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Coevolution in Lyme Disease

The previous blog entry on Reservoir Host of Lyme Disease introduced the ways in which Borrelia burgdorferi can suppress and/or evade the host’s immune system. But how did this spirochete gain these impressive abilities? Were they always able to use their host’s surface proteins? Or did they acquire this ability over time via coevolution with their hosts? And why do they only use the Ixodes tick as their vector? Is this tick species perhaps different compared to other ticks due to its coevolution with the bacterium? These are some of the questions we’ll explore in this blog.

Let’s first discuss the mechanisms responsible for B. burgdorferi recruiting host surface proteins in order to suppress the host’s immune system. An important gene cluster located on the bacterium’s plasmid is known as gbb54. This orthologous gene family is responsible for producing complement regulator-acquiring surface protein 1 (CRASP-1). This protein is the dominant factor-H-like protein 1 (FHL-1) and factor-H-binding protein of B. burgdorferi (Kraiczy et al. 2002). When these CRASP-1 surface proteins bind to either FHL-1 or factor-H, which are both complement inhibitory factors of the host’s immune system, it disrupts the C3b pathway (Merle et al. 2015). The bacterium is therefore able to avoid complement-mediated destruction in the same way the host’s own cells do.

Some speculate that B. burgdorferi coevolved with their hosts by generating the gbb54 orthologous gene family via gene duplication (Wallich et al. 2005). Bacteria with the gbb54 genes were probably more successful than their genetically inferior counterparts, as they could better cope with their host’s innate immune system. With the host selecting against the spirochetes without gbb54, it eventually led to all B. burgdorferi having this immunity suppression ability.

Additionally, this spirochete expresses not just one but multiple CRASP-1 proteins on their cell surface. It is believed that this is to ensure their survival within different hosts, as different species may express slightly different proteins (Stevenson et al. 2002; Miller et al. 2003). As a tick, you never know where your next blood meal will come from which results in them feeding off of a large variety of hosts. By having high CRASP-1 diversity, B. burgdorferi has coevolved with their vector’s sporadic feeding behavior so that it can successfully infect a wide array of hosts.

The two main vectors of B. burgdorferi in the United States are Ixodes scapularis (deer tick, blacklegged tick) and Ixodes pacificus (western blacklegged tick; CDC 2015). While I. pacificus is mainly confined to the Pacific Coast, I. scapularis can be found throughout the northeastern, mid-Atlantic, and north-central states. The bacterium is not found in non-Ixodes tick species (Magnarelli and Anderson 1988). So why does this spirochete only occur in the Ixodes tick? It is possible that their coevolution led to many characteristics that are favorable for B. burgdorferi as seen in the following three examples.

  1. As discussed earlier, B. burgdorferi synthesizes a suite of proteins that enable it to survive within its mammalian/avian hosts. It seems the spirochete expresses slightly different proteins when it resides within its Ixodes tick vector. These include outer surface proteins A and C (OspA, OspC). The OspA protein is synthesized when the bacterium enters the tick via its blood meal, which some researchers believe mediates their adherence to the tick’s gut (Pal et al. 2000). When the infected tick becomes engorged on its next host, B. burgdorferi multiply within the tick’s gut and levels of spirochetal OspA go down while OspC concentrations go up (Schwan and Piesman, 2000). This occurs via the downregulation of the OspA gene (ospA) and upregulation of the OspC gene (ospC) due to temperature changes in the tick’s gut (Schwan et al. 1995). The tick’s gut temperature increases from 24ºC to 34-37ºC as the tick sucks in the host’s warm blood, which triggers this genetic switch. The OspC protein is believed to help the spirochete invade the tick’s salivary glands so that they can be transferred into the next host together with the tick’s saliva (Gilmore and Piesman, 2000; Pal et al. 2004). It may also aid in colonizing tissues of its new host as B. burgdorferi continues expressing OspC within the mammalian/avian host (Montgomery et al. 1996; Pohl-Koppe et al. 2001). These Osp proteins are specialized towards the Ixodes tick family and will not function in other tick species. This shows how B. burgdorferi has coevolved with its Ixodes tick vector by expressing OspA when it needs to adhere to the tick’s gut (host-vector transmission) and expressing OspC when it needs to move from the tick to the next host (vector-host transmission).

  2. The Ixodes tick also produces proteins that are useful for B. burgdorferi. First, the previously discussed spirochetal OspA protein attaches to a tick receptor within Ixodes known as TROSPA (Pal et al. 2004). These TROSPA receptors help the bacterium adhere to the tick’s gut. Interestingly, the gene that expresses TROSPA (TROSPA) is upregulated directly following spirochetal infection but downregulated when the tick becomes engorged on its next host. Researchers believe the increase in TROSPA will aid in vector colonization while the TROSPA decrease will help the bacterium move from the vector to its next host. Another helpful Ixodes protein is Salp15, a protein found in the tick’s saliva. Salp15 is injected into the mammalian/avian host together with the tick’s saliva (and spirochete) and is responsible for inhibiting the host’s CD4+ T cell activation (Anguita et al. 2002). It also lowers the host’s production of interleukin-2 (IL-2). Other effects of Ixodes tick saliva on the host’s immune system include the inhibition of the complement cascade (Valenzuela et al. 2000), impairment of natural killer (NK) cell function (Kopecky and Kuthejlova, 1998), and the reduction of interferon-gamma (Schoeler et al. 1999). This immunosuppression of the host via the tick’s saliva allows for a more efficient transmission of B. burgdorferi into the host (Zeidner et al. 1996).

  3. Lastly, life history traits of the Ixodes tick are also tightly linked with the success of B. burgdorferi. While Ixodes ticks can mate off of their host as adults, they are much more likely to mate while the female is feeding on the host (Yuval et al. 1990). Ixodes ticks are also known to be more ectoparasitic than other tick species. This dependency of the tick on their hosts benefits the spirochete by supplying it with another host for infection.

I would like to add a side note here concerning the transmission of B. burgdorferi from vector to host. Most of the literature I found believed that B. burgdorferi is transmitted from the tick to the host via saliva. Burgdorfer et al (1989) speculated the transmission may be via tick regurgitation or fecal contamination. This was dismissed, however, when the spirochetes were found in both the tick’s salivary glands and saliva (Ribeiro et al. 1987; Zung et al. 1989). I do want to point out here that the bacterium has been found to exist in the tick’s feces, although they were no longer viable (Patton et al. 2011). It is likely that B. burgdorferi is not able to survive once outside the tick’s environment for an extended period of time.

Host Manipulation in Lyme Disease

So far, no host manipulation has been documented to exist with Lyme disease. Some studies, however, have found some suggestive evidence. Meiners et al (2011) found that ticks infected with Borrelia afzelii did not respond to the odors of accidental hosts while uninfected ticks did. Similarly, Vollandt et al (2011) found that infected ticks were only attracted to the odors of competent hosts, not accidental hosts. Other studies did not find the bacterium affecting the tick’s host choice behavior (Berret and Voordouw, 2015).

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