The skin as interface in the transmission of arthropod-borne pathogens

Microreview

The skin as interface in the transmission ofarthropod-borne pathogens

Freddy Frischknecht*Department of Parasitology, Hygiene Institute,Heidelberg University School of Medicine, ImNeuenheimer Feld 324, 69120 Heidelberg, Germany.

Summary

Animal skin separates the inner world of the bodyfrom the largely hostile outside world and is activelyinvolved 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 skinas harmless passengers or as disease-causingpathogens. Microbes have evolved numerous strate-gies that allow them to gain access to the layersunderneath the epidermis where they either multiplywithin the dermis or move to distant destinationswithin the body for replication. A number of viruses,bacteria and parasites use arthropod vectors, liketicks or mosquitoes, to deliver them into the dermiswhile taking their blood meal. Within the dermis, suc-cessful pathogens subvert the function of a variety ofskin resident cells or cells of the innate immunesystem that rush to the site of infection. In this reviewseveral interactions with cells of the skin by medicallyrelevant vector-borne pathogens are discussed tohighlight the different ways in which these pathogenshave come to survive within the skin and to usurp thedefence mechanisms of the host for their own ends.

On the way in

Approaching an animal from the outside, an arthropodcan recognize the skin already from a distance. Volatileproducts from the glands of the skin, often modified byskin resident bacteria, produce a smell that the best ofperfumes 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,

2004). Once on the host, the arthropod and the microor-ganisms it might carry face a thick layer of dead cells andtightly attached living keratinocytes within the epidermis(Fig. 1). While most pathogens would fail to penetrate thisfirst layer of defence, this is overcome by hijacking anarthropod and relying on its capacity to puncture a hole,which either directly deposits the pathogen within thedermis or opens up a gate of entry (Fig. 2A).

The skin hosts a number of different cell types that playa crucial role in fending off invading pathogens (Randolphet al., 2005; Sharp et al., 2005; Kissenpfennig and Malis-sen, 2006). During infection, rapid signalling events leadto the recruitment of circulating cells, such as neutrophilsand macrophages, to the site of entry (Urban et al., 2006).The perfect tuning of these defence mechanisms mostlyterminates an infection at an early stage. However, a largenumber of pathogens have managed to transform the skininto a port of entry, residence or exit site, often with thehelp 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 achievedto either subvert the function of individual skin cell types totheir own advantage or to circumvent them. The list is byno means complete but serves to highlight the limitedcurrent knowledge about individual strategies, being it toreplicate locally, use cells for transportation to other rep-lication sites or, as is the case for Plasmodium, to run pastall lines of defence. The text moves from simpler (viral) tomore complex (parasitic) pathogens and finishes with afew thoughts on the increasing complexity of the host–vector–pathogen triade.

Silent transmission of viruses through cells of theinnate immune system

A large number of arthropod-borne viruses can cause aneven larger number of human diseases, including denguefever, which affects some 50 million people annually, andtick-borne encephalitis (Labuda and Nuttall, 2004; Greenand Rothman, 2006). Dengue virus is transmitted byAedes mosquitoes and binds to skin resident dendriticcells, using DC-SIGN (dendritic cell-specific ICAM-3grabbing non-integrin, CD 209) (Wu et al., 2000;

Received 21 February, 2007; revised 28 March, 2007; accepted 29March, 2007. *For correspondence. E-mail [email protected]; Tel. (+49)6221566537; Fax (+49)6221564643.

Cellular Microbiology (2007) 9(7), 1630–1640 doi:10.1111/j.1462-5822.2007.00955.xFirst published online 8 May 2007

© 2007 The AuthorJournal compilation © 2007 Blackwell Publishing Ltd

Tassaneetrithep et al., 2003; Sakuntabhai et al., 2005).In vitro data show that the virus preferentially infectsimmature dendritic cells and seems to use DC-SIGN forclustering 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; Lozachet al., 2005). Dengue virus enters the host cell cyto-plasm after fusion of the envelope glycoprotein E withthe endosomal membrane is triggered at low pH (Modiset al., 2004). Eventually the virus spreads further toother immune cells and hepatocytes, causing eitherDengue fever or Dengue haemorrhagic fever (Greenand Rothman, 2006).

