Folia Entomológica Mexicana ISSN: 0430-8603 [email protected] Sociedad Mexicana de Entomología, A.C. México

Rebollar Téllez, Eduardo A. , bites and the risk of disease transmission Folia Entomológica Mexicana, vol. 44, núm. 2, 2005, pp. 247-265 Sociedad Mexicana de Entomología, A.C. Xalapa, México

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Ensayo

HUMAN BODY ODOR, MOSQUITO BITES AND THE RISK OF DISEASE TRANSMISSION

EDUARDO A. REBOLLAR-TÉLLEZ

Departamento de Enfermedades Infecciosas y Transmitidas por Vector, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Avenida Itzaés 490, Mérida, Yucatán 97000, MÉXICO. [email protected]

Rebollar-Téllez, E. A. 2005. Human body odor, mosquito bites and the risk of disease transmission. Folia Entomol. Mex., 44 (2): 247-265.

ABSTRACT. Mosquitoes and other blood feeding insects are temporal ectoparasites, which move away from the host after a blood meal. It is known that blood components are mainly utilized by mosquitoes for egg production and, in a few examples, as an energy supply. Odors emanating from the host have different substrates from which they originate (e.g. urine, faces, skin, breath). These odors are important as long-range and short-range cues for host recognition. However, the exact relationship between human body odors and the attractiveness to blood-sucking insects remains unknown. Furthermore, the basis as to why certain individuals are preferentially bitten by hungry mosquitoes more than others is unclear. The present review briefly summarizes the sources of human odor that might play a role in mosquito attraction. Evidence suggests that body odors are actually a by- product of the decomposition of odorless skin chemicals, and that the final attraction is due to the balance between attractive and non-attractive fractions. Finally, the implications of variable human attractiveness in areas of parasite transmission are discussed in relation with the vectorial capacity model. It is suggested that differences in attractiveness should be considered when assessing risk factors in those endemic transmission foci. KEY WORDS: mosquito attraction, human odors, skin bacteria, vectorial capacity.

Rebollar-Téllez, E. A. 2005. Olores corporales humanos, picaduras de mosquito y el riesgo de transmisión de enfermedades. Folia Entomol. Mex., 44 (2): 247-265.

RESUMEN. Los y otros insectos hematófagos son ectoparásitos temporales, los cuales se desprenden del hospedero después de una alimentación sanguínea. Se sabe que la sangre ingerida por los mosquitos es empleada en la producción de huevos y en algunos casos como fuente energética. Los olores emanados por un hospedero tienen varios orígenes, e.g. orina, heces, piel y aliento. Estos olores son importantes como atrayentes de largo y corto alcance en el reconocimiento por el hospedero. Sin embargo, la relación entre los olores corporales de humanos y su atractivo para los insectos hematófagos aún se desconoce. Más aún, se desconoce porqué ciertos individuos son preferentemente picados por mosquitos. En el presente ensayo se incluyen las posibles fuentes de olores corporales humanos que pueden ser importantes en la atracción a mosquitos. La evidencia sugiere que los olores corporales son en realidad producto de la descomposición bacterial de químicos inodoros de la piel y que la atracción final se debe al balance entre las fracciones atractivas y no atractivas. Finalmente, las implicaciones de una variación humana en atractividad en áreas de transmisión de parásitos es discutida dentro del marco del modelo de capacidad vectorial. Se sugiere que las diferencias en atracción deben de ser consideradas en las evaluaciones de factores de riesgo en focos endémicos. PALABRAS CLAVE: Atracción de mosquitos, olores humanos, bacterias de la piel, capacidad vectorial. Rebollar-Téllez: Human body odor and mosquito bites

