Cellular Microbiology (2007)
Microreview
The skin as interface in the transmission of
arthropod-borne pathogens
Freddy Frischknecht*
Department of Parasitology, Hygiene Institute,
Heidelberg University School of Medicine, Im
Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Summary
Animal skin separates the inner world of the body
from the largely hostile outside world and is actively
involved in the defence against microbes. However,
the skin is no perfect defence barrier and many micro-
organisms have managed to live on or within the skin
as harmless passengers or as disease-causing
pathogens. Microbes have evolved numerous strate-
gies that allow them to gain access to the layers
underneath the epidermis where they either multiply
within the dermis or move to distant destinations
within the body for replication. A number of viruses,
bacteria and parasites use arthropod vectors, like
ticks or mosquitoes, to deliver them into the dermis
while taking their blood meal. Within the dermis, suc-
cessful pathogens subvert the function of a variety of
skin resident cells or cells of the innate immune
system that rush to the site of infection. In this review
several interactions with cells of the skin by medically
relevant vector-borne pathogens are discussed to
highlight the different ways in which these pathogens
have come to survive within the skin and to usurp the
defence mechanisms of the host for their own ends.
On the way in
Approaching an animal from the outside, an arthropod
can recognize the skin already from a distance. Volatile
products from the glands of the skin, often modified by
skin resident bacteria, produce a smell that the best of
perfumes can only temporarily mask. Not surprisingly,
some of these odours play a role in attracting hae-
matophagous arthropods to their hosts (Braks et al.,
1999; Takken and Knols, 1999; Zwiebel and Takken,
Received 21 February, 2007; revised 28 March, 2007; accepted 29
March, 2007. *For correspondence. E-mail freddy.frischknecht@
med.uni-heidelberg.de; Tel. (+49)6221566537; Fax (+49)6221564643.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd
doi:10.1111/j.1462-5822.2007.00955.
2004). Once on the host, the arthropod and the microor-
ganisms it might carry face a thick layer of dead cells and
tightly attached living keratinocytes within the epidermis
(Fig. 1). While most pathogens would fail to penetrate this
first layer of defence, this is overcome by hijacking an
arthropod and relying on its capacity to puncture a hole,
which either directly deposits the pathogen within the
dermis or opens up a gate of entry (Fig. 2A).
The skin hosts a number of different cell types that play
a crucial role in fending off invading pathogens (Randolph
et al., 2005; Sharp et al., 2005; Kissenpfennig and Malis-
sen, 2006). During infection, rapid signalling events lead
to the recruitment of circulating cells, such as neutrophils
and macrophages, to the site of entry (Urban et al., 2006).
The perfect tuning of these defence mechanisms mostly
terminates an infection at an early stage. However, a large
number of pathogens have managed to transform the skin
into a port of entry, residence or exit site, often with the
help of the arthropod saliva. In this review, a small selec-
tion of viruses, bacteria and parasites of medical impor-
tance are discussed to illustrate how they have achieved
to either subvert the function of individual skin cell types to
their own advantage or to circumvent them. The list is by
no means complete but serves to highlight the limited
current knowledge about individual strategies, being it to
replicate locally, use cells for transportation to other rep-
lication sites or, as is the case for Plasmodium, to run past
all lines of defence. The text moves from simpler (viral) to
more complex (parasitic) pathogens and finishes with a
few thoughts on the increasing complexity of the host–
vector–pathogen triade.
Silent transmission of viruses through cells of the
innate immune system
A large number of arthropod-borne viruses can cause an
even larger number of human diseases, including dengue
fever, which affects some 50 million people annually, and
tick-borne encephalitis (Labuda and Nuttall, 2004; Green
and Rothman, 2006). Dengue virus is transmitted by
Aedes mosquitoes and binds to skin resident dendritic
cells, using DC-SIGN (dendritic cell-specific ICAM-3
grabbing non-integrin, CD 209) (Wu et al., 2000;
2 F. Frischknecht

A B
Oil gland Langerhans cell

E
ETC
M

D
CF
PC

Sweat Fatty Nerve Hair Venule Dermal Mast

Lymphatic PMN MΦ Endothelial
gland tissue ending follicle Artery dendritic cell
vessel cells
cell

C Arthropod

Skin
LN

Blood

Fig. 1. The mammalian skin.

A. Macroscopic cartoon of the skin showing the epidermis (E), dermis (D) and the subcutaneous layer (H). Various secretory glands, hair
follicle, blood and lymph vessels are indicated. PC, Pacinian corpuscle; M, hair erecter muscle.
B. Cartoon highlighting a selection of skin resident cells such as mast cells, Langerhans cells and dermal dendritic cells, as well as neutrophils
(PMN) and macrophages (MF) entering from the blood stream to a herd of infection. CF, collagen fibres; ETC, epidermal T cells.
C. Schematic of potential transmission routes through the skin. Pathogens are either directly injected into a blood vessel or deposited in the
skin. In the latter case, they can leave the skin either by belated entry into the blood or by lymphatic drainage or they replicate locally. From
the lymph node (LN) they might enter the blood from where they can again enter into different skin sites. Pathogens can replicate at any of
the described sites, or within other organs, and can be taken up either from the skin or a lesion at the original bite site or from blood or skin at
a more distant site.

Tassaneetrithep et al., 2003; Sakuntabhai et al., 2005).
In vitro data show that the virus preferentially infects
immature dendritic cells and seems to use DC-SIGN for
clustering on the cell surface, with the actual host recep-
tor responsible for internalization of the virus into endo-
somes not yet deciphered (Wu et al., 2000; Lozach
et al., 2005). Dengue virus enters the host cell cyto-
plasm after fusion of the envelope glycoprotein E with
the endosomal membrane is triggered at low pH (Modis
et al., 2004). Eventually the virus spreads further to
other immune cells and hepatocytes, causing either
Dengue fever or Dengue haemorrhagic fever (Green
and Rothman, 2006).
Tick-borne encephalitis virus (TBEV) is introduced into
the host during the comparatively extended bite of a tick,
which can suck blood for days. The virus seems to repli-
cate at the bite site within Langerhans cells, as well as
neutrophils and macrophages recruited from the blood to
the bite site (Labuda et al., 1996). Curiously, the virus can
be transmitted to an uninfected tick feeding at a distant
site on the same host without any detectable virus load in
the blood (Jones et al., 1987; Nuttall, 1998). When skin
samples from mice on which ticks were allowed to co-feed
were examined, only the skin patches at both bite sites
were infected. This suggests that immune cells carry the
virus from one bite site to the other without releasing it in
a global way. Indeed, even when animals were immunized
and produced a potent antibody response against TBEV
this route of transmission was still maintained, albeit at a
reduced level (Labuda et al., 1997). Interestingly, the effi-
ciency of blocking transmission between co-feeding ticks
was more pronounced when immunization was carried
out by natural bite compared with injection of viruses with
a syringe, suggesting that salivary components of the tick
might play a role in inducing anti TBEV immunity (Labuda
et al., 1997; Nuttall and Labuda, 2004).

