be that most infections are cleared (Trowsdale and Parham 2004Trowsdale J. Parham P. Mini-review defense strategies and immunity-related genes.Eur. J. Immunol. 2004; 34: 7-17Crossref PubMed Scopus (148) Google Scholar). 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. No infectious agent is descended from an ancestor that was killed before it could replicate. In fact some parasitic agents can have geologically long relationships with their host species such that the two are really coevolved. Despite the evolution of a multifaceted immune system, parasitism is a fundamental principle of life. 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 1980Price P.W. Evolutionary biology of parasites.Monogr. Popul. Biol. 1980; 15: 1-237Google Scholar). 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. A potential constraint on a parasitic agent is that it can avoid many immune strategies, but not all simultaneously. The cost is too high. For example, carrying episomal antibiotic resistance genes is a burden for the bacterium since it is more costly to replicate. In the absence of antibiotic selection, despite plasmid-based mechanisms to promote retention, resistance is eventually lost (Bingle and Thomas 2001Bingle L.E. Thomas C.M. Regulatory circuits for plasmid survival.Curr. Opin. Microbiol. 2001; 4: 194-200Crossref Scopus (55) Google Scholar). Success in parasite replication depends upon overcoming the selective pressures brought to bear by the host while carrying along a minimum of extraneous defensive machinery; however, reproductive success is more than just producing the most progeny—it is producing the most progeny who can themselves produce the most progeny. It is producing the most progeny that can successfully find a new host in which to replicate. The host-parasite relationship is intimate. If parasites are successful in infecting a certain host strain, that strain may be scarce in the next generation. Thus, in the next generation, the most successful parasites would be those variants that can infect a different strain. Likewise, in any given generation the most successful host, able to ward off infections, represents the largest target for the next generation of parasites (Hamilton et al. 1990Hamilton W.D. Axelrod R. Tanese R. Sexual reproduction as an adaptation to resist parasites (a review).Proc. Natl. Acad. Sci. USA. 1990; 87: 3566-3573Crossref PubMed Scopus (937) Google Scholar, Thompson 1994Thompson J.N. The coevolutionary process. University of Chicago Press, Chicago1994Crossref Google Scholar). Leigh Van Valen proposed this type of frequency-dependent selection and coevolution as a new evolutionary law, The Red Queen Hypothesis (Van Valen 1973Van Valen L. A New Evolutionary Law.Evolutionary Theory. 1973; 1: 1-30Google Scholar). He cited Lewis Carroll's Red Queen, “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that.” In this context there is never a “solution” to infectious agents. Even the acquired immune system, with its boundless plasticity, did not get us “somewhere else.” Each solution instead has within it the seeds of its own demise. 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. 1992Cooper E.L. Rinkevich B. Uhlenbruck G. Valembois P. Invertebrate immunity another viewpoint.Scand. J. Immunol. 1992; 35: 247-266Crossref Scopus (109) Google Scholar, Vilmos and Kurucz 1998Vilmos P. Kurucz E. Insect immunity evolutionary roots of the mammalian innate immune system.Immunol. Lett. 1998; 62: 59-66Crossref PubMed Scopus (196) Google Scholar, Soderhall and Cerenius 1998Soderhall K. Cerenius L. Role of the prophenoloxidase-activating system in invertebrate immunity.Curr. Opin. 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Coagulation in arthropods defence, wound closure and healing.Trends Immunol. 2004; 25: 289-294Abstract Full Text Full Text PDF Scopus (288) Google Scholar). 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. We think of the innate immune system as having been selected to prevent the initiation of an infection and limit the replication of infectious agents. In principle, it should exhibit little memory, with each incident of infection treated as a surprise; however, there is evidence that immunization of invertebrates can be protective (Keith et al. 1992Keith I.R. Paterson W.D. Airdrie D. Boston L.D. Defense mechanisms of the American lobster. Homarus americanus vaccination provided protection against gaffkemia infections in laboratory and field trials.Fish Shellfish Immunol. 1992; 2: 109-119Crossref Scopus (29) Google Scholar, Muta and Iwanaga 1996Muta T. Iwanaga S. The role of hemolymph coagulation in innate immunity.Curr. Opin. Immunol. 1996; 8: 41-47Crossref Scopus (228) Google Scholar, Kurtz and Franz 2003Kurtz J. Franz K. Innate defence evidence for memory in invertebrate immunity.Nature. 