Evolution of hematophagy (feeding on blood) cesses which lead an insect to be receptive to has evolved independently in several insect certain stimuli derived from a potential blood families as well as other arthropods (Balashov, source. During activation and orientation, chemi- 1984; Lehane, 1991). This has resulted in a wide cal stimuli are thought to be of extreme impor- range of life strategies to maximize uptake of tance in host-recognition by hematophagous in- blood and minimize the risk of mortality during sects. An important distinction has to be made the process of feeding on a vertebrate host (Knols here regarding the terms activator and attractant. and Meijerink, 1997). Lehane (1991) considers As previously stated, activation is not a behavior, three types of blood-sucking insects according to but is a chemical cue that loads a behavioral state the permanency on a host. These groups are: i) into “mode-on” without properly evoking a permanent ectoparasites with an absolute depen- measurable response or behavior. In contrast, an dence on the host, ii) periodic ectoparasites, attractant is that which causes an insect to flight which visit the host for certain periods of time upwind (taxis) towards the odor source, which is and iii) temporary ectoparasites, which are most an observable behavior (Willemse and Takken, commonly free-living species. This latter group 1994). Location of a host at distance is consi- contains winged species such as mosquitoes and dered to involve long-distance, medium-distance allies. Mosquitoes and other parasite vectors are and short-distance chemical clues (Knols, facultative or obliged blood-feeders. Blood is re- 1996a). The actual distinction of ranges for each quired in most instances for egg production of those attractants is entirely unknown, (anautogeny) and can in other cases be converted especially during changes in wind direction to triglycerides and glycogen and used as an e- and/or for moving targets. The complete behavior nergy supply during flight and survival (Edman of host-location is an incessant process by which et al., 1992). an insect is confronted with stimuli interwined Location of a blood source and feeding on it, with ever-changing conditions (Sutcliffe, 1986). has been termed “host-seeking behavior”, “host- Nonetheless, the use of such concepts help to location behavior” or “host-finding behavior” understand how blood-feeding insects locate a (Sutcliffe, 1987). These terms are sometimes host based on the way they perceive and respond used differently, but herein they are used indis- to prevailing stimuli. tinctly to describe the process by which a hema- Anecdotal and empirical experience with hu- tophagous insect locates a host (Knols, 1996a). mans (e.g. Kettle, 1969; Keystone, 1996) indi- There is no general agreement about the phases cates that there is selective feeding of hemato- or stages that comprise the entire host-seeking phagous insects on certain human individuals behavior. Takken (1996) and Knols (1996a) di- (see references further below). Thus, there are in- vided the host-seeking process into four stages: dividuals that are commonly besieged by hungry 1) appetitive search, 2) activation, 3) orientation, mosquitoes, whilst other individuals are hardly and 4) landing, whereas Sutcliffe (1986, 1987) bitten by the same species. Why are certain per- considered that activation and orientation are part sons individuals more prone to mosquito bites of a single component of the process. Activation than others? or what makes an “X” person diffe- in itself is not a behavior, its importance lies in rent from a “Y” person? are two currently unans- the fact that during this stage an insect will un- wered questions. There is a vast literature on leash a cascade of responses leading to location field and laboratory experiments dealing mainly of a vertebrate host. The first stage, appetitive with mosquitoes, suggesting that human body search, is driven by internal physiological pro- odor varies from person to person and that these