© 2007 The Author

Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology

The two ways to black death: transmission of the
plague bacteria
Yersinia pestis, the Gram-negative bacteria causing
bubonic plague, was a source of much havoc in human
history (Perry and Fetherston, 1997). Yersinia has
recently evolved to use flea-borne transmission, which
deposits the bacteria in the dermis (Hinnebusch, 2005).
Once there, Yersinia might inject proteins into the cyto-
plasm of dendritic cells, neutrophils and macrophages to
inhibit phagocytic uptake and allow the bacteria to repli-
cate locally in the extracellular space, although an initial
intracellular phase cannot be excluded (Fallman and
Gustavsson, 2005; Marketon et al., 2005). When dissemi-
nating to the draining lymph nodes, they again multiply
and cause the typical bubos (swollen and painful lymph
nodes) before entering the blood stream and causing
systemic disease. However, occasionally patients suffer
from systemic disease without prior history of bubos, sug-
gesting that some bacteria can either enter the blood at
the bite site or pass silently through the lymph nodes
(Perry and Fetherston, 1997). During a bite, the flea
deposits highly variable numbers (none to over 1.000 with
a mean of 80) of bacteria in the skin (Lorange et al.,
2005). Curiously, when mice were syringe-injected intra-
dermally with 100 bacteria they all first developed bubonic
symptoms before dying from systemic disease. However,
when mice were infected by flea bites, some mice devel-
oped systemic disease without first showing enlarged
lymph nodes (Sebbane et al., 2006). This raised the ques-
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
Arthropod-borne pathogen transmission 3
Fig. 2. Macroscopic changes in the skin
following mosquito bites.
A. Cartoon of a mosquito proboscis
penetrating the skin. The salivary canal
(yellow), blood canal (red), maxillae and
mandibles are shown (blue).
B. Haematoma as seen after mosquito bites
in the mouse ear.
C. Visible skin reactions to bites of Culex
mosquitoes by an infant (top) and of
Anopheles mosquitoes by an adult (bottom) 2
and 5 days after exposure respectively.
tion whether the difference between natural bite and
syringe delivery was due to simple mechanics, flea saliva,
or a particular bacterial factor. Yersinia uses a cell surface
protease, plasminogen activator (Pla), to degrade the
extracellular matrix, and Pla-negative Yersinia strains are
virulent only when injected intravenously but not when
injected subcutaneously (Sodeinde et al., 1992). During
natural bites, Pla-negative Yersinia never caused bubonic
plague, while both wild-type and Pla-negative strains
caused similar numbers (25–30%) of mice to die from
systemic plague in the absence of lymph node swelling
(Sebbane et al., 2006). These observations therefore
suggest that during natural transmission some bacteria
are indeed injected straight into the blood stream. Thus,
Yersinia is able to use both lymphatic drainage and the
blood stream on its way from the vector to establishing
itself in the host.
Choosing the impossible host cell: Anaplasma
As for the previously described pathogens, humans are
accidental hosts for the causative agent of granulocytic
anaplasmosis, the Gram-negative bacterium Anaplasma
phagocytophilum (Dumler et al., 2005; Rikihisa, 2006).
Transmitted by the bite of an Ixodes tick, Anaplasma
seeks out the most unlikely of host cells, the short-lived
neutrophil granulocytes (Fig. 3A). Neutrophils are the first
leukocytes to arrive from the blood stream at a site of
inflammation to phagocytize pathogens (Urban et al.,
4 F. Frischknecht
A transmission. Highly schematized cartoons
PMN
B promastigotes are naturally deposited in the
PMN
MΦ
2006). They bind the bacteria with the P-selectin glyco-
protein ligand-1, fucosylated, as well as sialylated
glycans, and at least one additional ligand (Goodman
et al., 1999; Herron et al., 2000; Carlyon and Fikrig, 2003;
Reneer et al., 2006). Upon uptake, the bacteria block the
fusion of lysosomes with the phagosome in which they
reside, while still allowing other phagosomes in their host
cell to mature (Gokce et al., 1999). Inhibiting superoxide
anion production allows the bacteria to survive within their
vacuole, and inhibition of apoptosis gains enough time for
multiplication (Carlyon and Fikrig, 2003; Ge and Rikihisa,
2006). Anaplasma further modulates neutrophil cytokine
production and induces IL-8, which leads to the recruit-
ment of additional neutrophils to the site of infection, thus
supplying the bacteria with new host cells (Akkoyunlu
et al., 2001). Eventually the bacteria can infect and repli-
cate within endothelial cells prior to establishing a persis-
tent infection (Munderloh et al., 2004). Replication in
endothelial cells might also allow the bacteria to continu-
ously infect circulating neutrophils to increase their
chances of transmission back to a tick (Herron et al.,
2005).
Trojan horses and altruistic heroes: neutrophils and
Leishmania
A large number of parasites reside within or enter our
bodies via the skin. Leishmania parasites cause a number
of different diseases, including cutaneous Leishmaniasis
(Murray et al., 2005). During the bite of a Phlebotomus
(Old World) or Lutzomyia (New World) sandfly around
1000 Leishmania parasites can be ejected (Rogers et al.,
2004). In the dermis, some species replicate within
macrophages and can cause visible skin reactions, the
hallmark of cutaneous Leishmaniasis. However, for Leish-
mania major, similar to Anaplasma, the first host cells
seem to be the neutrophil granulocytes, arriving at the site
of infection (Laskay et al., 2003) (Fig. 3B). Leishmania
promastigotes release a granulocyte chemotactic factor,
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
Fig. 3. Targeting neutrophils during
showing (A) Anaplasma replication within
neutrophils and (B) the Trojan horse strategy
PMN of Leishmania major. Anaplasma (green)
replicate within and recruit new neutrophils
(PMN, blue) to the site of replication but
EC eventually also infect endothelial cells (EC,
red). Living (elongated, light green) and
apoptotic (rounded, dark green) Leishmania
skin. Neutrophils (PMN, blue) phagocytose
both forms. Parasites delay neutrophil
apoptosis so that parasite-harbouring
neutrophils can be phagocytosed by
macrophages (MF, red) within which
Leishmania multiplies.
enter neutrophils and, upon uptake, seem to prevent pha-
gosomal maturation. In addition, intracellular parasites
delay the spontaneous apoptosis of neutrophils by one
day, probably through downregulation of caspase-3 activ-
ity (Aga et al., 2002). Macrophages, which subsequently
appear at the site of infection, first induce apoptosis of
neutrophils and then take up the infected apoptotic cells
(Laskay et al., 2003; van Zandbergen et al., 2004; Allen-
bach et al., 2006). On the apoptotic cell surface the
macrophage can recognize phosphatidylserine, which
silences phagocyte responses to antigens such as the
production of the pro-inflammatory cytokine TNF-a, and
leads to the release of anti-inflammatory cytokines such
as IL-10 and TGF-b (Henson et al., 2001; Ma et al., 2003;
Rahman and McFadden, 2006). Thus, the ingenuity of this
Trojan horse strategy lies in the effective downregulation
of a potential antiparasitic immune response originating
from the macrophage caused by the ingestion of an apo-
ptotic cell. The interference with apoptotic signalling of
L. major is not restricted to neutrophils, as intracellular
parasites can also confer resistance to apoptosis within
the macrophage by repressing mitochondrial release of
cytochrome c (Akarid et al., 2004).
A most curious finding about Leishmania transmission
concerns the observation that the presence of apoptotic
parasites (Arnoult et al., 2002; Wanderley et al., 2005;
Shaha, 2006) is crucial for the successful establishment
of the parasite within the skin and for disease progression
(van Zandbergen et al., 2006). Injection of ‘healthy’ para-
sites alone did not cause disease, while the presence of
apoptotic parasites contributed to parasite survival in neu-
trophils, probably through induction of TGF-b and down-
regulation of TNF-a.
Indeed, Leishmania parasites seem to be the masters
of modulating immune responses in the skin. As the case
with some viruses, Langerhans cells were originally pos-
tulated to take up Leishmania and then migrate to the
draining lymph node for the induction of specific T cell
responses (Moll et al., 1993). It is now believed that lymph
© 2007 The Author