Tick-borne encephalitis virus (TBEV) is introduced intothe 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 asneutrophils and macrophages recruited from the blood to

the bite site (Labuda et al., 1996). Curiously, the virus canbe transmitted to an uninfected tick feeding at a distantsite on the same host without any detectable virus load inthe blood (Jones et al., 1987; Nuttall, 1998). When skinsamples from mice on which ticks were allowed to co-feedwere examined, only the skin patches at both bite siteswere infected. This suggests that immune cells carry thevirus from one bite site to the other without releasing it ina global way. Indeed, even when animals were immunizedand produced a potent antibody response against TBEVthis route of transmission was still maintained, albeit at areduced level (Labuda et al., 1997). Interestingly, the effi-ciency of blocking transmission between co-feeding tickswas more pronounced when immunization was carriedout by natural bite compared with injection of viruses witha syringe, suggesting that salivary components of the tickmight play a role in inducing anti TBEV immunity (Labudaet al., 1997; Nuttall and Labuda, 2004).

A B

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MΦPMN Endothelialcells

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, hairfollicle, 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 theskin. In the latter case, they can leave the skin either by belated entry into the blood or by lymphatic drainage or they replicate locally. Fromthe lymph node (LN) they might enter the blood from where they can again enter into different skin sites. Pathogens can replicate at any ofthe 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 ata more distant site.

Arthropod-borne pathogen transmission 1631

© 2007 The AuthorJournal compilation © 2007 Blackwell Publishing Ltd, Cellular Microbiology, 9, 1630–1640

The two ways to black death: transmission of theplague bacteria

Yersinia pestis, the Gram-negative bacteria causingbubonic plague, was a source of much havoc in humanhistory (Perry and Fetherston, 1997). Yersinia hasrecently evolved to use flea-borne transmission, whichdeposits the bacteria in the dermis (Hinnebusch, 2005).Once there, Yersinia might inject proteins into the cyto-plasm of dendritic cells, neutrophils and macrophages toinhibit phagocytic uptake and allow the bacteria to repli-cate locally in the extracellular space, although an initialintracellular phase cannot be excluded (Fallman andGustavsson, 2005; Marketon et al., 2005). When dissemi-nating to the draining lymph nodes, they again multiplyand cause the typical bubos (swollen and painful lymphnodes) before entering the blood stream and causingsystemic disease. However, occasionally patients sufferfrom systemic disease without prior history of bubos, sug-gesting that some bacteria can either enter the blood atthe bite site or pass silently through the lymph nodes(Perry and Fetherston, 1997). During a bite, the fleadeposits highly variable numbers (none to over 1.000 witha 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 bubonicsymptoms before dying from systemic disease. However,when mice were infected by flea bites, some mice devel-oped systemic disease without first showing enlargedlymph nodes (Sebbane et al., 2006). This raised the ques-

tion whether the difference between natural bite andsyringe delivery was due to simple mechanics, flea saliva,or a particular bacterial factor. Yersinia uses a cell surfaceprotease, plasminogen activator (Pla), to degrade theextracellular matrix, and Pla-negative Yersinia strains arevirulent only when injected intravenously but not wheninjected subcutaneously (Sodeinde et al., 1992). Duringnatural bites, Pla-negative Yersinia never caused bubonicplague, while both wild-type and Pla-negative strainscaused similar numbers (25–30%) of mice to die fromsystemic plague in the absence of lymph node swelling(Sebbane et al., 2006). These observations thereforesuggest that during natural transmission some bacteriaare indeed injected straight into the blood stream. Thus,Yersinia is able to use both lymphatic drainage and theblood stream on its way from the vector to establishingitself in the host.

Choosing the impossible host cell: Anaplasma

As for the previously described pathogens, humans areaccidental hosts for the causative agent of granulocyticanaplasmosis, the Gram-negative bacterium Anaplasmaphagocytophilum (Dumler et al., 2005; Rikihisa, 2006).Transmitted by the bite of an Ixodes tick, Anaplasmaseeks out the most unlikely of host cells, the short-livedneutrophil granulocytes (Fig. 3A). Neutrophils are the firstleukocytes to arrive from the blood stream at a site ofinflammation to phagocytize pathogens (Urban et al.,

Fig. 2. Macroscopic changes in the skinfollowing mosquito bites.A. Cartoon of a mosquito proboscispenetrating the skin. The salivary canal(yellow), blood canal (red), maxillae andmandibles are shown (blue).B. Haematoma as seen after mosquito bitesin the mouse ear.C. Visible skin reactions to bites of Culexmosquitoes by an infant (top) and ofAnopheles mosquitoes by an adult (bottom) 2and 5 days after exposure respectively.

