Pathogenic mimicry: We’re not so different, you and I 

Watercolour bacteria mimic

Pathogens go to great lengths to disguise themselves from our immune systems—mimicry is one of their greatest defences. Image credit: Elena Mozhvilo via Unsplash

We like to imagine ourselves as inherently different from pathogens (disease-causing microbes). In fact, physical differences between pathogens and their hosts serve as immunogenic signals for detection and clearance of that pathogen. This distinction typically ensures pathogen elimination while simultaneously evading an autoimmune response. 

In reality, some pathogens have evolved to mimic certain host features to evade immune clearance, or to alter the usual immune response. In doing so, the pathogen improves its infection in the host, and ensures its survival.  

Pathogenic mimics and their role in infection

Pathogens can mimic the host by producing proteins that imitate host proteins. Many mimicry proteins are competitive inhibitors of host receptors and may bind in place of the original ligand, blocking signalling. Others can bind in allosteric sites (alternative binding sites to the usual substrate binding site) that change the structure of the host protein, preventing substrate-binding and downstream signalling. 

Mimicry of the immune system

To understand how pathogens interact with their host it is worth considering the immune system. The innate immune response (IIR) is the first line of defence that detects pathogens once they have breached epithelial barriers. To do this, the IRR employs a series of receptors, called pattern recognition receptors (PRRs), like the well-characterised Toll-like Receptors (TLRs), found at host cell surface and organelle membranes. PRRs bind components of foreign organisms that are not found in healthy human cells, called PAMPs (Pathogen Associated Molecular Patterns). Human TLRs for example, bind a variety of PAMPs—in other words, we can innately distinguish many different pathogenic targets, and at the same time signal infection. 

When a TLR binds its target PAMP, there are a series of signalling reactions that elicit an immune response. One of these immune responses is immune cell migration. During immune cell migration, white blood cells such as neutrophils and monocytes travel towards the site of infection to destroy the pathogen, and prevent further damage of the host. Monocytes are then able to differentiate into dendritic cells that activate T cells, bridging the innate and adaptive immune systems. Another immune response is the release of proteins called cytokines. Cytokines are released predominantly by macrophages, the first cells to recognise pathogens, and T-helper cells, white blood cells involved in activation of cells of the adaptive immune system. The release of cytokines stimulates a proinflammatory response, helping to coordinate the immune response against a specific pathogen.  

Given the principal role of TLRs in immunity, they are an obvious target for pathogens to mimic. Thus, human pathogens such as poxvirus (responsible for diseases such as small pox), and E. coli (bacteria implicated in a number of diseases) release mimics that alter TLR signalling. In the case of E. coli, they release TLR-domain containing proteins, namely TcpC. Despite retaining the key structural domain of human TLRs, the functional differences result in blockage of immune signalling. Key signalling molecules like Nuclear Factor Κappa B (NF-κB), which regulates proteins involved in innate immunity, are down-regulated by mimics, ultimately reducing cytokine and chemokine (cytokines involved specifically in immune cell migration) production. 

Given the principal role of TLRs in immunity, they are an obvious target for pathogens to mimic.

Indeed, disrupting the coordination of the immune response is a key way of improving the pathogen’s infection. In order to do this, some viruses produce cytokine and chemokine mimics to modulate the antiviral immune response in favour of the pathogen. For instance, Epstein-Barr Virus (a member of the herpes family) produces a mimic of IL-10 that suppresses production of pro-inflammatory cytokines. This form of mimicry is thought to aid in viral evasion of the immune system.  

Not only so, but some viruses release soluble versions of receptors, or binding-partners for cytokines and chemokines. These mimics lack the anchoring domains that would otherwise localise the receptors to membranes. This results in decreasing concentrations of inflammatory signals in the blood, due to the host signal binding to soluble mimics instead of host receptors. Viral infection is thus bolstered by hijacking the usual immune response.  

Mimicry of the cell cycle

Not all protein mimics simulate components of the immune system to improve pathogenic infection. Instead, some mimic cellular components involved in cell cycle control. Cells contain a multitude of lifecycle-control factors that can either promote cellular survival or induce apoptosis (cell death). Many of these factors are attractive targets for viruses, where avoiding signal-induced death allows increased viral assembly. 

For example, the adenovirus, responsible for a range of diseases, produces a mimic of the host BCL-2 proteins. BCL-2 proteins typically promote apoptosis of cells, while mimicry of these proteins promotes cellular survival. The anti-apoptotic mimics of adenovirus permit persistent infection of the host, through inhibition of pro-apoptotic pathways, such as those promoted by tissue necrosis factor-α (TNF-α), a pro-apoptotic cytokine. 

As a side effect of cell cycle dysregulation, some of the viruses that affect the cell cycle have also been shown to promote cancer development in their hosts.  

Evolution and its role in mimicry

The question is therefore how the host is able to withstand infection by pathogens that mimic features of its immune system and dysregulates cell division. 

The question is therefore how the host is able to withstand infection by pathogens that mimic features of its immune system and dysregulates cell division. 

Mimicry surfaces in two ways: convergent or divergent evolution. In convergent evolution, the viral and host proteins evolve independently from one another. This process creates protein features that are analogous to each other, despite differences in the underlying protein sequence. Conversely, host mimicry may evolve in a pathogen due to horizontal gene transfer from the host to the pathogen, and subsequent divergence of this sequence in the pathogen. 

The mimics can be “perfect” copies of the host protein, or they can be so-called “imperfect mimics“. Imperfect mimics differ from the original protein, but its differences can serve to benefit the pathogen. Having an exact copy of the host protein renders it victim to the multitude of regulations that host signalling molecules are under. Therefore, there is a functional benefit of diverting from the original structure, and producing a mimic that is not restricted by regulatory mechanisms in the host. The evolutionary drive to produce imperfect mimics that help the pathogen infect its host more optimally must be equally matched in the host to prevent infections from becoming unmanageable. 

A key example of imperfect mimicry can once again be found in the poxvirus. In healthy human cells, RNA can be found as single-stranded mRNA, used as a template for translation (protein synthesis). During viral infection, viral double stranded RNA is injected into cells, where it behaves as a PAMP. Eukaryotic translation initiation requires initiation factors such as eIF2α. Upon viral replication inside cells, protein kinase R (PKR), an enzyme that adds a phosphate marker to its target molecules, phosphorylates eIF2α, preventing viral translation and replication. To bypass this, poxvirus produces the imperfect viral mimic K3L. K3L out-competes eIF2α for PKR binding, due to having higher affinity (stronger binding) for the enzyme. This helps to restore translation of viral proteins and promotes host infection. 

Thus, pathogen mimicry acts as a selective pressure to the hosts to find ways to differentiate between mimic and host proteins. The host protein must maintain its ability to specifically recognise its substrate, while simultaneously avoiding binding the mimic. The pressure is therefore on the host to differentiate its own proteins from the mimic without sacrificing function.  

As such, there is a constant evolutionary race between the pathogen and the host to be able to deal with mimicry. On one hand, pathogen selection pressure drives imperfect mimics that promote pathogen survival and infection. On the other hand, evolution in the host plays a key role in combating microbial mimicry. Yet, in the constant interplay between host and pathogen, only one can truly remain on top.