node resident dendritic cells take up soluble parasite anti-
gens (Iezzi et al., 2006; Kissenpfennig and Malissen,
2006). Another class of T cells regulates the immune
response at the bite site in a manner dependent on the
presence of Leishmania-infected dendritic cells (Belkaid
et al., 2002; Belkaid and Rouse, 2005). However, little is
known as to how many transmitted parasites are taken up
by neutrophils, macrophages or dendritic cells. Using the
knowledge of host parasite interactions in the skin avail-
able today, it should now be possible to directly observe
some of the described interactions using relatively simple
in vivo imaging approaches with naturally transmitted fluo-
rescent parasites (Amino et al., 2007).
Quickly runaway for a living: Plasmodium
sporozoites
Using the above-mentioned in vivo imaging approaches,
malaria parasites were revealed to be less patient in their
strategy for host infection (Vanderberg and Frevert, 2004;
Amino et al., 2006). Transmission to the vertebrate host
occurs during the bite of a female Anopheles mosquito
when a few to a few dozen Plasmodium sporozoites are
injected into the dermis of the host (Beier, 1998; Frisch-
knecht et al., 2004; Amino et al., 2006). Instead of
hanging around at the bite site, they move at high speed
to possibly circumvent the host immune defence, as well
as to partly access the blood stream (Vanderberg and
Frevert, 2004). Sporozoites entering the mammalian
blood are transported throughout the circulation, arrest in
the liver and can eventually enter hepatocytes to differen-
tiate into blood cell invading merozoites (Prudencio et al.,
2006). Similar to Yersinia-infected fleas and Leishmania-
infected sandflies, the presence of Plasmodium sporozoi-
tes in a mosquito increases the time spent on probing for
blood vessels, which could aid in depositing sporozoites
in the skin (Rossignol et al., 1984). In analogy to the
situation with Yersinia, a small number of sporozoites may
also be directly injected into the blood, as excision of the
bite site immediately after a mosquito bite lowered the
efficiency of, but did not completely prevent, transmission
(Sidjanski and Vanderberg, 1997). Sporozoites deposited
in the dermis can move at velocities of 1–2 mm s-1 for
several minutes before associating with, and entering
into, blood vessels (Vanderberg and Frevert, 2004; Amino
et al., 2006). The velocity of sporozoite movement, as well
as the percentage of sporozoites entering the blood as
observed after natural bites into the skin of hairless mice,
decreases with time (Amino et al., 2006). However, not
many details are currently known about how sporozoites
migrate in the skin. Clearly, they use their own substrate-
dependent and actin-myosin-based gliding machinery
(Baum et al., 2006; Heintzelman, 2006) but whether they
continuously move through cells, as in the liver (Pruden-
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
Arthropod-borne pathogen transmission 5
cio et al., 2006), or along cells similar to T cells within
lymph nodes (Bajenoff et al., 2006), or migrate along col-
lagen or elastin fibres or both is not known. Occasionally,
sporozoites were observed moving at decreased speed
when encountering blood vessels (Amino et al., 2006) but
whether this is a general feature due to specific protein–
protein interactions remains to be established. Similarly, it
is still speculation if sporozoites in the skin use chemot-
actic cues during migration as has been suggested to
occur in the mosquito prior to salivary gland invasion
(Akaki and Dvorak, 2005). While some sporozoites enter
lymphatic vessels and are subsequently destroyed in the
draining lymph node, the majority appear to stay in the
skin for at least several hours, and little is known about
their fate (Amino et al., 2006). Sporozoites, in a number of
avian and reptile malaria species, can replicate locally
within macrophages (Huff, 1949) and these may well be
the destination for some of the sporozoites found in the
mammalian skin after a natural bite despite earlier find-
ings of the contrary when sporozoites were injected using
syringes (Lloyd and Sommerville, 1949).
Modulation of natural infection by insect saliva
When studying the cellular and molecular biology of infec-
tion one mainly relies on investigating the interaction
between isolated pathogens and host cells. At best, this
can lead to the simple overlooking of interesting details,
and at worst, to establishing wrong biological concepts.
However, as described above, even in vivo studies often
mimic only partially natural situations when, for example,
pathogens are injected using a syringe. Four main arte-
facts plague the syringe approach. First, infection may not
be at the proper site, for example, by introducing patho-
gens into the blood or muscle rather than into the skin.
Second, one might inject a volume of liquid far exceeding
the naturally deposited volume. Third, isolated pathogens
might not be injected at their most infection-competent
state due to prior manipulations. Fourth, salivary, or other
components of the vector, might be excluded from needle
injection, or not be present in their natural concentrations.
Many of the pathogens described above show different
infection dynamics depending on whether they are
injected using a syringe or their natural vector. Plasmo-
dium sporozoites provide an interesting case study
for highlighting the difference of the syringe versus
natural injection approaches, albeit not all aspects are
understood. Clearly, even when injected by syringe intra-
venously, sporozoites are not as infectious as when
injected by natural bite (Vaughan et al., 1999). Similar
differences were shown in avian malaria when sporozoi-
tes were injected intradermally (Krettli and Dantas, 2000).
However, any injected volume that has been used experi-
mentally greatly exceeded the tiny volume (< 1 nl per
6 F. Frischknecht
minute of salivation) injected by a natural bite (Rossignol
et al., 1984). Furthermore, of the thousands of sporozoi-
tes that can reside in the salivary glands, only a few are
transmitted during a bite, and these might differ in their
ability to cause infection from the many that are not trans-
mitted (Beier, 1998; Frischknecht et al., 2004). Finally,
Anopheles saliva is highly active in the skin (Fig. 2),
causing the degranulation of mast cells, which in turn
leads to the influx of leukocytes to the bite site, as well as
to the draining lymph nodes (Demeure et al., 2005). Both
TNF-a and IL-10 are released by mast cells, but while
TNF-a does not contribute to leukocyte influx as during
bacterial infection, IL-10 plays a role in reducing delayed-
type hypersensitivity (Malaviya et al., 1996; McLachlan
et al., 2003; Demeure et al., 2005; Depinay et al., 2006).
However, whether Anopheles saliva, which clearly aids
the mosquito during the blood meal (Ribeiro et al., 1984;
Ribeiro and Francischetti, 2003), modulates either initial
or subsequent infection by Plasmodium sporozoites
remains to be determined.
A role for salivary gland components in infection of
L. major co-injected using a syringe has also been estab-
lished (Titus and Ribeiro, 1988; Belkaid et al., 1998). Later
it was shown that a Leishmania mexicana-derived fila-
mentous proteophosphoglycan, which is produced by the
parasite in the fly gut to force regurgitation during the
blood meal and thus during transmission, enhances
disease progression even stronger and, interestingly, in
an antagonistic manner to saliva (Rogers et al., 2004).
This indicates that different factors injected into the skin
during a single transmission might modulate the local
immune response in opposite ways.
Most of the co-injected proteins seem to modulate the
success of a given pathogen by acting on the host.
However, a salivary gland protein interacting with a patho-
gen, the Lyme disease causing Borrelia burgdorferi, was
found in the tick Ixodes scapularis (Ramamoorthi et al.,
2005). Termed Salp15, the tick protein is upregulated in
infected glands, binds to the outer surface protein C of
Borrelia, and protects it from antibody-mediated killing in
the skin. Indeed, when Salp15 expression in the tick was
reduced by RNAi, which did not affect the number of
bacteria entering the glands or being transmitted, the
Borrelia deposited in the skin were less infectious
(Ramamoorthi et al., 2005).
Interfering with transmission in the skin
As components that are co-injected during transmission
clearly modulate the success of infection, it was postu-
lated that immune reactions against these components
could interfere with the transmitted pathogens. Indeed,
people who react strongly against tick bites were shown to
be less likely infected by Borrelia (Burke et al., 2005) and
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
similar observation were made for Leishmania (Gomes
et al., 2002). For this parasite it was also found that prior
exposure to sandfly bites resulted in a protection against
infection, which was mediated by a strong delayed-type
hypersensitivity response and INF-g production at the bite
site (Kamhawi et al., 2000). Immunization with purified
proteins from the salivary gland, as well as the above-
mentioned glycans also protected against infection
(Morris et al., 2001; Valenzuela et al., 2001; Rogers et al.,
2006).
While these results are promising, they might not be
transferable to all vector-borne pathogens. For example,
as Anopheles bites suppress delayed-type hypersensitiv-
ity responses, a similar vaccination strategy could fail for
the fast moving malaria parasites. Migration of malaria
parasites, however, may already be stopped in the skin by
antibodies produced from prior vaccination with attenu-
ated liver-stage vaccines (Matuschewski, 2006). These
antibodies could interfere with sporozoite surface proteins
inhibiting motility (Vanderberg and Frevert, 2004). Recent
data also show that tsetse fly bites do not protect from
subsequent infection by Trypanosoma brucei, the caus-
ative agent of sleeping sickness, which probably rapidly
enter the blood stream, although saliva accelerates the
onset of Trypanosoma infection in a mouse model (Caljon
et al., 2006). Finally, a different vaccine target was iden-
tified in ticks to inhibit TBEV, where infection is also modu-
lated by saliva components (Nuttall and Labuda, 2004).
During the extended bite of a tick, a number of tick pro-
teins form a cement-like structure that solidly anchors the
tick feeding apparatus in the skin. Immunization with a
purified cement protein led to an immune response that
disrupted the skin at the bite site, resulting (among other
effects) in impaired feeding, and protected challenged
animals through a delayed-type hypersensitivity reaction
(Labuda et al., 2006).
Attracting the very beasts of burden
Another strategy to inhibit vector-borne diseases is trap-
ping or diverting the vector well before the bite. Both the
skin and the pathogens themselves can play an active
role in attracting vectors to the host. Investigating the
underlying mechanisms in the laboratory, however, has
some practical limitations. For example, when studying
the natural transmission of Plasmodium, we mainly rely on
rodent model systems, combining the use of the Asian
mosquito Anopheles stephensi with the African tree rat
parasites Plasmodium yoelii or P. berghei and a variety of
European or American laboratory mice or Norwegian rats.
Therefore, these models might reveal the correct cellular
reactions, such as the migration pattern of the parasites in
the skin, but fail in uncovering more subtle (i.e. molecular)
details, or even detect artificial ones (Cohuet et al., 2006).
© 2007 The Author
 Arthropod-borne pathogen transmission 7