248 Folia Entomol. Mex., 44(2) (2005) differences are responsible for the uneven biting is often neglected by physicians as well rates in a human population. Many vector-borne as by patients. Eccrine sweat gland function has parasitic diseases (e.g. , dengue fever, been shown to decrease with age (Inoue et al., leishmaniases and onchocerciasis, among others) 1999a). However, differences between young and are caused by the infectious bite of dipterian vec- old males were not observed in all body sites, but tors. Recently Gibson and Torr (1999) extensi- were limited to the back and thighs of older ma- vely reviewed the visual and odorous factors go- les (Inoue et al., 1999a). Decreased sweating in verning host-seeking behavior in dipterans. older men might be due to an age-related modi- Therefore, this review intends only to present the fication of the sensitivity of thermoreceptors to possible origins of variation in human odors, in a temperature and, hence, sweat production (Inoue normal versus a pathological condition, and to et al., 1999b). Sweating rate also varies during briefly summarize what is known from laboratory the menstrual cycle, females at the follicular pha- and field experiments on human odors and their se having higher sweating rates than females at influence on mosquito biting rates. Finally, the the luteal phase (Kolka and Stephenson, 1989). importance of understanding the physiological Apocrine sweat glands, on the other hand, are status of experimental insects, and the impli- subcutaneous in the armpit, the areola of the cations of different human attraction on disease breast and areas around the anus and groin. They transmission are discussed. are linked to a hair follicle and their secretion be- Human skin and gland secretions. The skin is gins to function at puberty, producing a more vis- composed of two basic layers; the outer epider- cous secretion than that of the eccrine glands. Se- mis and the inner dermis (Thibodeau and Patton, baceous glands are associated with those areas 1993). In the epidermis, up to five distinct strata where hair grows, producing an oily secretion, can be found, and are named the stratum cor- which prevents fungal invasions. Gland compo- neum, stratum lucidum, stratum granulosum, sition has been described to be rich in trigly- stratum spinosum and stratum basale. Whereas cerides, waxes, fatty acids, and cholesterol the dermis is composed of a thin papillary and (Thibodeau and Patton, 1993). Up to 400-900 thicker reticular layer. glands can be found per square centimeter in Segregated on particular areas of the human bo- hairy areas, while the rest of the body contains dy, there are three types of sweat glands: eccrine, fewer than 100 per cm2 (Wood and Bladon, apocrine and sebaceous. Eccrine sweat glands are 1985). the most numerous, except on lips, ear canals, Sources of body odors. glands penis and nail beds. Their function a) Expired volatiles in human breath. throughout human life is osmoregulation, and One of the main chemicals constantly released their secretion is basically a wateryliquid rich in by humans is carbon dioxide (CO2). Expired hu- salts, ammonia, uric acid, urea and other wastes. man breath contains approximately 4.5% CO2 Densities of eccrine sweat glands vary between a- which is approximately 100-times higher than the natomical sites, being as high as 600-700 concentration of CO2 in the atmospheric levels glands/cm2 in palms of the hands and soles of the (Gillies, 1980). Carbon dioxide emission through feet, and as low as 64 glands/cm2 on the back human skin has been estimated to be in the range -5 2 -5 (Benohanian, 2001). Sometimes eccrine glands of 1.8 x 10 ml CO2/cm /min to 4.6 x 10 ml 2 produce more sweat than required for ther- CO2/cm /min (Frame et al., 1972; Carlson et al., moregulation, a condition called hyperhidrosis 1992). This is approximately 0.3% to 1.5% of (HH) (Benohanian, 2001). Prevalence of HH in that expired from the lungs (Gillies, 1980).

