A dark, shadowy figure stealthily makes its way through a well-fortified house, successfully sidestepping traps, inactivating alarms, and taking down every guard that it encounters. This may sound like a typical scene from any ninja movie, but a similar scenario occurs whenever a bacterial pathogen successfully enters and infects our bodies. Much like a ninja, disease-causing bacteria, including Mycobacterium tuberculosis, Neisseria meningitidis, Escherichia coli, and others, are all highly skilled in the age-old art of immune evasion.
Immune evasion strategies are those bacterial pathogens use to avoid or inactivate host defenses and ensure their own survival within a host. Bacteria are multifaceted in their methods used to escape immune detection. They employ tactics such as modulating their cell surfaces, releasing proteins to inhibit or degrade host immune factors, or even mimicking host molecules. Mastery of these camouflaging and precise weaponry techniques by bacterial pathogens significantly complicates efforts to develop new vaccines and innovative treatments.
To understand how bacteria could develop such intricate evasive techniques, consider how bacterial pathogens have evolved with humans for centuries. For example, researchers have found evidence of M. tuberculosis, the causative agent of tuberculosis, in 9,000-year-old human remains. After spending so much time together, it’s no surprise that these pathogens are equipped with such host-specific and effective ways to hide from our immune responses. I'll cover just a few of the tactics that bacteria have evolved that help them evade immune detection.
Hidden in Plain Sight: Cell Wall Modification, Capsule Production, and Mimicry
The cell wall of a bacterial pathogen is often the first target of the human immune system, which uses tools such as antibodies and antimicrobial peptides (AMPs) to kill and neutralize the bacteria. Because the cell wall is also a bacterium’s first line of defense, it is not surprising that modulation of this outermost layer is an evasive technique used widely across bacterial species.
E. coli, S. enterica, and various other gram-negative organisms acylate the lipid A component of the lipopolysaccharide in their cell walls (see Figures 1 and 2), thereby changing their negatively charged surface to a positive charge. This alteration allows the bacterial cells to repel positively charged AMPs produced by host immune cells. Masking negatively charged cell surfaces is not unique to gram-negative bacteria: several gram-positive pathogens, such as Staphylococcus aureus and Listeria monocytogenes, reduce the negative charge of cell wall teichoic acids via D-alanylation.
Figure 1: Orientation of LipidA within the gram-negative cell wall.
Neisseria meningitidis, which lives in the human upper respiratory tract as a commensal organism, causes systemic infection if the bacteria begin replicating in the bloodstream. A major contributor to the success of N. meningitidis as a pathogen is its its physical “cloak,” or polysaccharide capsule, which helps protect the bacteria from many of our body’s defenses by hiding it from the immune system. The genes necessary for capsule synthesis are downregulated during early infection to allow for invasion of host cells. However, the bacteria produce capsule once again upon entering the bloodstream in order to survive in the presence of immune factors, such as complement, that are found there. Researchers have found that the capsular polysaccharide even provides protection of N. meningitidis against AMPs found inside of host cells.
Figure 2: LPS acetylation, with lipid A acyl groups shown in black.
In some bacterial species, polysaccharide capsules serve not only a physical barrier, but also as a an advanced camouflaging system. For instance, the capsule of certain strains of E. coli and that of N. meningitidis serotype B contains polysaccharides that are structurally similar to polysaccharide found on the surface of some mammalian cells. In fact, the similarity of these capsular polysaccharides to those found on certain cells within infant brains has been implicated in the success of these pathogens in causing severe neural disease.
Bacterial Sabotage: Inhibition via Effector Proteins
While bacteria are able to avoid detection and harm by the immune system through self-modulation and mimicry, they can also directly block host immunity with weapons known as effector proteins. Bacterial pathogens secrete these proteins to inhibit immune responses through direct interactions with host proteins and immune factors.
S. aureus is a common commensal organism that sometimes can cause serious infections. Recurrent S. aureus infections are common due to poor adaptive immune responses, such as a lack of adequate antibody production. This is due in large part to S. aureus effector proteins, like staphylococcal protein A (SpA), that inhibit effective immune responses. SpA functions in two ways to protect S. aureus from the adaptive immune response. First, SpA binds directly to antibodies, which prevents recognition and subsequent killing of S. aureus. Second, SpA also binds to B-cell receptors, thus inactivating the very cells tasked with generating a protective immune response.
You might say that M. tuberculosis (Mtb) is one of the most skilled evasive bacterial pathogens there is. Mtb causes active, symptomatic tuberculosis disease in some people it infects, but the majority of the people infected experience only latent tuberculosis infection. In this state, bacteria can lie dormant and persist within its host’s lungs for decades. This is because Mtb hides out in alveolar macrophages, the primary innate immune cells meant to engulf, or phagocytose, invading organisms. The normal process of these macrophage once they engulf bacteria, includes maturation of the phagosomal compartment housing the bacteria. The maturation step introduces antimicrobial peptides and enzymes while acidifying the environment, all to degrade the invader. Mtb employs a full toolbox of mechanisms to effectively inhibit this process, one of which is secretion of the tyrosine phosphatase, PtpA. PtpA inactivates the host vacuolar ATPase necessary for phagosomal acidification by interacting with one specific region of the protein. By inhibiting the acidification of the Mtb-containing phagosomal compartment, Mtb creates a comfortable niche for itself to persist within the host macrophages.
Bacterial pathogens, although small, single-celled organisms, are far from predictable or simplistic in their defense mechanisms. Much like a ninja, they are highly skilled at avoiding detection while taking down their enemies. Whether camouflage through mimicry and cell wall modifications, or direct hand-to-hand combat via effector proteins, new, more intricate strategies of bacterial immune evasion are constantly discovered. Often, bacteria will employ evasion methods overlapping in function, which can make them even more difficult to combat. While we may never discover all their secrets, sustained research of the host-pathogen interface of these bacteria will continue to bring us closer to finally eradicating the diseases that they cause.