A 1 B
ria vector
acte resident
n tb

s
ide pathogens

ile
es

lat
nr
i 2

vo
sk
skin surface

host
resident
pathogens 3

Fig. 4. Multi-body problem of pathogen transmission.

A. Schematic of the influence of microorganisms on the transmission of arthropod-borne pathogens. Attraction of arthropods from the
environment to the host (1), transmission of pathogens into the skin (2), and dissemination/replication (3) are indicated by big arrows. Smaller
arrows indicate the potentially modulating influences on transmission success by host and vector resident pathogens, as well as host
skin-derived volatiles, which can themselves be modulated by skin resident bacteria or host resident pathogens.
B. The physical three-body problem illustrated with the chaotic pendulum at the Kirchhoff Institute for Physics in Heidelberg. The behaviour of
the linked parts of the pendulum depends highly on the initial conditions, where even a tiny change can cause enormous differences to the
motion pattern in a very short time.

Thus, one must choose more natural settings when study-
ing the most fine-tuned interactions such as host-finding
behaviour of insect vectors. Indeed, for a small mosquito
to find its gigantic blood resource is no small feat. While
seeking a victim it exploits olfactory information derived
from volatile substances emanated by a warm-blooded
animal (Braks et al., 1999; Takken and Knols, 1999;
Zwiebel and Takken, 2004). The simplest signal might well
be carbon dioxide exhaled by the host, but several
hundred substances are contained in our breath and
several hundred more make up the distinct smell of our
skin. One of these, the water-soluble lactic acid from skin
sweat glands, has been shown to attract the yellow fever
virus vector Aedes aegypti. Attraction can be inhibited by
the commonly used mosquito repellent DEET (Dogan
et al., 1999). Curiously, it was shown that aged rather than
fresh sweat is a better attractant for the human malaria
vector Anopheles gambiae (Braks and Takken, 1999).
Bacteria living on the human skin modify the products
from sweat glands and thus significantly increase the
number of organisms involved in the already complex
vector–pathogen–host interplay (Fig. 4). Brevibacterium
linens is one such skin resident that is also essential for
the maturation of Limburger cheese ‘aroma’, known to
attract Anopheles mosquitoes (de Jong and Knols, 1995;
Knols et al., 1997) albeit not as well as the natural skin
aroma from, for example, worn socks (Njiru et al., 2006).
Not only bacteria living on the skin can alter the attrac-
tiveness for vectors. Drinking beer or being pregnant can
also apparently increase the likelihood of being bitten by
mosquitoes (Ansell et al., 2002; Shirai et al., 2002).
Furthermore, mosquitoes are not the only arthropods
attracted by the distinct smell of skin, the parasites them-
selves are often increasing this attraction. Hosts, such as
oxen, hamsters, lab mice and humans, infected with Try-
panosoma, Leishmania or malaria parasites are more
likely to attract tsetse flies, sandflies or mosquitoes,
respectively, than uninfected hosts (Baylis and Mbwabi,
1995; O’Shea et al., 2002; Ferguson and Read, 2004;
Lefevre et al., 2006). Once the vector has landed on a
host, the time required to feed could also be modified,
possibly by altered blood haemostasis in the punctured
skin (Rossignol et al., 1985). Finally, a number of behav-
ioural differences, such as increased risk taking, have
been observed in parasite-infected hosts and vectors that
may well affect the transmission success of a pathogen
(Moore, 2002; Lindova et al., 2006; Schaub, 2006).
The increasingly inaccurately named triade of four
and more
To further complicate matters, multiple pathogens can
inhabit a vector, which can influence the transmission
efficiency of each pathogen (Turell et al., 1984; Vaughan
and Turell, 1996; McKenzie and Bossert, 1997; Belongia,
2002; Paul et al., 2002). Albeit most of these competitions
happen within the vector the contribution of skin cells to
transmission efficiency should not be excluded. Indeed,
when mice were co-infected with Anaplasma and Borrelia,
a changed immune response, including a decreased acti-
vation of macrophages, led to a higher load of both bac-
teria, resulting in an increased transmission back to the
tick (Thomas et al., 2001). A further increase in complexity
may come from differences between simultaneous and