1632 F. Frischknecht


2006). They bind the bacteria with the P-selectin glyco-protein ligand-1, fucosylated, as well as sialylatedglycans, and at least one additional ligand (Goodmanet al., 1999; Herron et al., 2000; Carlyon and Fikrig, 2003;Reneer et al., 2006). Upon uptake, the bacteria block thefusion of lysosomes with the phagosome in which theyreside, while still allowing other phagosomes in their hostcell to mature (Gokce et al., 1999). Inhibiting superoxideanion production allows the bacteria to survive within theirvacuole, and inhibition of apoptosis gains enough time formultiplication (Carlyon and Fikrig, 2003; Ge and Rikihisa,2006). Anaplasma further modulates neutrophil cytokineproduction and induces IL-8, which leads to the recruit-ment of additional neutrophils to the site of infection, thussupplying the bacteria with new host cells (Akkoyunluet 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 inendothelial cells might also allow the bacteria to continu-ously infect circulating neutrophils to increase theirchances of transmission back to a tick (Herron et al.,2005).

Trojan horses and altruistic heroes: neutrophils andLeishmania

A large number of parasites reside within or enter ourbodies via the skin. Leishmania parasites cause a numberof different diseases, including cutaneous Leishmaniasis(Murray et al., 2005). During the bite of a Phlebotomus(Old World) or Lutzomyia (New World) sandfly around1000 Leishmania parasites can be ejected (Rogers et al.,2004). In the dermis, some species replicate withinmacrophages and can cause visible skin reactions, thehallmark of cutaneous Leishmaniasis. However, for Leish-mania major, similar to Anaplasma, the first host cellsseem to be the neutrophil granulocytes, arriving at the siteof infection (Laskay et al., 2003) (Fig. 3B). Leishmaniapromastigotes release a granulocyte chemotactic factor,

enter neutrophils and, upon uptake, seem to prevent pha-gosomal maturation. In addition, intracellular parasitesdelay the spontaneous apoptosis of neutrophils by oneday, probably through downregulation of caspase-3 activ-ity (Aga et al., 2002). Macrophages, which subsequentlyappear at the site of infection, first induce apoptosis ofneutrophils 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 themacrophage can recognize phosphatidylserine, whichsilences phagocyte responses to antigens such as theproduction of the pro-inflammatory cytokine TNF-a, andleads to the release of anti-inflammatory cytokines suchas IL-10 and TGF-b (Henson et al., 2001; Ma et al., 2003;Rahman and McFadden, 2006). Thus, the ingenuity of thisTrojan horse strategy lies in the effective downregulationof a potential antiparasitic immune response originatingfrom the macrophage caused by the ingestion of an apo-ptotic cell. The interference with apoptotic signalling ofL. major is not restricted to neutrophils, as intracellularparasites can also confer resistance to apoptosis withinthe macrophage by repressing mitochondrial release ofcytochrome c (Akarid et al., 2004).

A most curious finding about Leishmania transmissionconcerns the observation that the presence of apoptoticparasites (Arnoult et al., 2002; Wanderley et al., 2005;Shaha, 2006) is crucial for the successful establishmentof 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 ofapoptotic 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 mastersof modulating immune responses in the skin. As the casewith some viruses, Langerhans cells were originally pos-tulated to take up Leishmania and then migrate to thedraining lymph node for the induction of specific T cellresponses (Moll et al., 1993). It is now believed that lymph

Fig. 3. Targeting neutrophils duringtransmission. Highly schematized cartoonsshowing (A) Anaplasma replication withinneutrophils and (B) the Trojan horse strategyof Leishmania major. Anaplasma (green)replicate within and recruit new neutrophils(PMN, blue) to the site of replication buteventually also infect endothelial cells (EC,red). Living (elongated, light green) andapoptotic (rounded, dark green) Leishmaniapromastigotes are naturally deposited in theskin. Neutrophils (PMN, blue) phagocytoseboth forms. Parasites delay neutrophilapoptosis so that parasite-harbouringneutrophils can be phagocytosed bymacrophages (MF, red) within whichLeishmania multiplies.

