Redefining the Immune System as a Social Interface for Cooperative Processes

Viewed from a neo-Darwinian perspec-tive, the main function of the metazoanimmune system (IS) is to insure hostintegrity against invading microorganisms,which are only considered as selfishcompetitors that reduce the host’s resourc-es, inflict tissue damage, and ultimatelycompromise host fitness. Coevolution ofthe host and these competitors has beendescribed as a perpetual arms race (knownas the Red Queen hypothesis, Van Valen,[1]). This vision implicitly suggests that‘‘The IS evolved under selective pressureimposed by infectious microorganisms’’(Janeway, [2]) and that the ultimateobjective of the IS is to conserve theintegrity and sterility of the host(Figure 1A). In fact, numerous observa-tions from microbiology and ecology havechallenged this paradigm and suggest thatinfectious organisms and the IS play acrucial, unexpected role in evolution:(i) The immune system performsa large list of ‘‘nonimmuno-logical’’ tasks. Highly conservedcomponents of the innate andadaptive IS of vertebrate are alsoinvolved in processes other thanjust participating in immune re-sponses against invading microor-ganisms. We can take the exampleof phagocytosis, a well-conservedmechanism present in unicellulareukaryotes and all animal metazo-ans [3], that has clearly playedseveral distinct roles during evolu-tion. In amoebae, phagocytosisallows for the internalization ofbacteria that constitute an essentialsource of nutriments. In metazo-ans, this property is mainly limitedto professional phagocytes, such asmacrophages, that target ‘‘altered/dying self’’ particles and occasion-ally invading microorganisms. Byeliminating apoptotic cells, phago-cytosis plays a major role inembryogenesis during tissue re-modeling and in preventing auto-immune reactions. Similarly, com-plement and natural IgM [4]collaborate with phagocytic cells toeliminate apoptotic cells. Likewise,macrophages, generally consideredas immune effector cells, have beenshown to participate in the regula-tion of a growing list of processescrucial for tissue development andhomeostasis, such as neuronal pat-terning, angiogenesis, bone mor-phogenesis,metabolism,andwoundhealing [5]. Thus, highly conservedmolecules,processes,andcellsoftheIS can be ascribed to distinctphysiological functions during evo-lution, with no clear link to patho-gen-imposed selective pressures. (ii) The infectious organism pro-motes host genetic diversity.Genetic variation in natural popu-lations is a prime prerequisite forthe response of populations toselection pressure. In antagonistcoevolution, hosts are selected toevade infection whereas the path-ogen is selected to infect the host.In 1949, Haldane proposed that animportant positive impact of thisphenomenon is the maintenance ofhigh genetic diversity among bothhost and pathogen populations:‘‘Just because of its rarity it willbe resistant to diseases whichattack the majority of its fellows. ’’This hypothesis has since beenlargely confirmed [6,7]. A recentstudy even suggests that pathogenshave a higher impact on humangenetic diversity than climate con-ditions [8]. (iii) Infection favors free circula-tion of genetic innovations.The sequencing of whole genomeshas demonstrated that symbioticmicroorganism interactions favorhorizontal genetic transfers (HGT)and thus the rapid spread in manylineages of genetic innovations thatwould have otherwise taken mil-lions of years [9]. A fascinatingexample demonstrating that infec-tion can contribute to biologicalinnovation is the acquisition byhost vertebrates of recombinase-activating genes (RAGs) [10] andSyncitin [11] genes from viruses.These viral genes have allowed fordevelopment of the adaptive ISand the syncytiotrophoblast, re-spectively. Thus, infectious organ-isms appear to have been essentialduring evolution to maintain di-versity and allow free circulation ofgenes by HGT, transforming the‘‘tree of life’’ proposed by neo-Darwinian theories into a dynamicand interconnected ‘‘net of life. ’’(iv) Chronic infection can im-prove host resistance to infec-tion. Infectious organisms are inconstant competition with otherinfectious organisms to invadeand persist in their specific host (aform of ‘‘apparent competition’’). They can compete together bycross-reacting with the host im-