© 2007 The Author

Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
8 F. Frischknecht
subsequent infection. Although in the Anaplasma–
Borrelia case no major differences were detected in mice
that were first infected with Anaplasma and 1 week later
with Borrelia compared with the co-infection studies
(Holden et al., 2005), this might well be the case for other
combinations of pathogens.
In conclusion, the exact outcome of the most basic
cellular interactions in this host–vector–pathogen triad is
highly unpredictable due to the fact that each single trans-
mission event for a given pathogen is likely a unique event
that will never again occur in precisely the same way
(Fig. 4). Indeed, chaos theory provides that just the differ-
ent numbers of pathogens with different amounts of saliva
injected into different regions of the skin will make sure
that no bite is ever the same, even in the absence of (i)
co-infection, (ii) modulation by resident skin fauna or (iii)
presence of prior host infection by the same or a different
pathogen.
This review could only highlight some aspects of skin
biology in the transmission of vector-borne pathogens.
Even for those relatively well-studied pathogens, a vast
number of open questions remain for our understanding
of the underlying basic biological processes of infection.
As understanding these might help in the development of
vaccines or drugs, we will certainly witness many more
interesting studies in the coming years.
Acknowledgements
I thank Rogerio Amino, Marek Cyrklaff, Maik Lehmann, Kai
Matuschewski, Markus Meissner, Petra Rohrbach, Ger van
Zandbergen and my colleagues in the lab for critically reading the
manuscript, Yves Cully for drawing panels for Figs 1 and 2 as well
as Sylvia Münter for Fig. 2B. I apologize to the many colleagues
whose work could not be cited. My work is funded by the German
Federal Ministry for Education and Research (BMBF-BioFuture),
the German Research Foundation (SFB 544 and SPP 1128) and
the Heidelberg University School of Medicine.
References
Aga, E., Katschinski, D.M., van Zandbergen, G., Laufs, H.,
Hansen, B., Muller, K., et al. (2002) Inhibition of the spon-
taneous apoptosis of neutrophil granulocytes by the intra-
cellular parasite Leishmania major. J Immunol 169: 898–
905.
Akaki, M., and Dvorak, J.A. (2005) A chemotactic response
facilitates mosquito salivary gland infection by malaria
sporozoites. J Exp Biol 208: 3211–3218.
Akarid, K., Arnoult, D., Micic-Polianski, J., Sif, J., Estaquier,
J., and Ameisen, J.C. (2004) Leishmania major-mediated
prevention of programmed cell death induction in infected
macrophages is associated with the repression of mito-
chondrial release of cytochrome c. J Leukoc Biol 76:
95–103.
Akkoyunlu, M., Malawista, S.E., Anguita, J., and Fikrig, E.
(2001) Exploitation of interleukin-8-induced neutrophil
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
chemotaxis by the agent of human granulocytic
ehrlichiosis. Infect Immun 69: 5577–5588.
Allenbach, C., Zufferey, C., Perez, C., Launois, P., Mueller,
C., and Tacchini-Cottier, F. (2006) Macrophages induce
neutrophil apoptosis through membrane TNF, a process
amplified by Leishmania major. J Immunol 176: 6656–
6664.
Amino, R., Thiberge, S., Martin, B., Celli, S., Shorte, S.,
Frischknecht, F., and Menard, R. (2006) Quantitative
imaging of Plasmodium transmission from mosquito to
mammal. Nat Med 12: 220–224.
Amino, R., Franke-Fayard, B., Janse, C.J., Waters, A.P.,
Menard, R., and Frischknecht, F. (2007) Imaging parasites
in vivo. In Imaging Cellular and Molecular Biological
Function. Frischknecht, F., and Shorte, S.L. (eds). Heidel-
berg: Springer (in press).
Ansell, J., Hamilton, K.A., Pinder, M., Walraven, G.E., and
Lindsay, S.W. (2002) Short-range attractiveness of preg-
nant women to Anopheles gambiae mosquitoes. Trans R
Soc Trop Med Hyg 96: 113–116.
Arnoult, D., Akarid, K., Grodet, A., Petit, P.X., Estaquier, J.,
and Ameisen, J.C. (2002) On the evolution of programmed
cell death: apoptosis of the unicellular eukaryote Leishma-
nia major involves cysteine proteinase activation and
mitochondrion permeabilization. Cell Death Differ 9:
65–81.
Bajenoff, M., Egen, J.G., Koo, L.Y., Laugier, J.P., Brau, F.,
Glaichenhaus, N., and Germain, R.N. (2006) Stromal cell
networks regulate lymphocyte entry, migration, and territo-
riality in lymph nodes. Immunity 25: 989–1001.
Baum, J., Papenfuss, A.T., Baum, B., Speed, T.P., and
Cowman, A.F. (2006) Regulation of apicomplexan actin-
based motility. Nat Rev Microbiol 4: 621–628.
Baylis, M., and Mbwabi, A.L. (1995) Feeding behaviour of
tsetse flies (Glossina pallidipes Austen) on Trypanosoma-
infected oxen in Kenya. Parasitology 110: 297–305.
Beier, J.C. (1998) Malaria parasite development in
mosquitoes. Annu Rev Entomol 43: 519–543.
Belkaid, Y., and Rouse, B.T. (2005) Natural regulatory T cells
in infectious disease. Nat Immunol 6: 353–360.
Belkaid, Y., Kamhawi, S., Modi, G., Valenzuela, J., Noben-
Trauth, N., Rowton, E., et al. (1998) Development of a
natural model of cutaneous leishmaniasis: powerful effects
of vector saliva and saliva preexposure on the long-term
outcome of Leishmania major infection in the mouse ear
dermis. J Exp Med 188: 1941–1953.
Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M., and
Sacks, D.L. (2002) CD4+CD25+ regulatory T cells control
Leishmania major persistence and immunity. Nature 420:
502–507.
Belongia, E.A. (2002) Epidemiology and impact of coinfec-
tions acquired from Ixodes ticks. Vector Borne Zoonotic Dis
2: 265–273.
Braks, M.A.H., and Takken, W. (1999) Incubated alkaline
human sweat but not fresh acidic sweat attracts the malaria
mosquito Anopheles gambiae sensu stricto. J Chem Ecol
25: 663–672.
Braks, M.A., Anderson, R.A., and Knols, B.G. (1999) Info-
chemicals in mosquito host selection: human skin micro-
flora and Plasmodium parasites. Parasitol Today 15: 409–
413.
© 2007 The Author