PMNMΦ

PMN

PMN

EC

A

B



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 immuneresponse at the bite site in a manner dependent on thepresence of Leishmania-infected dendritic cells (Belkaidet al., 2002; Belkaid and Rouse, 2005). However, little isknown as to how many transmitted parasites are taken upby neutrophils, macrophages or dendritic cells. Using theknowledge of host parasite interactions in the skin avail-able today, it should now be possible to directly observesome of the described interactions using relatively simplein vivo imaging approaches with naturally transmitted fluo-rescent parasites (Amino et al., 2007).

Quickly runaway for a living: Plasmodiumsporozoites

Using the above-mentioned in vivo imaging approaches,malaria parasites were revealed to be less patient in theirstrategy for host infection (Vanderberg and Frevert, 2004;Amino et al., 2006). Transmission to the vertebrate hostoccurs during the bite of a female Anopheles mosquitowhen a few to a few dozen Plasmodium sporozoites areinjected into the dermis of the host (Beier, 1998; Frisch-knecht et al., 2004; Amino et al., 2006). Instead ofhanging around at the bite site, they move at high speedto possibly circumvent the host immune defence, as wellas to partly access the blood stream (Vanderberg andFrevert, 2004). Sporozoites entering the mammalianblood are transported throughout the circulation, arrest inthe 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 forblood vessels, which could aid in depositing sporozoitesin the skin (Rossignol et al., 1984). In analogy to thesituation with Yersinia, a small number of sporozoites mayalso be directly injected into the blood, as excision of thebite site immediately after a mosquito bite lowered theefficiency of, but did not completely prevent, transmission(Sidjanski and Vanderberg, 1997). Sporozoites depositedin the dermis can move at velocities of 1–2 mm s-1 forseveral minutes before associating with, and enteringinto, blood vessels (Vanderberg and Frevert, 2004; Aminoet al., 2006). The velocity of sporozoite movement, as wellas the percentage of sporozoites entering the blood asobserved after natural bites into the skin of hairless mice,decreases with time (Amino et al., 2006). However, notmany details are currently known about how sporozoitesmigrate in the skin. Clearly, they use their own substrate-dependent and actin-myosin-based gliding machinery(Baum et al., 2006; Heintzelman, 2006) but whether theycontinuously move through cells, as in the liver (Pruden-

cio et al., 2006), or along cells similar to T cells withinlymph 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 speedwhen encountering blood vessels (Amino et al., 2006) butwhether this is a general feature due to specific protein–protein interactions remains to be established. Similarly, itis still speculation if sporozoites in the skin use chemot-actic cues during migration as has been suggested tooccur in the mosquito prior to salivary gland invasion(Akaki and Dvorak, 2005). While some sporozoites enterlymphatic vessels and are subsequently destroyed in thedraining lymph node, the majority appear to stay in theskin for at least several hours, and little is known abouttheir fate (Amino et al., 2006). Sporozoites, in a number ofavian and reptile malaria species, can replicate locallywithin macrophages (Huff, 1949) and these may well bethe destination for some of the sporozoites found in themammalian skin after a natural bite despite earlier find-ings of the contrary when sporozoites were injected usingsyringes (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 interactionbetween isolated pathogens and host cells. At best, thiscan lead to the simple overlooking of interesting details,and at worst, to establishing wrong biological concepts.However, as described above, even in vivo studies oftenmimic only partially natural situations when, for example,pathogens are injected using a syringe. Four main arte-facts plague the syringe approach. First, infection may notbe 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 exceedingthe naturally deposited volume. Third, isolated pathogensmight not be injected at their most infection-competentstate due to prior manipulations. Fourth, salivary, or othercomponents of the vector, might be excluded from needleinjection, or not be present in their natural concentrations.

