The evolutionary arms race between organisms shaped the genotypes of both host and pathogen. For example, Mycobacterium tuberculosis, a species of pathogenic bacteria lethally affecting the mammalian respiratory system, has been in an intense arms race with humans through millennia, shaping adaptation in both species13,14. Even within the host, adaptive evolution of bacterial strains may occur because of immunological pressure upon infection15. Also, man-made interventions like antibiotics apply selective pressures on bacteria, resulting in evolutionary resistance in initially susceptible strains16. Host-pathogen interactions have therefore adapted numerous long-term relationships in symbiosis, either to the detriment of the host (parasitic, also known as cheater cells), to the benefit of only one party without harming the other (commensalistic), or even to the benefit of both (mutualistic). The immune system has evolved to minimize detriment to the host, recognizing and dealing with cheater cells. Some cheaters live inside host cells (viruses), some attach to the organism (fungi), some associate with the organism but do not penetrate the interior (parasitic worms in the gut) and others cycle through all stages of symbiosis. As a result, the immune system has developed a wide plethora of responses specifically tailored to these stages of cheating. For example, viruses do not have the machinery to build proteins and duplicate their RNA/DNA. For this, they inject themselves in the cytosol of cells, hijacking the host cells for their own replication. Receptors recognizing viruses have therefore evolved in the cytoplasm of many cells. Recognition of viral nucleotides by TLR7, -8 or -9, leads to the appropriate antiviral response/cascade; the production of type I interferons, presentation of virus-specific antigens on MHC class I and eventually inducting of virus-specific cytotoxic CD8+ T cells, which can recognize and kill infected cells17. Cytotoxic CD8+ T cells in turn produce the cytokine IFNγ whenever a virus-infected cell is recognized, leading to upregulation of antigen processing and MHC class I in surrounding cells so all virus-infected cells show themselves for cytotoxic eradication18,19. For pathogens with a dominant extracellular phase, host cell killing is often unnecessary. Instead, the immune system employs soluble mediators that opsonize extracellular pathogens as a tag for phagocytosis. For example, soluble complement factor C1q directly binds a variety of molecular patterns on bacteria, initiating the classical complement pathway involving immune cell recruitment, phagocytosis and cell lysis20. The adaptive immune system also employs soluble mediators in the form of neutralizing single BCRs (antibodies), produced by B cells. When B cells recognize their cognate antigen in lymphoid organs under inflammatory conditions, they differentiate into antibody-producing plasma cells releasing antibodies into the circulation21. Circulating antibodies then opsonize their target, leading to antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells equipped with antibody-binding receptors (Fragment, crystallizable; Fc receptors) like natural killer (NK) cells, macrophages, DCs and granulocytes21. Evidently, while evolved at individual historic events, the innate and adaptive immune system have since developed a reciprocal dependency to most efficiently deal with continually evolving cheater cells. In vaccinology, therapeutics are designed to capitalize on the hosts efficiency to counteract cheater cells through engagement of components that activate both the innate and adaptive immune system.
13. Saelens, J. W., Viswanathan, G. & Tobin, D. M. Mycobacterial Evolution Intersects With Host Tolerance. Front. Immunol. 10, 528 (2019).
14. Pepperell, C. S. et al. The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations. PLOS Pathog. 9, e1003543 (2013).
15. Young, B. C. et al. Severe infections emerge from commensal bacteria by adaptive evolution. Elife 6, e30637 (2017).
16. Davies, J. & Davies, D. Origins and Evolution of Antibiotic Resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010).
17. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).
18. Zhou, F. Molecular Mechanisms of IFN-γ to Up-Regulate MHC Class I Antigen Processing and Presentation. Int. Rev. Immunol. 28, 239–260 (2009).
19. Kloetzel, P. M. & Ossendorp, F. Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr. Opin. Immunol. 16, 76–81 (2004).
20. Walport, M. J. Complement. N. Engl. J. Med. 344, 1058–1066 (2001). 21. Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol.18, 46 (2017).
Sjoerd's thoughts on academic vaccine research 