Burke, G., Wikel, S.K., Spielman, A., Telford, S.R., McKay,
K., and Krause, P.J. (2005) Hypersensitivity to ticks and
Lyme disease risk. Emerg Infect Dis 11: 36–41.
Caljon, G., Van Den Abbeele, J., Stijlemans, B., Coosemans,
M., De Baetselier, P., and Magez, S. (2006) Tsetse fly
saliva accelerates the onset of Trypanosoma brucei infec-
tion in a mouse model associated with a reduced host
inflammatory response. Infect Immun 74: 6324–6330.
Carlyon, J.A., and Fikrig, E. (2003) Invasion and survival
strategies of Anaplasma phagocytophilum. Cell Microbiol
5: 743–754.
Cohuet, A., Osta, M.A., Morlais, I., Awono-Ambene, P.H.,
Michel, K., Simard, F., et al. (2006) Anopheles and Plas-
modium: from laboratory models to natural systems in the
field. EMBO Rep 7: 1285–1289.
Demeure, C.E., Brahimi, K., Hacini, F., Marchand, F.,
Peronet, R., Huerre, M., et al. (2005) Anopheles mosquito
bites activate cutaneous mast cells leading to a local
inflammatory response and lymph node hyperplasia.
J Immunol 174: 3932–3940.
Depinay, N., Hacini, F., Beghdadi, W., Peronet, R., and
Mecheri, S. (2006) Mast cell-dependent down-regulation of
antigen-specific immune responses by mosquito bites.
J Immunol 176: 4141–4146.
Dogan, E.B., Ayres, J.W., and Rossignol, P.A. (1999) Behav-
ioural mode of action of deet: inhibition of lactic acid
attraction. Med Vet Entomol 13: 97–100.
Dumler, J.S., Choi, K.S., Garcia-Garcia, J.C., Barat, N.S.,
Scorpio, D.G., Garyu, J.W., et al. (2005) Human granulo-
cytic anaplasmosis and Anaplasma phagocytophilum.
Emerg Infect Dis 11: 1828–1834.
Fallman, M., and Gustavsson, A. (2005) Cellular mecha-
nisms of bacterial internalization counteracted by Yersinia.
Int Rev Cytol 246: 135–188.
Ferguson, H.M., and Read, A.F. (2004) Mosquito appetite for
blood is stimulated by Plasmodium chabaudi infections in
themselves and their vertebrate hosts. Malar J 3: 12.
Frischknecht, F., Baldacci, P., Martin, B., Zimmer, C.,
Thiberge, S., Olivo-Marin, J.C., et al. (2004) Imaging
movement of malaria parasites during transmission by
Anopheles mosquitoes. Cell Microbiol 6: 687–694.
Ge, Y., and Rikihisa, Y. (2006) Anaplasma phagocytophilum
delays spontaneous human neutrophil apoptosis by modu-
lation of multiple apoptotic pathways. Cell Microbiol 8:
1406–1416.
Gokce, H.I., Ross, G., and Woldehiwet, Z. (1999) Inhibition of
phagosome-lysosome fusion in ovine polymorphonuclear
leucocytes by Ehrlichia (Cytoecetes) phagocytophila.
J Comp Pathol 120: 369–381.
Gomes, R.B., Brodskyn, C., de Oliveira, C.I., Costa, J.,
Miranda, J.C., Caldas, A., et al. (2002) Seroconversion
against Lutzomyia longipalpis saliva concurrent with the
development of anti-Leishmania chagasi delayed-type
hypersensitivity. J Infect Dis 186: 1530–1534.
Goodman, J.L., Nelson, C.M., Klein, M.B., Hayes, S.F., and
Weston, B.W. (1999) Leukocyte infection by the granulo-
cytic ehrlichiosis agent is linked to expression of a selectin
ligand. J Clin Invest 103: 407–412.
Green, S., and Rothman, A. (2006) Immunopathological
mechanisms in dengue and dengue hemorrhagic fever.
Curr Opin Infect Dis 19: 429–436.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
Arthropod-borne pathogen transmission 9
Heintzelman, M.B. (2006) Cellular and molecular mechanics
of gliding locomotion in eukaryotes. Int Rev Cytol 251:
79–129.
Henson, P.M., Bratton, D.L., and Fadok, V.A. (2001) The
phosphatidylserine receptor: a crucial molecular switch?
Nat Rev Mol Cell Biol 2: 627–633.
Herron, M.J., Nelson, C.M., Larson, J., Snapp, K.R., Kansas,
G.S., and Goodman, J.L. (2000) Intracellular parasitism by
the human granulocytic ehrlichiosis bacterium through the
P-selectin ligand, PSGL-1. Science 288: 1653–1656.
Herron, M.J., Ericson, M.E., Kurtti, T.J., and Munderloh, U.G.
(2005) The interactions of Anaplasma phagocytophilum,
endothelial cells, and human neutrophils. Ann N Y Acad Sci
1063: 374–382.
Hinnebusch, B.J. (2005) The evolution of flea-borne trans-
mission in Yersinia pestis. Curr Issues Mol Biol 7: 197–212.
Holden, K., Hodzic, E., Feng, S., Freet, K.J., Lefebvre, R.B.,
and Barthold, S.W. (2005) Coinfection with Anaplasma
phagocytophilum alters Borrelia burgdorferi population
distribution in C3H/HeN mice. Infect Immun 73: 3440–
3444.
Huff, C.G. (1949) Life cycles of malaria parasites with special
reference to the newer knowledge of pre-erythrocytic
stages. In Malariology. Boyd, M.F. (ed.). Philadelphia: W.B.
Saunders, pp. 54–64.
Iezzi, G., Frohlich, A., Ernst, B., Ampenberger, F., Saeland,
S., Glaichenhaus, N., and Kopf, M. (2006) Lymph node
resident rather than skin-derived dendritic cells initiate spe-
cific T cell responses after Leishmania major infection.
J Immunol 177: 1250–1256.
Jones, L.D., Davies, C.R., Steele, G.M., and Nuttall, P.A.
(1987) A novel mode of arbovirus transmission involving a
nonviremic host. Science 237: 775–777.
de Jong, R., and Knols, B.G. (1995) Olfactory responses of
host-seeking Anopheles gambiae s.s. Giles (Diptera:
Culicidae). Acta Trop 59: 333–335.
Kamhawi, S., Belkaid, Y., Modi, G., Rowton, E., and Sacks,
D. (2000) Protection against cutaneous leishmaniasis
resulting from bites of uninfected sand flies. Science 290:
1351–1354.
Kissenpfennig, A., and Malissen, B. (2006) Langerhans cells
– revisiting the paradigm using genetically engineered
mice. Trends Immunol 27: 132–139.
Knols, B.G.J., Loon, J.J.A., Cork, A., Robinson, R.D., Adam,
W., Meijerink, J., et al. (1997) Behavioural and electro-
physiological responses of the female malaria mosquitoe
Anopheles gambiae (Diptera: Culicidae) to Limburger
cheese volatiles. Bull Entomol Res 87: 151–159.
Krettli, A.U., and Dantas, L.A. (2000) Which routes do Plas-
modium sporozoites use for successful infections of verte-
brates? Infect Immun 68: 3064–3065.
Labuda, M., and Nuttall, P.A. (2004) Tick-borne viruses.
Parasitology 129 (Suppl.): S221–S245.
Labuda, M., Austyn, J.M., Zuffova, E., Kozuch, O., Fuchs-
berger, N., Lysy, J., and Nuttall, P.A. (1996) Importance of
localized skin infection in tick-borne encephalitis virus
transmission. Virology 219: 357–366.
Labuda, M., Kozuch, O., Zuffova, E., Eleckova, E., Hails,
R.S., and Nuttall, P.A. (1997) Tick-borne encephalitis virus
