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Reservoir host of Lyme Disease

A reservoir host is commonly defined as an animal or plant that harbors a pathogen and serves as a source of infection for other individuals (Studdert et al. 2007). There are several species that can serve as a reservoir for Borrelia burgdorferi, the etiologic agent of Lyme disease. Some species, however, are more competent reservoirs for the spirochete than others. The white-footed mouse (Peromyscus leucopus) is known to be one of the most competent reservoirs for B. burgdorferi (Levine et al. 1985; Donahue et al. 1987; Ostfeld et al. 1996; CFSPH 2011). Other possible reservoir species include short-tailed shrews ( Blarina brevicauda ), eastern chipmunks (Tamias striatus), the deer mouse (Peromyscus maniculaus), the brush mouse (Peromyscus boylii), and the western gray squirrel (Sciurus griseus) (CFSPH 2011).



Mather et al (1989) estimates that one white-footed mouse infects as many nymphal ticks as 12 chipmunks or 221 voles. This blog will therefore focus on the white-footed mouse.



The white-footed mouse has a broad distribution that ranges from southern Canada to Central America. Population densities may reach as high as 15 individuals/acre and they serve as an important prey species for several predators, including owls, weasels, and snakes (Marsh and Howard 1990). The mouse plays an important role in the life cycle of the vector of Lyme disease, the deer tick (Ixodes scapularis). A tick’s life cycle consists of four stages: egg, larva, nymph, and adult. The six-legged larvae generally feed on small mammals, with the white-footed mouse being the species most commonly parasitized (Main et al. 1982; Bosler et al. 1984; Anderson et al. 1987; Lane et al. 1991). Most white-footed mice are infected with B. burgdorferi, which then results in all larvae feeding on them becoming infected with the spirochete as well (Mather et al. 1989). Once their first blood meal is complete, the ticks drop off of the host and begin to molt into an eight-legged nymph. The nymphs will molt into adults once they acquire a successful blood meal. Adult ticks typically attach to larger mammals, such as white-tailed deer (Odocoileus virginianus), domestic pets, and humans. Any host the tick feeds on can infect it with B. burgdorferi, although the infection most commonly stems from their first blood meal (Ostfeld et al. 1995).



Some people attempt to stop the spread of Lyme disease with the use of “tick tubes,” which are hollow pipes stuffed with pesticide-treated cotton balls. The idea behind this is that the white-footed mice, and other rodents, will use the pesticide-treated cotton balls in their burrows. This results in ticks on the mice becoming exposed to the pesticide, which will ultimately lead to their death before they can infect a new host with the spirochete.



So why are white-footed mice such a good reservoir for B. burgdorferi? While some researchers found that white-footed mice do mount an antibody response to the bacterium, consisting of both IgG and IgM (Schwan et al. 1989), others found that the majority of B. burgdorferi proteins do not elicit an antibody response during infection (Barbour et al. 2008). Donahue et al (1987) found that white-footed mice can remain infective for at least 200 days after a single infective tick bite. As these mice experience constant feeding by deer ticks due to their similar wooded habitat requirements, most of them have a persistent spirochetal infection (Magnarelli et al. 1988). This long-term infection can lead to the rodent’s high infectivity of the tick larvae.

But why aren’t these mice able to fight off the spirochetal infection? Potential reasons for their persistent infections of B. burgdorferi include the bacterium’s active immune suppression and immune evasion. Let’s first discuss the active immune suppression. There are several ways B. burgdorferi has managed to suppress their host’s immune system. First, the spirochete is able to avoid pathogen opsonization by recruiting the host’s complement inhibitory factors onto its own cell surface (Embers et al. 2004). These inhibitory factors inactivate the C3b pathway, which is normally responsible for pathogen opsonization and cell apoptosis via the formation of C3 convertase (Merle et al. 2015). This ultimately results in phagocytes not destroying the bacterium. Another way in which B. burgdorferi suppresses the host’s immune system is via the suppression of inflammatory cytokines. The spirochete produces interleukin-10 (IL-10), which is an anti-inflammatory cytokine that downregulates the production and function of inflammatory cytokines (Giambartolomei et al. 1998; Murphy et al. 2000). This results in the bacterium mitigating the host’s early inflammatory response to infection. Lastly, B. burgdorferi also seems to release soluble antigens, which leads to the formation of immune complexes (antigen/antibody aggregates). This strategy seems to be responsible for the spirochete’s effective prevention of opsonization when in vivo (Coyle et al. 1990; Schutzer et al. 1990). It can also lead to false seronegativity in patients who actually are in fact infected with B. burgdorferi.




Borrelia burgdorferi can also evade the host’s immune system. One way the spirochete accomplishes this is via phase and antigenic variation. Some bacteria employ gene switching to create a diverse array of surface glycoproteins. A diverse surface-exposed lipoprotein (VlsE) is created by B. burgdorferi via genetic recombination involving a linear plasmid containing 15 non-expressed, or silent, vls genetic cassette sequences and the central domain of the expressed VlsE cassette region (Zhang et al. 1997). This can lead to the production of millions of antigenic variants in mammalian hosts, such as the white-footed mouse. Other possible strategies for increasing VlsE diversity include mutation and selective (on-off) expression of genes encoding antigenic proteins (Embers et al. 2004). While the host’s antibodies may evolve to recognize some of these antigenic variants, others will remain unnoticed by the host’s immune system. Physical seclusion is another strategy employed by B. burgdorferi to evade the host’s immune system. Following the localized phase of infection, the spirochete typically spreads into its preferred organs: eyes, central nervous system, and joints. These areas contain extracellular fluids that do not circulate though the conventional lymphatics, making the bacterium less accessible to the host’s immune cells/molecules (Janeway and Travers 1996). Additionally, B. burgdorferi can also hide itself either inside a host cell or within a cyst membrane. Cells commonly invaded include endothelial cells, fibroblasts, macrophages, Kupffer cells, and synovial cells (Ma et al. 1991; Klempner et al. 1993; Montgomery et al. 1993; Girschick et al. 1996; Sambri et al. 1996). Cyst formation typically occurs in response to nutritional stress or the presence of β-lactum antibiotics (Murgia et al. 2002). Once conditions become favorable again, the spirochetes will emerge from their cells or cysts (Gruntar et al. 2001).



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References

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