249 Rebollar-Téllez: Human body odor and mosquito bites

Carbon dioxide is thought to be a mosquito pounds contained in exhaled air (Manolis, 1983), attractant (Gillies, 1980), and has been shown to including isoprene, the predominant hydrocarbon have a dose-response relationship with some exhaled in human breath which can range from mosquito species (Costantini et al., 1996) and 30 to 70% of the total hydrocarbons (Gelmont et sandflies (Pinto et al., 2001). These reports indi- al., 1981). Some compounds are used by physi- cate that proportionally more mosquitoes and cians as markers for the diagnosis of diseases sandflies were captured with increasing dosages such as diabetes, cirrhosis, and uremia as well as of carbon dioxide. Gibson et al. (1997) documen- dietary states (Manolis, 1983). Some investiga- ted that Anopheles pharoensis Theobald were tions also have attempted to characterize com- 200% more attracted to carbon dioxide-baited plex molecules such as drugs and toxic agents in traps than to human-baited traps. In contrast, human breath (Krotoszynski et al., 1977). Signi- carbon dioxide did not attract Culex quinquefas- ficant amounts of volatile chemicals also can be ciatus Say in a dual-port olfactometer (Mboera et absorbed by the body and detected in human al., 1998). Carbon dioxide was shown to be breath (Špan.l et al., 1996). attractive to Anopheles stephensi Patton, but not to Anopheles gambiae Giles even under the same b) Volatiles of the human body experimental conditions (Takken et al., 1997). In Overall body odor is mainly the result of che- addition, carbon dioxide synergizes the action of micals emanated by the skin. At least 400 com- other chemicals such as octenol (Takken and pounds have been detected by coupled gas- Kline, 1989) and lactic acid (Kline et al., 1990). chromatography/ mass spectrometry (GC/MS), of The actual role (attractant or activator) of carbon which only 135 have been properly identified dioxide seems to be variable depending on the (Sastry et al., 1980). Many of these compounds concentration released by the host and by the spe- are volatile, and represent a range of environmen- cies of mosquito. The actual reasons why carbon tal contaminants, normal and pathological meta- dioxide attracts certain mosquito species and its bolites, by-products of symbiotic mode of action remains unknown (critically re- and other processes. The main constituents of viewed by Mboera and Takken, 1997). Another human skin emanations are carboxylic acids, fact which has often been ignored is that carbon although other groups such as alcohols, aldehy- dioxide is likely perceived by mosquitoes within des, aromatic hydrocarbons, amines, esters, ha- puffs of air (Gillies, 1980) rather than as a con- lides, heterocyclics, ketones, sulfides and thiols tinuous flow often employed in laboratory expe- have been listed as normal components of skin riments. Dekker et al. (2002) showed that A. emanations (Bernier et al., 2000). It has been gambiae were more attracted to turbulent air con- known for decades (see Labows, 1979 for taining carbon dioxide than a homogeneous air references) that human body odors can be used in flow. Therefore, caution is recommended when the diagnosis of disease. Unusual odors in a di- interpreting the effect of this chemical on mos- seased individual may occur in breath, sweat and quitoes based on results from a constant flow in urine (Labows, 1979). An example of patho- laboratory assays. Along with CO2, other volatile logical production of metabolites is that referred compounds such as alkanes, aromatic hydrocar- to as “fish odor syndrome”, caused by an ab- bons, alcohols, aldehydes, ketones, amines and normal excretion of tertiary aliphatic amine (tri- sulphur compounds, also have been identified in methylamine) in breath, urine, sweat, saliva and human breath (Sastry et al., 1980). In a normal vaginal secretions. The smell of trimethylamine, subject there could be as many as 200 com- resembles that of “rotten fish”, and individuals