transmission between ticks cofeeding on specific immune
natural rodent hosts. Virology 235: 138–143.
10 F. Frischknecht
Labuda, M., Trimnell, A.R., Lickova, M., Kazimirova, M.,
Davies, G.M., Lissina, O., et al. (2006) An antivector
vaccine protects against a lethal vector-borne pathogen.
PLoS Pathog 2: e27.
Laskay, T., van Zandbergen, G., and Solbach, W. (2003)
Neutrophil granulocytes – Trojan horses for Leishmania
major and other intracellular microbes? Trends Microbiol
11: 210–214.
Lefevre, T., Koella, J.C., Renaud, F., Hurd, H., Biron, D.G.,
and Thomas, F. (2006) New prospects for research on
manipulation of insect vectors by pathogens. PLoS Pathog
2: e72.
Lindova, J., Novotna, M., Havlicek, J., Jozifkova, E.,
Skallova, A., Kolbekova, P., et al. (2006) Gender differ-
ences in behavioural changes induced by latent
toxoplasmosis. Int J Parasitol 36: 1485–1492.
Lloyd, O.C., and Sommerville, T. (1949) The fate of sporo-
zoites of Plasmodium cynomolgi injected into the skin of
rhesus monkeys. Proc Path Soc 61: 144–146.
Lorange, E.A., Race, B.L., Sebbane, F., and Joseph Hinne-
busch, B. (2005) Poor vector competence of fleas and the
evolution of hypervirulence in Yersinia pestis. J Infect Dis
191: 1907–1912.
Lozach, P.Y., Burleigh, L., Staropoli, I., Navarro-Sanchez, E.,
Harriague, J., Virelizier, J.L., et al. (2005) Dendritic cell-
specific intercellular adhesion molecule 3-grabbing non-
integrin (DC-SIGN)-mediated enhancement of dengue
virus infection is independent of DC-SIGN internalization
signals. J Biol Chem 280: 23698–23708.
Ma, J., Chen, T., Mandelin, J., Ceponis, A., Miller, N.E.,
Hukkanen, M., et al. (2003) Regulation of macrophage
activation. Cell Mol Life Sci 60: 2334–2346.
McKenzie, F.E., and Bossert, W.H. (1997) Mixed-species
Plasmodium infections of Anopheles (Diptera: Culicidae).
J Med Entomol 34: 417–425.
McLachlan, J.B., Hart, J.P., Pizzo, S.V., Shelburne, C.P.,
Staats, H.F., Gunn, M.D., and Abraham, S.N. (2003) Mast
cell-derived tumor necrosis factor induces hypertrophy of
draining lymph nodes during infection. Nat Immunol 4:
1199–1205.
Malaviya, R., Ikeda, T., Ross, E., and Abraham, S.N. (1996)
Mast cell modulation of neutrophil influx and bacterial
clearance at sites of infection through TNF-alpha. Nature
381: 77–80.
Marketon, M.M., DePaolo, R.W., DeBord, K.L., Jabri, B., and
Schneewind, O. (2005) Plague bacteria target immune
cells during infection. Science 309: 1739–1741.
Matuschewski, K. (2006) Vaccine development against
malaria. Curr Opin Immunol 18: 449–457.
Modis, Y., Ogata, S., Clements, D., and Harrison, S.C. (2004)
Structure of the dengue virus envelope protein after mem-
brane fusion. Nature 427: 313–319.
Moll, H., Fuchs, H., Blank, C., and Rollinghoff, M. (1993)
Langerhans cells transport Leishmania major from the
infected skin to the draining lymph node for presentation to
antigen-specific T cells. Eur J Immunol 23: 1595–1601.
Moore, J. (2002) Parasites and the Behaviour of Animals.
Oxford: Oxford University Press.
Morris, R.V., Shoemaker, C.B., David, J.R., Lanzaro, G.C.,
and Titus, R.G. (2001) Sandfly maxadilan exacerbates
infection with Leishmania major and vaccinating against it
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
protects against L. major infection. J Immunol 167: 5226–
5230.
Munderloh, U.G., Lynch, M.J., Herron, M.J., Palmer, A.T.,
Kurtti, T.J., Nelson, R.D., and Goodman, J.L. (2004) Infec-
tion of endothelial cells with Anaplasma marginale and
A. phagocytophilum. Vet Microbiol 101: 53–64.
Murray, H.W., Berman, J.D., Davies, C.R., and Saravia, N.G.
(2005) Advances in leishmaniasis. Lancet 366: 1561–
1577.
Njiru, B.N., Mukabana, W.R., Takken, W., and Knols, B.G.
(2006) Trapping of the malaria vector Anopheles gambiae
with odour-baited MM-X traps in semi-field conditions in
western Kenya. Malar J 5: 39.
Nuttall, P.A. (1998) Displaced tick–parasite interactions at the
host interface. Parasitology 116 (Suppl.): S65–S72.
Nuttall, P.A., and Labuda, M. (2004) Tick–host interactions:
saliva-activated transmission. Parasitology 129 (Suppl.):
S177–S189.
O’Shea, B., Rebollar-Tellez, E., Ward, R.D., Hamilton, J.G.,
el Naiem, D., and Polwart, A. (2002) Enhanced sandfly
attraction to Leishmania-infected hosts. Trans R Soc Trop
Med Hyg 96: 117–118.
Paul, R.E., Nu, V.A., Krettli, A.U., and Brey, P.T. (2002)
Interspecific competition during transmission of two sym-
patric malaria parasite species to the mosquito vector. Proc
Biol Sci 269: 2551–2557.
Perry, R.D., and Fetherston, J.D. (1997) Yersinia pestis –
etiologic agent of plague. Clin Microbiol Rev 10: 35–66.
Prudencio, M., Rodriguez, A., and Mota, M.M. (2006) The
silent path to thousands of merozoites: the Plasmodium
liver stage. Nat Rev Microbiol 4: 849–856.
Rahman, M.M., and McFadden, G. (2006) Modulation of
tumor necrosis factor by microbial pathogens. PLoS
Pathog 2: e4.
Ramamoorthi, N., Narasimhan, S., Pal, U., Bao, F., Yang,
X.F., Fish, D., et al. (2005) The Lyme disease agent
exploits a tick protein to infect the mammalian host. Nature
436: 573–577.
Randolph, G.J., Angeli, V., and Swartz, M.A. (2005)
Dendritic-cell trafficking to lymph nodes through lymphatic
vessels. Nat Rev Immunol 5: 617–628.
Reneer, D.V., Kearns, S.A., Yago, T., Sims, J., Cummings,
R.D., McEver, R.P., and Carrlyon, J.A. (2006) Character-
ization of a sialic acid- and P-selectin glycoprotein ligand-
1-independent adhesin activity in the granulocytotropic
bacterium Anaplasma phagocytophilum. Cell Microbiol 8:
1972–1984.
Ribeiro, J.M., and Francischetti, I.M. (2003) Role of arthropod
saliva in blood feeding: sialome and post-sialome
perspectives. Annu Rev Entomol 48: 73–88.
Ribeiro, J.M., Rossignol, P.A., and Spielman, A. (1984) Role
of mosquito saliva in blood vessel location. J Exp Biol 108:
1–7.
Rikihisa, Y. (2006) Ehrlichia subversion of host innate
responses. Curr Opin Microbiol 9: 95–101.
Rogers, M.E., Ilg, T., Nikolaev, A.V., Ferguson, M.A., and
Bates, P.A. (2004) Transmission of cutaneous leishmania-
sis by sand flies is enhanced by regurgitation of fPPG.
Nature 430: 463–467.
Rogers, M.E., Sizova, O.V., Ferguson, M.A., Nikolaev, A.V.,
and Bates, P.A. (2006) Synthetic glycovaccine protects
© 2007 The Author