2003; 425: 37-38Crossref Scopus (318) Google Scholar). The invention of an acquired immune system at the dawn of vertebrate evolution was the raw material for rapid variation and selection. Whereas the innate specificity for pathogens must have evolved by trial and error at each generation, the acquired immune system could be selected to provide vast potential for recognition. The problem of refining each specific receptor on an evolutionary time scale was eliminated. As its name implies, the specificity for pathogens is acquired anew in each individual. This novel mechanism of selection must, at one time, have conveyed a strong advantage since all vertebrates, other than jawless fish, appear to have descended from a single species, a species that evolved exactly three lymphocyte types, each expressing a unique antigen-specific, clonally distributed class of receptor: αβ T cells that recognize antigen peptides presented by MHC molecules, antibody-producing B cells, and γδ T cells possibly necessary for negative regulation (Rast et al. 1997Rast J.P. Anderson M.K. Strong S.J. Luer C. Litman R.T. Litman G.W. alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny.Immunity. 1997; 6: 1-11Abstract Full Text Full Text PDF Scopus (223) Google Scholar, Nam et al. 2003Nam B.H. Hirono I. Aoki T. 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Litman G.W. Flajnik M.F. Terminal deoxynucleotidyl transferases from elasmobranchs reveal structural conservation within vertebrates.Immunogenetics. 2003; 55: 594-604Crossref Scopus (15) Google Scholar). Over millions of years, this ancestral vertebrate species evolved the process into a complex physiological system with the basic components of the present day acquired immune system. A conclusion is that from sharks to aardvarks (as well as velociraptors and pterodactyls), all vertebrates arose from this aquatic predecessor lineage that happened upon the process of gene rearrangements. 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 1990Nauciel C. Role of CD4+ T cells and T-independent mechanisms in acquired resistance to Salmonella typhimurium infection.J. Immunol. 1990; 145: 1265-1269Google Scholar, Weintraub et al. 1997Weintraub B.C. Eckmann L. Okamoto S. Hense M. Hedrick S.M. Fierer J. Role of αβ and γδ T cells in the host response to Salmonella infection as demonstrated in T-cell-receptor-deficient mice of defined Ity genotypes.Infect. Immun. 1997; 65: 2306-2312Google Scholar). It also confers memory upon surviving individuals, such that reinfection is much less likely. A novel type of immune system has been recently revealed to exist in our most distant vertebrate relatives, the jawless fish (Pancer et al. 2004Pancer Z. Amemiya C.T. Ehrhardt G.R. Ceitlin J. Gartland G.L. Cooper M.D. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey.Nature. 2004; 430: 174-180Crossref PubMed Scopus (532) Google Scholar). Lampreys presumably branched off the vertebrate lineage prior to the invention of RAG-mediated gene rearrangements, and they have apparently developed a parallel alternative to the acquired immune system. This immune mechanism is based on clonally distributed leucine-rich repeat receptors (similar to Toll-like receptors) that appear to be diversified by a novel mechanism of genetic rearrangement. It may be focused on the recognition of PAMPs, or it may be able to combine leucine-rich repeat domains to extend the recognition specificity to a larger set of biochemical determinates. The distinction has important implications for self versus non-self recognition in these animals, but the possibility exists that the lamprey immune system has selective aspects of both acquired and innate immunity. If it is restricted to the recognition of PAMPs, then it lacks the attendant costs associated with self-recognition (see below), and yet the organism may still benefit from the immune memory associated with clonal expansion. Such an immune system seems to blur the distinction between innate and acquired immunity. Of the many implications from this discovery, one is yet another affirmation of the notion that evolution is not directed toward an optimal solution. There are many biological solutions to each problem, and that which is selected is greatly influenced by chance. Since a clonally selected, somatically diversified receptor system evolved at least twice, I conclude that it most certainly conveys a selective advantage in a world of infectious agents. 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 2002Janeway C.A.J. Medzhitov R. Innate immune recognition.Annu. Rev. Immunol. 2002; 20: 197-216Crossref PubMed Scopus (6152) Google Scholar). 