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NEWS AND VIEWS
The challenge remains to harness the potential
of such cells for therapeutic benefit.
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Lyme disease agent borrows a practical coat
Patricia Rosa
The bacterium that causes Lyme disease is a manipulative creature. This pathogen exploits a component in the
saliva of its vector, a tick, to facilitate invasion of vertebrate hosts.
A sense of repugnance usually accompanies
the sight of an engorged tick, distended by a
recent bloodmeal. What this encounter rarely
elicits is an appreciation of one of the finer
aspects of successful tick feeding: the distinctive cargo of tick saliva.
Along with much of the aqueous content of
the imbibed blood, tick saliva also delivers a battery of factors designed to counteract the host’s
effort to rid itself of this ectoparasite1. Pathogens
transmitted by tick vectors can benefit from the
altered physiology at the feeding site to gain
entry and establish infection in an otherwise
immunocompetent mammalian host2.
A recent study in Nature by Ramamoorthi et
al. suggests that the bacterium Borrelia burgdorferi, the tick-transmitted agent of Lyme
disease, can bind a specific component of tick
saliva that subsequently enhances the bacterium’s survival in a vertebrate host3. What’s
more, expression of both the bacterial outer
surface protein and tick salivary protein is
induced as the tick feeds.
B. burgdorferi is maintained in nature in
an infectious cycle that includes a tick vector
(Fig. 1) and a reservoir in small mammals;
humans can acquire Lyme disease when
infected ticks feed upon them. Lyme disease
is probably the most common vector-borne
bacterial disease in the world.
In addition to transmitting B. burgdorferi,
ticks can serve as vectors for other important
human and animal pathogens. Substantial effort
has therefore focused on determining how ticks
successfully feed upon vertebrate hosts and how
to interrupt this process in order to prevent
The author is in the Laboratory of Zoonotic
Pathogens, Rocky Mountain Laboratories, National
Institute of Allergy and Infectious Diseases, National
Institutes of Health, Hamilton, Montana 59840, USA.
e-mail: [email protected]
pathogen transmission. Several years ago, Das et
al. identified and characterized a number of tick
salivary gland proteins that were induced during tick feeding4. Anguita et al. later showed that
one of these tick proteins, Salp15, contributes
considerably to the immunosuppressive activity
of tick saliva deposited in the skin5.
The Lyme disease bacterium replicates and
resides in the midgut of an infected tick and
moves transiently through the tick salivary
glands during tick feeding. This transition into
the salivary glands is accompanied by a major
phenotypic switch at the bacterial surface,
from outer surface protein (Osp)A to OspC6.
Recent studies present conflicting views on
the role of OspC in B. burgdorferi. Pal et al.
found that OspC facilitated bacterial invasion
of, and binding to, salivary glands, suggesting that OspC might serve as a ligand for a
salivary gland receptor7. In contrast, Grimm
et al. saw no requirement for OspC in salivary gland localization by the bacterium, but
found that OspC was absolutely required for
infection of mice by B. burgdorferi after either
tick bite or needle inoculation8.
Ramamoorthi et al. asked whether any of
the tick salivary gland components known to
be induced during tick feeding were further
elevated by infection with B. burgdorferi3.
They found a considerable increase in the
transcript encoding Salp15 in B. burgdorferi–
infected salivary glands, although the increase
in Salp15 protein was more modest. Quite
striking was the apparent specific interaction
between tick Salp15 and bacterial OspC, both
in vitro and in vivo.
Anguita et al. had previously shown that
Salp15 inhibited the IgG antibody response to
a foreign antigen in mice by blocking CD4+
T-cell activation5. Given the immunosuppressive and OspC-binding properties of Salp15,
Ramamoorthi et al. next asked whether a coating of Salp15 enhanced B. burgdorferi infec-
NATURE MEDICINE VOLUME 11 | NUMBER 8 | AUGUST 2005
Courtesy of Utpal Pal and Erol Fikrig, Yale University
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
enhancing stem cells that already reside in the
tissue would circumvent this major problem
of delivery.
The study by Collins et al. provides formal
proof that the satellite cell is a muscle stem cell.
Figure 1 Ventral view of a live Ixodes scapularis
tick. The tick was injected with fluorescent dyes
(SYTO 9 and propidium iodide) and imaged by
confocal microscopy.
tion in mice3. The authors injected mice with
B. burgdorferi together with Salp15, and found
a substantial increase in the bacterial load in
mice several weeks after inoculation. Salp15
also protected B. burgdorferi from antibodymediated killing, both in vitro and in mice
immune to B. burgdorferi as a result of prior
infection. Finally, the influence of Salp15 on
B. burgdorferi in mice was assessed after transmission from normal and salp15-deficient ticks.
Depletion of Salp15 in ticks by RNA interference decreased the bacterial load in both naive
and immune mice 7 days after transmission.