against the bite of leishmania-infected sand flies. J Infect
Dis 194: 512–518.
Rossignol, P.A., Ribeiro, J.M., and Spielman, A. (1984)
Increased intradermal probing time in sporozoite-infected
mosquitoes. Am J Trop Med Hyg 33: 17–20.
Rossignol, P.A., Ribeiro, J.M., Jungery, M., Turell, M.J.,
Spielman, A., and Bailey, C.L. (1985) Enhanced mosquito
blood-finding success on parasitemic hosts: evidence for
vector-parasite mutualism. Proc Natl Acad Sci USA 82:
7725–7727.
Sakuntabhai, A., Turbpaiboon, C., Casademont, I., Chuan-
sumrit, A., Lowhnoo, T., Kajaste-Rudnitski, A., et al. (2005)
A variant in the CD209 promoter is associated with severity
of dengue disease. Nat Genet 37: 507–513.
Schaub, G.A. (2006) Parasitogenic alterations of vector
behaviour. Int J Med Microbiol 296 (Suppl. 40): 37–40.
Sebbane, F., Jarrett, C.O., Gardner, D., Long, D., and Hin-
nebusch, B.J. (2006) Role of the Yersinia pestis plasmino-
gen activator in the incidence of distinct septicemic and
bubonic forms of flea-borne plague. Proc Natl Acad Sci
USA 103: 5526–5530.
Shaha, C. (2006) Apoptosis in Leishmania species & its
relevance to disease pathogenesis. Indian J Med Res 123:
233–244.
Sharp, L.L., Jameson, J.M., Witherden, D.A., Komori, H.K.,
and Havran, W.L. (2005) Dendritic epidermal T-cell
activation. Crit Rev Immunol 25: 1–18.
Shirai, O., Tsuda, T., Kitagawa, S., Naitoh, K., Seki, T.,
Kamimura, K., and Morohashi, M. (2002) Alcohol ingestion
stimulates mosquito attraction. J Am Mosq Control Assoc
18: 91–96.
Sidjanski, S., and Vanderberg, J.P. (1997) Delayed migration
of Plasmodium sporozoites from the mosquito bite site to
the blood. Am J Trop Med Hyg 57: 426–429.
Sodeinde, O.A., Subrahmanyam, Y.V., Stark, K., Quan, T.,
Bao, Y., and Goguen, J.D. (1992) A surface protease and
the invasive character of plague. Science 258: 1004–1007.
Takken, W., and Knols, B.G. (1999) Odor-mediated behavior
of Afrotropical malaria mosquitoes. Annu Rev Entomol 44:
131–157.
Tassaneetrithep, B., Burgess, T.H., Granelli-Piperno, A.,
Trumpfheller, C., Finke, J., Sun, W., et al. (2003) DC-SIGN
(CD209) mediates dengue virus infection of human den-
dritic cells. J Exp Med 197: 823–829.
Thomas, V., Anguita, J., Barthold, S.W., and Fikrig, E. (2001)
Coinfection with Borrelia burgdorferi and the agent of
human granulocytic ehrlichiosis alters murine immune
responses, pathogen burden, and severity of Lyme
arthritis. Infect Immun 69: 3359–3371.
© 2007 The Author
Journal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology
Arthropod-borne pathogen transmission 11
Titus, R.G., and Ribeiro, J.M. (1988) Salivary gland lysates
from the sand fly Lutzomyia longipalpis enhance Leishma-
nia infectivity. Science 239: 1306–1308.
Turell, M.J., Rossignol, P.A., Spielman, A., Rossi, C.A.,
and Bailey, C.L. (1984) Enhanced arboviral transmission
by mosquitoes that concurrently ingested microfilariae.
Science 225: 1039–1041.
Urban, C.F., Lourido, S., and Zychlinsky, A. (2006) How do
microbes evade neutrophil killing? Cell Microbiol 8: 1687–
1696.
Valenzuela, J.G., Belkaid, Y., Garfield, M.K., Mendez, S.,
Kamhawi, S., Rowton, E.D., et al. (2001) Toward a defined
anti-Leishmania vaccine targeting vector antigens: charac-
terization of a protective salivary protein. J Exp Med 194:
331–342.
Vanderberg, J.P., and Frevert, U. (2004) Intravital microscopy
demonstrating antibody-mediated immobilisation of
Plasmodium berghei sporozoites injected into skin by
mosquitoes. Int J Parasitol 34: 991–996.
Vaughan, J.A., and Turell, M.J. (1996) Facilitation of Rift
Valley fever virus transmission by Plasmodium berghei
sporozoites in Anopheles stephensi mosquitoes. Am J Trop
Med Hyg 55: 407–409.
Vaughan, J.A., Scheller, L.F., Wirtz, R.A., and Azad, A.F.
(1999) Infectivity of Plasmodium berghei sporozoites deliv-
ered by intravenous inoculation versus mosquito bite:
implications for sporozoite vaccine trials. Infect Immun 67:
4285–4289.
Wanderley, J.L., Benjamin, A., Real, F., Bonomo, A., Moreira,
M.E., and Barcinski, M.A. (2005) Apoptotic mimicry: an
altruistic behavior in host/Leishmania interplay. Braz J Med
Biol Res 38: 807–812.
Wu, S.J., Grouard-Vogel, G., Sun, W., Mascola, J.R., Brach-
tel, E., Putvatana, R., et al. (2000) Human skin Langerhans
cells are targets of dengue virus infection. Nat Med 6:
816–820.
van Zandbergen, G., Klinger, M., Mueller, A., Dannenberg,
S., Gebert, A., Solbach, W., and Laskay, T. (2004) Cutting
edge: neutrophil granulocyte serves as a vector for Leish-
mania entry into macrophages. J Immunol 173: 6521–
6525.
van Zandbergen, G., Bollinger, A., Wenzel, A., Kamhawi, S.,
Voll, R., Klinger, M., et al. (2006) Leishmania disease
development depends on the presence of apoptotic pro-
mastigotes in the virulent inoculum. Proc Natl Acad Sci
USA 103: 13837–13842.
Zwiebel, L.J., and Takken, W. (2004) Olfactory regulation of
mosquito–host interactions. Insect Biochem Mol Biol 34:
645–652.