Many of the pathogens described above show differentinfection dynamics depending on whether they areinjected using a syringe or their natural vector. Plasmo-dium sporozoites provide an interesting case studyfor highlighting the difference of the syringe versusnatural injection approaches, albeit not all aspects areunderstood. Clearly, even when injected by syringe intra-venously, sporozoites are not as infectious as wheninjected by natural bite (Vaughan et al., 1999). Similardifferences 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



minute of salivation) injected by a natural bite (Rossignolet al., 1984). Furthermore, of the thousands of sporozoi-tes that can reside in the salivary glands, only a few aretransmitted during a bite, and these might differ in theirability 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 turnleads to the influx of leukocytes to the bite site, as well asto the draining lymph nodes (Demeure et al., 2005). BothTNF-a and IL-10 are released by mast cells, but whileTNF-a does not contribute to leukocyte influx as duringbacterial infection, IL-10 plays a role in reducing delayed-type hypersensitivity (Malaviya et al., 1996; McLachlanet al., 2003; Demeure et al., 2005; Depinay et al., 2006).However, whether Anopheles saliva, which clearly aidsthe mosquito during the blood meal (Ribeiro et al., 1984;Ribeiro and Francischetti, 2003), modulates either initialor subsequent infection by Plasmodium sporozoitesremains to be determined.

A role for salivary gland components in infection ofL. major co-injected using a syringe has also been estab-lished (Titus and Ribeiro, 1988; Belkaid et al., 1998). Laterit was shown that a Leishmania mexicana-derived fila-mentous proteophosphoglycan, which is produced by theparasite in the fly gut to force regurgitation during theblood meal and thus during transmission, enhancesdisease progression even stronger and, interestingly, inan antagonistic manner to saliva (Rogers et al., 2004).This indicates that different factors injected into the skinduring a single transmission might modulate the localimmune response in opposite ways.

Most of the co-injected proteins seem to modulate thesuccess 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, wasfound in the tick Ixodes scapularis (Ramamoorthi et al.,2005). Termed Salp15, the tick protein is upregulated ininfected glands, binds to the outer surface protein C ofBorrelia, and protects it from antibody-mediated killing inthe skin. Indeed, when Salp15 expression in the tick wasreduced by RNAi, which did not affect the number ofbacteria entering the glands or being transmitted, theBorrelia deposited in the skin were less infectious(Ramamoorthi et al., 2005).

Interfering with transmission in the skin

As components that are co-injected during transmissionclearly modulate the success of infection, it was postu-lated that immune reactions against these componentscould interfere with the transmitted pathogens. Indeed,people who react strongly against tick bites were shown tobe less likely infected by Borrelia (Burke et al., 2005) and

similar observation were made for Leishmania (Gomeset al., 2002). For this parasite it was also found that priorexposure to sandfly bites resulted in a protection againstinfection, which was mediated by a strong delayed-typehypersensitivity response and INF-g production at the bitesite (Kamhawi et al., 2000). Immunization with purifiedproteins 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 betransferable to all vector-borne pathogens. For example,as Anopheles bites suppress delayed-type hypersensitiv-ity responses, a similar vaccination strategy could fail forthe fast moving malaria parasites. Migration of malariaparasites, however, may already be stopped in the skin byantibodies produced from prior vaccination with attenu-ated liver-stage vaccines (Matuschewski, 2006). Theseantibodies could interfere with sporozoite surface proteinsinhibiting motility (Vanderberg and Frevert, 2004). Recentdata also show that tsetse fly bites do not protect fromsubsequent infection by Trypanosoma brucei, the caus-ative agent of sleeping sickness, which probably rapidlyenter the blood stream, although saliva accelerates theonset of Trypanosoma infection in a mouse model (Caljonet 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 thetick feeding apparatus in the skin. Immunization with apurified cement protein led to an immune response thatdisrupted the skin at the bite site, resulting (among othereffects) in impaired feeding, and protected challengedanimals 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 theskin and the pathogens themselves can play an activerole in attracting vectors to the host. Investigating theunderlying mechanisms in the laboratory, however, hassome practical limitations. For example, when studyingthe natural transmission of Plasmodium, we mainly rely onrodent model systems, combining the use of the Asianmosquito Anopheles stephensi with the African tree ratparasites Plasmodium yoelii or P. berghei and a variety ofEuropean or American laboratory mice or Norwegian rats.Therefore, these models might reveal the correct cellularreactions, such as the migration pattern of the parasites inthe skin, but fail in uncovering more subtle (i.e. molecular)details, or even detect artificial ones (Cohuet et al., 2006).