Ramamoorthi et al. propose that the
OspC-mediated binding of Salp15 armors
B. burgdorferi against neutralizing antibodies
that the bacterium encounters after transmission
to an immune host3 (Fig. 2). In Lyme-endemic
areas, infected ticks frequently feed on mice with
preexisting antibodies against B. burgdorferi. The
authors suggest that the influence of Salp15 on
the outcome of B. burgdorferi infection is most
important in this natural setting3.
831
NEWS AND VIEWS
a
b
Tick infected with
Borrelia burgdorferi
OspC+ bacteria, Salp15+ tick:
survival in host
Spirochete
Spirochete
OspC
Neutralizing
antibody
Salivary gland
granules
OspC+ bacteria, Salp15– tick:
clearance in host
Feeding tick
OspC– bacteria, Salp15+ tick:
clearance in host
OspC
Borrelia burgdorferi
Salp15
Katie Ris
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
Salp15
Figure 2 Tick salivary protein binds and protects Lyme disease agent Borrelia burgdorferi. (a) As an infected tick feeds, B. burgdorferi migrates to the salivary
glands and is transmitted through the saliva to a vertebrate host. At the same time, B. burgdorferi undergoes a dramatic switch in the major surface protein
from OspA (blue bacteria) to OspC (red bacteria). As depicted in the magnified image, B. burgdorferi encounters the tick protein Salp15 in the salivary
glands, and Salp15 binds to OspC. (b) In the presence of neutralizing antibodies from an immune vertebrate host, B. burgdorferi with both OspC and Salp15
on their surface preferentially survive, relative to those in which either Salp15 or OspC is missing.
A remaining question is whether the binding
of Salp15 to OspC enhances B. burgdorferi infection or whether Salp15 does this alone. Mouse
colonization experiments were conducted with
a mixture of bacteria and soluble Salp15. A more
convincing argument for the in vivo significance
of Salp15–B. burgdorferi binding could be made
if the bacteria were rinsed after incubation with
Salp15, before injection into mice. Without
these data, one wonders whether the increased
bacterial load in mice several weeks later is not
the result of coinjected unbound Salp15, given
its documented immunosuppressive activity5?
If so, this represents an example of the potentiation of vector-borne pathogen infection by a
salivary component, as first described in 1988 by
Titus and Ribeiro9. Consistent with this alternative interpretation, coinjection of Salp15 with
B. burgdorferi increased the infectious load but
did not decrease the infectious dose, which
was already quite low. That is, Salp 15 did not
enhance the survival of the infecting bacteria,
but rather the level to which they subsequently
replicated.
832
Another question that arises is whether
Salp15 represents the previously described,
but unidentified salivary gland receptor for
OspC7. This specific ligand-receptor interaction was proposed by this same group to be
a necessary step for invasion of the salivary
glands by B. burgdorferi7. If Salp15 is the salivary gland receptor for B. burgdorferi, then
depletion of it by RNA interference should
block transmission to mice, but by an entirely
different mechanism than that currently suggested by Ramamoorthi et al3.
However Salp15 operates, antibodies that
recognize surface-bound Salp15 might mark
B. burgdorferi for clearance by the host.
Alternatively, antibodies to Salp15 ingested
by feeding ticks might block B. burgdorferi
entry into the salivary glands. Or, as originally envisioned, vaccination with a tick
salivary protein might provide immunity
against tick feeding and thereby prevent
transmission of pathogens4,10. A previous Lyme disease vaccine directed against
OspA is no longer available11,12. Although it
effectively blocked transmission of B. burgdorferi, it fell out of favor because of the
concern that it might eliecit a self-reactive
immune response. Vaccinating against Salp15
might be an effective strategy to disarm
B. burgdorferi.
1. Valenzuela, J.G. Parasitology 129, S83–S94 (2004).
2. Nuttall, P.A. & Labuda, M. Parasitology 129, S177S189 (2004).
3. Ramamoorthi, N. et al. Nature 436, 573–577
(2005).
4. Das, S. et al. J. Infect. Dis. 184, 1056–1064
(2001).
5. Anguita, J. et al. Immunity 16, 849–859 (2002).
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Rosa, P.A. Proc. Natl. Acad. Sci. USA 92, 2909–2913
(1995).
7. Pal, U. et al. J. Clin. Invest. 113, 220–230 (2004).
8. Grimm, D. et al. Proc. Natl. Acad. Sci. USA 101,
3142–3147 (2004).
9. Titus, R.G. & Ribeiro, J.M.C. Science 239, 1306–1308
(1988).
10. Brossard, M. & Wikel, S. K. Parasitology 129, S161–
S176 (2004).
11. Stere, A.C. et al. N. Engl. J. Med. 339, 209–215
(1998).
12. Sigal, L.H. t al. N. Engl. J. Med. 339, 216–222
(1998).
VOLUME 11 | NUMBER 8 | AUGUST 2005 NATURE MEDICINE