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A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice.

Larsson C, Lundqvist J, van Rooijen N, Bergström S - PLoS Negl Trop Dis (2009)

Bottom Line: Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential.These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms.B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration.

View Article: PubMed Central - PubMed

Affiliation: Umeå University, Department of Molecular Biology and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.

ABSTRACT
Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.

No MeSH data available.


Related in: MedlinePlus

Splenomegaly in infected mice.Although expansion of B- and T-cells is the major cause of splenomegaly in wild-type animals, SCID BEIGE mice infected with B. recurrentis A17 displayed significant (p<0.01) splenomegaly,which indicates a T-, B-, and NK-cell-independent immune response.
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pntd-0000522-g003: Splenomegaly in infected mice.Although expansion of B- and T-cells is the major cause of splenomegaly in wild-type animals, SCID BEIGE mice infected with B. recurrentis A17 displayed significant (p<0.01) splenomegaly,which indicates a T-, B-, and NK-cell-independent immune response.

Mentions: We conducted tests to determine whether any of the commercially available immunodeficient mouse strains can support growth of B. recurrentis. Initially, the two B. recurrentis strains A11 and A17, and B. duttonii strain 1120K3 were inoculated into immunocompetent wild-type BALB/c mice, NUDE mice lacking T-cells, SCID mice lacking B- and T-cells, and SCID BEIGE mice lacking B-, T-, and NK-cells. As expected, only B. duttonii established detectable infection in the BALB/c mice (Figure 1A), which concurred with the results of similar previous experiments [22],[24]. The total B. duttonii spirochetemia did not differ significantly between NUDE mice and BALB/c mice (Figure 1A–B), and neither the A11 nor the A17 B. recurrentis strain caused detectable spirochetemia in BALB/c or NUDE mice, indicating that T-cells are of minor importance for RF immune defense. However, both the B. recurrentis strains did establish infection in SCID and SCID BEIGE mice, although the spirochetemia was about 200-fold lower than that caused by B. duttonii infection (Figures 1 C–D and 2). Due to the lack of antibodies, B. recurrentis spirochetemia did not display a relapsing pattern. Instead, spirochete titers remained fairly constant over time, and there were only minor fluctuations between the mice, which were probably caused by individual, biological variations in the host-pathogen interactions (Figure 2). Both the A11 and A17 bacteria were persistent and remained at fairly low levels in the blood (about 2×105/ml) at least until day 150 post infection. The A11 strain caused a significantly (p<0.01) milder infection, with spirochetemia about half the magnitude of that caused by the A17 strain in both SCID and SCID BEIGE mice (Figure 2). The animals behaved normally and showed no outer sign of disease, and their weight pattern corresponded to what was seen in uninfected animals (data not shown). To ascertain whether the passage through SCID BEIGE mice rendered the bacteria capable of causing spirochetemia in wild-type mice, we inoculated four BALB/c mice with spirochetes obtained from two A11-infected and two A17-infected animals. None of those four mice developed detectable spirochetemia. The B. recurrentis A17 infection induced significant (p<0.01) splenomegaly in SCID BEIGE mice. However, the spleens were much smaller in B-cell- and T-cell-deficient mice than in wild-type mice (Figure 3), which implies activation and multiplication of splenic immune cells. Surprisingly, B. duttonii did not cause a lethal infection in the B-cell-deficient animals, despite the indispensable role of B-cells suggested by the antibody-mediated clearance of antigenic variants in immunocompetent models (Figure 1C, D). Although both B. recurrentis and B. duttonii spirochetemia were higher in B-cell-deficient mice (p = 0.02), which verifies significance of the B-cells, the disease was kept under control by B-cell-independent mechanisms (Figures 1C, D and 2).


A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice.

Larsson C, Lundqvist J, van Rooijen N, Bergström S - PLoS Negl Trop Dis (2009)

Splenomegaly in infected mice.Although expansion of B- and T-cells is the major cause of splenomegaly in wild-type animals, SCID BEIGE mice infected with B. recurrentis A17 displayed significant (p<0.01) splenomegaly,which indicates a T-, B-, and NK-cell-independent immune response.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2742892&req=5

pntd-0000522-g003: Splenomegaly in infected mice.Although expansion of B- and T-cells is the major cause of splenomegaly in wild-type animals, SCID BEIGE mice infected with B. recurrentis A17 displayed significant (p<0.01) splenomegaly,which indicates a T-, B-, and NK-cell-independent immune response.
Mentions: We conducted tests to determine whether any of the commercially available immunodeficient mouse strains can support growth of B. recurrentis. Initially, the two B. recurrentis strains A11 and A17, and B. duttonii strain 1120K3 were inoculated into immunocompetent wild-type BALB/c mice, NUDE mice lacking T-cells, SCID mice lacking B- and T-cells, and SCID BEIGE mice lacking B-, T-, and NK-cells. As expected, only B. duttonii established detectable infection in the BALB/c mice (Figure 1A), which concurred with the results of similar previous experiments [22],[24]. The total B. duttonii spirochetemia did not differ significantly between NUDE mice and BALB/c mice (Figure 1A–B), and neither the A11 nor the A17 B. recurrentis strain caused detectable spirochetemia in BALB/c or NUDE mice, indicating that T-cells are of minor importance for RF immune defense. However, both the B. recurrentis strains did establish infection in SCID and SCID BEIGE mice, although the spirochetemia was about 200-fold lower than that caused by B. duttonii infection (Figures 1 C–D and 2). Due to the lack of antibodies, B. recurrentis spirochetemia did not display a relapsing pattern. Instead, spirochete titers remained fairly constant over time, and there were only minor fluctuations between the mice, which were probably caused by individual, biological variations in the host-pathogen interactions (Figure 2). Both the A11 and A17 bacteria were persistent and remained at fairly low levels in the blood (about 2×105/ml) at least until day 150 post infection. The A11 strain caused a significantly (p<0.01) milder infection, with spirochetemia about half the magnitude of that caused by the A17 strain in both SCID and SCID BEIGE mice (Figure 2). The animals behaved normally and showed no outer sign of disease, and their weight pattern corresponded to what was seen in uninfected animals (data not shown). To ascertain whether the passage through SCID BEIGE mice rendered the bacteria capable of causing spirochetemia in wild-type mice, we inoculated four BALB/c mice with spirochetes obtained from two A11-infected and two A17-infected animals. None of those four mice developed detectable spirochetemia. The B. recurrentis A17 infection induced significant (p<0.01) splenomegaly in SCID BEIGE mice. However, the spleens were much smaller in B-cell- and T-cell-deficient mice than in wild-type mice (Figure 3), which implies activation and multiplication of splenic immune cells. Surprisingly, B. duttonii did not cause a lethal infection in the B-cell-deficient animals, despite the indispensable role of B-cells suggested by the antibody-mediated clearance of antigenic variants in immunocompetent models (Figure 1C, D). Although both B. recurrentis and B. duttonii spirochetemia were higher in B-cell-deficient mice (p = 0.02), which verifies significance of the B-cells, the disease was kept under control by B-cell-independent mechanisms (Figures 1C, D and 2).

Bottom Line: Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential.These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms.B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration.

View Article: PubMed Central - PubMed

Affiliation: Umeå University, Department of Molecular Biology and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.

ABSTRACT
Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.

No MeSH data available.


Related in: MedlinePlus