Adapt and die: Does innate immunity target pathogen mutation?
Pattern recognition is one of the mechanisms by which the immune system discriminates pathogens from self. Immune cells are not simply identifying common pathogenic patterns, but instead, respond to fragments of pathogens released during unsuccessful pathogenic adaptation activities.
In 1989, Charles Janeway introduced the concept of Pattern Recognition Receptors (PRRs), a class of specialised innate immune receptors responsible for detecting specific molecules associated with pathogens (aka Pathogen-Associated Molecular Patterns—PAMPs) to trigger effective immune responses. After years of intense research (and a Nobel prize), Janeway’s ‘Pattern Recognition Theory’ now provides a fundamental framework for the functioning of the innate immune system.
The term PAMP represents a diverse set of non-self-molecules (cell wall components, nucleic acids, lipopolysaccharides (LPS), carbohydrates, etc.) essential to pathogen viability and virulence. Despite structural differences, entirely unrelated pathogens often share common molecular features that enabled the innate immune system to develop pattern recognition. For instance, the lipid A region of LPS is essential for the pro-inflammatory activity of Gram-negative bacteria and is highly conserved among them, whereas the core region and the O side chain may be variable among closely related strains and go unnoticed by the innate immune system.
Notably, PAMPs are produced by both pathogenic and non-pathogenic (commensal) microorganisms. Furthermore, non-pathogen-derived PAMPs can stimulate innate immunity just as effectively as PAMPs from pathogenic bacteria, albeit for different purposes. For instance, the LPS of commensal Gram-negative bacteria in the GI tract is recognised by PRRs to stimulate the production of antimicrobial peptides and mucus for the maintenance of gut homeostasis and protection against pathogen invasion. This close interdependence means that the host immune system must ignore/tolerate PAMPs derived from commensal pathogens to avoid harming the host.
The question arises as to how PRRs can distinguish between ‘healthy’ encounters with commensals and ‘potentially harmful’ encounters with pathogens productively? Anti-inflammatory cytokines and compartmentalisation may play an important role in preventing the inappropriate triggering of innate immune responses, but the underlying mechanisms are not well understood.
In light of this, a hypothesis by Jonathan Kagan recently published in Science proposes that PRRs might not respond to PAMPs per se. Kagan suggests that the immune system may not always be actively searching for and detecting pathogens and that PRRs do not respond to PAMPs per se. Instead, they respond to PAMPs released by pathogens as a result of unsuccessful or poorly executed biochemical mistakes, such as low-fidelity genomic replication, maladaptive/untidy mutations or failed attempts to colonise a host.
Indeed, during an infection, not all pathogens within an infectious group are guaranteed to be successful in infecting the host. There will be individual pathogens that make ‘mistakes,’ and according to Kagan, this can lead to the release of PAMPs and the engagement of PRRs, further triggering a rapid, multifaceted immune response that eventually activates the adaptive immune response.
This idea may seem counterintuitive, but it is supported by years of research showing inconsistencies between PRR-mediated detection and successful pathogen sensing. For example, most PRRs detect features of viral/bacterial nucleic acids that are found concealed inside themselves. PRRs have also been found to detect nucleic acids in lysosomes designed to break down pathogens. Another example includes lipid A, the toxic moiety of LPS anchored in the outer bacterial membrane that is only immunostimulatory when released from the bacterial wall.
It is actually common for microorganisms to make random mistakes during infection. In fact, many evolutionary biologists have suggested that microorganisms often choose to have low-fidelity metabolic activities to create variations within the population. This allows them to adapt/evolve rapidly and efficiently to changing environments or to enhance their infectious strategies to evade the immune system. Therefore, by detecting PAMPs that are released as a result of low-fidelity biochemical activities, PRRs may inadvertently be targeting the process that enables microbes to adapt and evolve.
This idea may seem counterintuitive, but it is supported by years of research showing inconsistencies between PRR-mediated detection and successful pathogen sensing. For example, most PRRs detect features of viral/bacterial nucleic acids that are found concealed inside themselves. PRRs have also been found to detect nucleic acids in lysosomes designed to break down pathogens. Another example includes lipid A, the toxic moiety of LPS anchored in the outer bacterial membrane that is only immunostimulatory when released from the bacterial wall.
The authors also suggest that this mechanism may provide a selective advantage for commensal bacteria to coexist with the host, as it allows them to stimulate innate immune defences without causing disease. Overall, the idea aligns with Polly Matzinger’s ‘Danger Theory,’ which states that the context of antigen encounters (damage vs. homeostasis) is more important to the immune system than the origin of the antigens (self vs. non-self).
Of course, our understanding of immunity has evolved significantly since the time Charlie’s paper was published. Assuming Kagan’s hypothesis is correct, we may need to reconsider the conceptual foundation of our understanding of innate immune recognition, innate control of the adaptive immune response and self/non-self discrimination—as well as how they can be modulated for the development of new vaccines, immunotherapies and drugs. However, a better understanding of unsuccessful pathogenic activities, the evolutionary dynamics of host-pathogen interactions and the role of commensal bacteria is still needed to fully comprehend the potential implications of this concept.
Image Credit: Bigstock
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