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. Clearly, the explanation is quite different, and if nothing else, I hope that this article provokes immunologists to consider in detail the evolutionary significance of the acquired immune system. I propose that we are looking backward from a human perspective and perhaps asking the wrong question. Perhaps the question is not why invertebrates manage to succeed in the absence of an acquired immune system, but rather, why do we vertebrates have pathogens that necessitate acquired immunity? 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 1994Read A.F. The evolution of virulence.Trends Microbiol. 1994; 2: 73-76Abstract Full Text PDF Scopus (272) Google Scholar, Cooper et al. 2002Cooper V.S. Reiskind M.H. Miller J.A. Shelton K.A. Walther B.A. Elkinton J.S. Ewald P.W. Timing of transmission and the evolution of virulence of an insect virus.Proc. R. Soc. Lond. B. Biol. Sci. 2002; 269: 1161-1165Crossref Scopus (42) Google Scholar, Ewald 1995Ewald P.W. The evolution of virulence a unifying link between parasitology and ecology.J. Parasitol. 1995; 81: 659-669Crossref Scopus (140) Google Scholar, Day 2003Day T. Virulence evolution and the timing of disease life-history events.Trends Ecol. Evol. 2003; 18: 113-118Abstract Full Text Full Text PDF Scopus (110) Google Scholar). 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 1999Ewald P.W. Using evolution as a tool for controlling infectious diseases.in: Trevathan W.R. Smith E.O. McKenna J.J. Evolutionary Medicine. Oxford University Press, Oxford1999: 271-312Google Scholar). 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. Predictably, once infected with B. anthracis, the acquired immune system offers the host little protection. 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. 2004Leroy E.M. Rouquet P. Formenty P. Souquiere S. Kilbourne A. Froment J.M. Bermejo M. Smit S. Karesh W. Swanepoel R. et al.Multiple Ebola virus transmission events and rapid decline of central African wildlife.Science. 2004; 303: 387-390Crossref Scopus (511) Google Scholar). 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 2002Hilleman M.R. Realities and enigmas of human viral influenza pathogenesis, epidemiology and control.Vaccine. 2002; 20: 3068-3087Crossref PubMed Scopus (256) Google Scholar). This is an oversimplification of the complexity of virulence (Day and Proulx 2004Day T. Proulx S.R. A general theory for the evolutionary dynamics of virulence.Am. Nat. 2004; 163: 40-63Crossref Scopus (171) Google Scholar), but it is clear that no matter what the mode of transmission, there are still costs to the parasite associated with virulence. This does not mean that parasites naturally evolve to a benign state, but no parasite would be successful it if ravaged a host before it could be transmitted. 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. Another way of looking at this is that acquired immunity was not a final solution to the problem of parasitism. There is no final solution. As novel as the acquired immune was, for rapidly multiplying agents, it was just another hurdle. It may have driven parasites to invent new strategies for fitness, but it did not convey invincibility or anything like it. To say the combination of innate and acquired immunity is the optimal defense is a misunderstanding of the evolutionary landscape. I don't believe there is an optimal defense. I don't believe there is a conceivable immune system that could not be obviated once the barriers to infection have been breached. For all animals and their parasites, generation upon generation, it has been evolutionary thrust and parry, until today as it was a million years ago and as it will be a million years hence, each and every species is literally plagued by parasitic microbial agents and viruses. 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 2000Moret Y. Schmid-Hempel P. Survival for immunity the price of immune system activation for bumblebee workers.Science. 2000; 290: 1166-1168Crossref PubMed Scopus (850) Google Scholar), 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 2003Rolff J. Siva-Jothy M.T. Invertebrate ecological immunology.Science. 2003; 301: 472-475Crossref Scopus (408) Google Scholar). The problem for biologists is to understand how substantially different strategies of defense can be equally successful in host-parasite evolution. 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. 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. Instead, it should be more importantly tied to other factors that have been found to affect aging and survival. To make this point, I wish to briefly address four aspects of invertebrate biology related to survival and parasitism: the lifespan of invertebrates, the causes of death in insects, parasites that infect both vertebrates and invertebrates, and insect viruses. 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. 1986Ennis G.P. Colllins P.W. Dawe G. Fisheries and populat