Thus, one must choose more natural settings when study-ing the most fine-tuned interactions such as host-findingbehaviour of insect vectors. Indeed, for a small mosquitoto find its gigantic blood resource is no small feat. Whileseeking a victim it exploits olfactory information derivedfrom volatile substances emanated by a warm-bloodedanimal (Braks et al., 1999; Takken and Knols, 1999;Zwiebel and Takken, 2004). The simplest signal might wellbe carbon dioxide exhaled by the host, but severalhundred substances are contained in our breath andseveral hundred more make up the distinct smell of ourskin. One of these, the water-soluble lactic acid from skinsweat glands, has been shown to attract the yellow fevervirus vector Aedes aegypti. Attraction can be inhibited bythe commonly used mosquito repellent DEET (Doganet al., 1999). Curiously, it was shown that aged rather thanfresh sweat is a better attractant for the human malariavector Anopheles gambiae (Braks and Takken, 1999).Bacteria living on the human skin modify the productsfrom sweat glands and thus significantly increase thenumber of organisms involved in the already complexvector–pathogen–host interplay (Fig. 4). Brevibacteriumlinens is one such skin resident that is also essential forthe maturation of Limburger cheese ‘aroma’, known toattract Anopheles mosquitoes (de Jong and Knols, 1995;Knols et al., 1997) albeit not as well as the natural skinaroma 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 canalso apparently increase the likelihood of being bitten bymosquitoes (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 asoxen, hamsters, lab mice and humans, infected with Try-panosoma, Leishmania or malaria parasites are morelikely 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 ahost, the time required to feed could also be modified,possibly by altered blood haemostasis in the puncturedskin (Rossignol et al., 1985). Finally, a number of behav-ioural differences, such as increased risk taking, havebeen observed in parasite-infected hosts and vectors thatmay well affect the transmission success of a pathogen(Moore, 2002; Lindova et al., 2006; Schaub, 2006).

The increasingly inaccurately named triade of fourand more

To further complicate matters, multiple pathogens caninhabit a vector, which can influence the transmissionefficiency of each pathogen (Turell et al., 1984; Vaughanand Turell, 1996; McKenzie and Bossert, 1997; Belongia,2002; Paul et al., 2002). Albeit most of these competitionshappen within the vector the contribution of skin cells totransmission 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 thetick (Thomas et al., 2001). A further increase in complexitymay come from differences between simultaneous and

vola

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ent b

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vectorresident

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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 theenvironment to the host (1), transmission of pathogens into the skin (2), and dissemination/replication (3) are indicated by big arrows. Smallerarrows indicate the potentially modulating influences on transmission success by host and vector resident pathogens, as well as hostskin-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 ofthe linked parts of the pendulum depends highly on the initial conditions, where even a tiny change can cause enormous differences to themotion pattern in a very short time.



subsequent infection. Although in the Anaplasma–Borrelia case no major differences were detected in micethat were first infected with Anaplasma and 1 week laterwith Borrelia compared with the co-infection studies(Holden et al., 2005), this might well be the case for othercombinations of pathogens.

In conclusion, the exact outcome of the most basiccellular interactions in this host–vector–pathogen triad ishighly unpredictable due to the fact that each single trans-mission event for a given pathogen is likely a unique eventthat 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 salivainjected into different regions of the skin will make surethat 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 differentpathogen.

This review could only highlight some aspects of skinbiology in the transmission of vector-borne pathogens.Even for those relatively well-studied pathogens, a vastnumber of open questions remain for our understandingof the underlying basic biological processes of infection.As understanding these might help in the development ofvaccines or drugs, we will certainly witness many moreinteresting studies in the coming years.

Acknowledgements

I thank Rogerio Amino, Marek Cyrklaff, Maik Lehmann, KaiMatuschewski, Markus Meissner, Petra Rohrbach, Ger vanZandbergen and my colleagues in the lab for critically reading themanuscript, Yves Cully for drawing panels for Figs 1 and 2 as wellas Sylvia Münter for Fig. 2B. I apologize to the many colleagueswhose work could not be cited. My work is funded by the GermanFederal Ministry for Education and Research (BMBF-BioFuture),the German Research Foundation (SFB 544 and SPP 1128) andthe Heidelberg University School of Medicine.

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The skin as interface in the transmission of arthropod-borne pathogens

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