Hypothesis paper
Does the immune system identify necessarily conserved pathogenic epitopes by finding similarities to the host proteome?
Chris Forden
forden.immunesig.org
650-843-0751
The immune system targets and remembers epitopes on large molecules which are dangerous and/or foreign. However pathogens frequently switch or mutate their proteins, sometimes during the course of an infection in one patient, and often as the pathogen spreads from host to host over the course of many years. Hosts are under extreme evolutionary selection pressure to remember those epitopes on the pathogen, that will be conserved, that is will remain unchanged. Therefore if it is possible for the host to identify necessarily conserved epitopes, the host will do so and use that information to optimize its expenditure of resources on refining its idiotypes with which it recognizes pathogens, and on remembering the epitopes.
Fortunately for hosts, there appear to be at least several ways they might identify necessarily conserved epitopes. Early viral proteins (EVPs) bind to molecules in the host’s presentation pathways for antigens and danger-signals, to disrupt their function. Therefore selectively targeting peptides of EVPs as immunodominant epitopes, is beneficial in part because EVPs therefore tend to be conserved. First-order B cell networking can also identify host-binding, conserved epitopes; the idiotype that binds to a pathogen's epitope that binds to the host, lacks an opposing anti-idiotype in the B repertoire that would otherwise diminish the idiotype’s quantity. APCs that endocytose host-pathogen complexes, pair stimulatory endogenous peptides in the immune synapse with the pathogen’s binding antigen. Thymocytes are selected for maximum sensitivity to almost-self, such as mutated self or the pathogen's mimic of a host ligand, which often has higher affinity and stronger signal strength than the host ligand. (The host benefits from reserving the highest affinity, strongest signaling molecule for pathogenic use because such reservation directs the evolution of the pathogenic mimic to be similar to, but not identical to the host ligand.) These proposed mechanisms share exploitation of the pathogen's need to bind host molecules to position itself inside the host, or to manipulate the host; therefore each conserved pathogenic epitope may have similarity to one or more host binding sites or ligands, usually as a complementary shape and charge distribution to a host binding site, and sometimes as a slight variation on a host ligand. Immunodominance can be construed as the result of the host’s selective targeting of pathogenic epitopes that are likely to be conserved and therefore reencountered in the near and distant future.
Excessive intimacy, specifically binding to the host, may be a special danger signal that not only indicates pathogenicity, but also points directly to the necessarily conserved epitopes in the pathogen’s repertoire. Commensal organisms may not need to manipulate or tightly bind to the host, whereas very intimate binding to the host is an almost universal need of pathogens. As a result of host identification of conserved pathogenic epitopes, a pathogen is under extreme selection pressure to hide its conserved epitopes, which it can do by only revealing their active binding shapes only after they undergo conformational change just before binding. Understanding these effects might help us design effective vaccines and therapies.
Pathogens are free to vary most of their surface coats within wide limits imposed by the necessity of structural integrity. Furthermore, pathogens sometimes decorate their exteriors with arbitrary molecules, hung from the structural shell. Viruses frequently mutate such decorations. Many eukaryotic pathogens store genetic instructions for a huge repertoire of arbitrary decorations. Consequently, accurate, long-term memorization of pathogenic decoration consumes host resources while conferring little host benefit.
In contrast, pathogens that enter or cling to host cells require epitopes that mate with binding sites on the host cell. The shapes of such epitopes are highly constrained; only a few sequences of amino acids will create a molecular shape capable binding tightly to a specific site on the host. Host efforts to accurately identify and remember these fewer, conserved epitopes will conserve host resources and confer the long lasting benefit of defending the host against pathogens it is likely to encounter in the future. Such likely future pathogens include pathogens that mutate into new versions during an infection inside one host, pathogens which are cleared by the host yet are reintroduced into the host after mutating inside other hosts, and unrelated pathogens which happen to have independently evolved the same conserved epitopes for binding to the same host molecules.
We have long recognized that the rapid reproductive rates of
pathogens, pose tremendous challenges to host immune systems. If the immune system works by identifying
similarities between the host and pathogens, it can partially negate the
advantage pathogens possess due to their relatively rapid evolution. Perhaps an individual host, and even a
collection of species of hosts, can manipulate a pathogen’s evolution by
exploiting its need to conserve its similarity to hosts. Recognizing that the immune system searches
for similarities between the host and pathogenic epitopes, is not a reversal of
the principle of discrimination against non-self antigens, but an intriguing philosophical
variation on it.