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Host’s Immune Response to Borrelia burgdorferi

Borrelia burgdorferi is a relatively large spirochete responsible for causing Lyme disease. Although it is definitely a very successful bacterium, our body’s immune system does provide some protection. This blog will introduce ways in which our bodies deal with B. burgdorferi and discuss how these strategies affect the pathogen.

As the spirochete enters the skin via a tick bite, B. burgdorferi is able to avoid the first line of defense of our innate immune system (Nester et al. 2004). Once it enters our skin, the bacterium multiplies and migrates outward in a radial fashion. Its cell walls typically cause an initial inflammatory response, the second line of defense of our innate immune system (Nester et al. 2004). This reaction involves defensive blood cells, also known as leukocytes or white-blood cells. Leukocytes are split up into granulocytes and agranulocytes (Bauman 2014). Granulocytic leukocytes include neutrophils, basophils, and eosinophils. Neutrophils and eosinophils can phagocytize pathogens, while basophils release a suite of inflammatory chemicals including histamines. These granulocytic cells leave the bloodstream via diapedesis in order to get to the site of infection. Agranulotyic leukocytes include lymphocytes and monocytes. While most lymphocytes are involved in adaptive immunity, natural killer lymphocytes function in innate defense by secreting toxins onto the surfaces of virally infected cells and tumors. Monocytes are white-blood cells that leave the blood and mature into macrophages, which are phagocytic cells. Macrophages devour a variety of things including bacteria, fungi, spores, dust, and dead body cells. While some macrophages exit the bloodstream via diapedesis (wandering macrophages), other types of macrophages are fixed and do not wander (ex. alveolar macrophages, microglia). Each leukocyte targets different intruders (Bauman 2014). As B. burgdorferi is a bacterium, neutrophils and macrophages will be especially important (Tilly et al. 2008). Neutrophils generate extracellular fibers called neutrophil extracellular traps (NETs) that bind to and kill bacteria specifically. They can also kill nearby invaders by producing a variety of chemicals, such as superoxide radicals, hydrogen peroxide, and nitric oxide (Bauman 2014).



Another important player in our body’s second line of defense is the complement system. This set of serum proteins, designated numerically according to the order of their discovery, circulate in the blood and tissue fluids. The complement system can be activated via three different pathways: classical pathway, alternate pathway, and lectin pathway (Bauman 2014).

  • The classical pathway is activated by antigen-antibody complexes.
  • The alternate pathway is activated when C3b binds to a pathogen or pathogenic products, microbial surfaces, and antibody molecules.
  • The lectin pathway is activated by the interaction of microbial carbohydrates with mannose-binding proteins (lectin) in plasma and tissue fluids.

The outcome of these different pathways is the same: inflammation, lysis of foreign cells, and opsonization (Bauman 2014). Inflammation results due to C3a and C5a inducing changes in endothelial cells and mast cells, which leads to an increased vascular permeability. C5a also attract phagocytes to the area (chemoattractant). The lysis of foreign cells is when C5b, C6, C7, C8, and multiple C9s make a donut-shaped structure called the membrane attack complex (MAC). This is especially effective for gram negative bacteria. Borrelia burgdorferi, like most spirochetes, have a gram-negative bacterial type cell wall due to the presence of an outer membrane that contains lipopolysaccharide-like substances, an inner membrane, and a periplasmic space which contains a layer of peptidoglycan (Bauman 2014). Lastly, opsonization occurs when C3b opsonins bind to foreign materials, which ultimately results in phagocytosis. Complement-mediated opsonization is common with B. burgdorferi infections (Tilly et al. 2008).


Once the initial inflammatory response of the innate immune system is finished, the adaptive immune system kicks in. Bacteria can be intracellular and/or extracellular. Although B. burgdorferi can reside in our cells, it spends the majority of its time in the extracellular fluid (Embers et al. 2004). It therefore expresses primarily exogenous antigens to our body’s immune system. Immune cells, or antigen presenting cells, ingest these bacteria/bacterial antigens and express these foreign antigens on their plasma membrane via type II major histocompatibility complex (MHC) proteins (Janeway et al. 2011; Bauman 2014). Once helper T (CD4) lymphocytes bind to the presented antigen, they activate both (1) macrophages that have engulfed the antigen and (2) B cells that can bind to the antigen recognized by the T helper cells. The now-activated B cells proliferate and differentiate into antibody-secreting cells (plasma cells), which results in the mass-production of antibodies that can bind to the antigen presented by the type II MHC proteins. There are five different types of antibodies: IgG, IgM, IgA, IgD, and IgE. Each has its own function and specialty (see table). Once an antibody is attached to the antigen, it can function in several different ways (Bauman 2014): (1) activation of complement and inflammation, (2) neutralization (neutralizing a pathogen’s virulence), (3) opsonization (death by phagocytosis), (4) killing via oxidation by catalyzing the production of hydrogen peroxide, (5) agglutination (hinders activity of pathogenic organism), and (6) antibody-dependent cellular cytotoxicity (death by apoptosis).


Given our defense mechanisms, how can B. burgdorferi still persist in our bodies? First, they produce interleukin-10 (IL-10) when they enter the body. This anti-inflammatory cytokine downregulates the production and function of inflammatory cytokines (Giambartolomei et al. 1998; Murphy et al. 2000). Meanwhile, the tick’s saliva helps decrease our body’s production of interleukin 2 (IL-2) and interferon-gamma (Schoeler et al. 1999; Anguita et al. 2002). Another way in which they affect our body’s second line of defense is via the suppression of the complement cascade. The bacterium does this by recruiting the host’s complement inhibitory factors onto its own cell surface. Proteins in the tick’s saliva also help with inhibiting our complement cascade (Valenzuela et al. 2000).

Once our adaptive immune system is ready, it should be able to produce antibodies to target and remove B. burgdorferi. This spirochete, however, can change its outer membrane proteins via genetic rearrangement, resulting in antigenically different variants for the bacterium (Zhang et al. 1997; Embers et al. 2004). This makes it a lot more difficult for our immune cells to recognize B. burgdorferi and clear it from our blood and tissues. The tick’s saliva also contains proteins that can inhibit the activation of T helper cells (Anguita et al. 2002). Borrelia burgdorferi is also known to hide within the body. It accomplishes this by either residing in areas that are not checked by our immune system as much (ex. eyes, central nervous system, joints), or hiding itself within a cell or a cyst (Ma et al. 1991; Klempner et al. 1993; Montgomery et al. 1993; Girschick et al. 1996; Janeway and Travers, 1996; Sambri et al. 1996). As you can imagine, it is tricky to mount an immune response to an antigen the body can’t even find!

Even though our bodies have a very powerful immune system, capable of numerous pathogen-deadly responses, B. burgdorferi has learned to cope with some of them making this spirochete an extremely successful pathogen. It seems that our bodies are in need of developing new strategies of dealing with this bacterium. It is our turn to make a move towards the infamous evolutionary arms race between host and pathogen in the case of Lyme disease!


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References

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