250 Folia Entomol. Mex., 44(2) (2005) with impaired oxidation of trimethylamine may found in higher amounts in males (Zeng et al., suffer from this condition (Rehman, 1999). 1996). Contributors of axillary odor are andros- It is well-known that certain areas of the human tenone (5a-androst-16-en-3-one), androstenol body possess a unique odor, produced partially (5a-androst-16-en-3a-ol), isovaleric acid by microbial action. For example, human scalp is (Labows, 1998), dehydroepiandrosterone (DHA) a lipid-rich area due to its high density of seba- and steroid transformations by Staphylococcus ceous glands (Sastry et al., 1980). Two microor- (Gower et al., 1997). ganisms Pityrosporum ovale and Propioni- Another source of strong body odor are human bacterium acnes are thought to produce scalp feet. Such odor is commonly referred as “cheesy” odor. The former species transform long-chain and could be related to hyperhidrosis of the feet fatty acids into more volatile chemicals, while the (Tachibana, 1976). Gender differences in foot- latter species hydrolyzes triglycerides into their wear are an intrinsic determinant of foot micro- individual fatty-acids (Sastry et al., 1980). A cor- enviroment, with male footwear more enclosed relation between the distribution of propioniba- than that which is worn by females (Marples, cteria on human skin and the production of free- 1982). Repulsively smelling volatiles are produ- fatty acids has been reported (Kearney et al., ced as a result of bacterial action, although the 1984). An overpowering (at least for humans) identity of the causative organisms is yet under- source of volatile body odors is the armpit termined. It has been reported that persons har- (axillae) region. The unmistakable human axi- bouring high bacterial populations on their feet llary odor is a combination of secretions from are more predisposed to develop foot odor syn- eccrine, apocrine and sebaceous glands together drome, than those individuals with low bacterial with the local microflora (Sastry et al., 1980 and populations (Marshall et al., 1988). Rennie et al., 1990). It is presumed that freshly Some of the previously described pathological isolated secretions of apocrine glands in the arm- conditions or bacteria-originated odors in the hu- pits is odorless (Gower et al., 1985). Studies man body, may be extreme states, but they illus- have shown that the axillary odor is absent if trate how individuals may possess a unique body gram-positive bacteria are eliminated from the odor composition due to these processes. Most skin (Marples, 1969). Not all species of skin bac- papers dealing with human attractants have so far teria have the ability to produce the axillary odor, overlooked the fact that humans living in en- and it seems to be confined to the aerobic coryne- demic areas may have a different body odor pro- form bacterium xerosis (Rennie file due to malnutrition, bad hygienic habits, et al., 1990). Normally cholesterol, dehydro- and/or infection by parasites. The association bet- epiandrosterone sulphate and androstenone sul- ween these conditions and mosquito attraction phate are present in apocrine secretions, which and biting rates, is unknown and deserves future are odorless (Labows et al., 1979). However, if attention. apocrine secretion is incubated with coryneform Variation in human odours and their bacteria, then the axillary odor is re-established attractiveness to mosquitoes. Humans, like (Gower et al., 1985). Currently, it has been other mammals may possess individual differen- suggested that axillary odor is due to C61 – C 1ces in odors and these odors may convey infor- branched and unsaturated acids, predominantly mation on individual identity, sex, age, and moti- (E)-3-methyl-2-hexenoic acid (3M2H) (Zeng et vational state (Halpin, 1986). Whether or not al., 1991, 1992). These major constituents are these individual odors have evolved from selec- present both in males and females, but they are tive pressures or are by-products of other meta-

251 Rebollar-Téllez: Human body odor and mosquito bites bolic processes, it may be possible that these years old only slight differences of attractiveness differences in odor composition have been ex- to A. aegypti were found (Maibach et al., 1966b). ploited by hematophagous insects. There is over- Finally, Clyde and Shute (1958) found no evi- whelming evidence that individuals possess di- dence for selective feeding of anopheline mos- fferent degrees of attractiveness to mosquitoes quitoes on different age groups. Some authors, and other blood-sucking insects. The word but with equivocal results also have explored the “attractiveness” by itself may not be adequate to influence of the female menstrual cycle upon describe individual differences on human sub- mosquito attraction. Roessler (1963) tested a jects (B. G. J. Knols, personal communication), group of human females at different stages of the but for convenience it is used herein in its broad- menstrual cycle, and found their attraction was est definition. Human sweat was first suspected greatest 18 days after menses. On the other hand, of being attractive to mosquitoes by Howlett Gilbert et al. (1966) found that women tested 1 to (1910) and Rudolfs (1922), although they found 4 days before bleeding were the most attractive to little evidence to support their hypotheses. Mer et A. aegypti. Pregnant women have been reported al. (1947) were convinced that odors emanating to attract twice as many A. gambiae in experi- from the human body were attractive to Anophe- mental bednets and were observed to exhale 21% les but they provided little evidence to support more than non-pregnant women (Lindsay et al., their statement. Later studies (Brown et al., 1951; 2000). Thompson and Brown, 1955; Maibach et al., Despite existing evidence, consistent differen- 1966a; Skinner et al., 1965a; 1968; Khan et al., ces in human attraction to mosquitoes is still con- 1969; Price et al., 1979; Schreck et al, 1981, troversial. A more generalistic picture from these 1992; Eiras and Jepson, 1991; Braks et al., 1997, studies is difficult due to differences in, for 1999b; Rebollar-Téllez et al., 1999), obtained example, mosquito species, age of mosquitoes, better results, using hand-odors or sweat samples. experimental design, and evaluation techniques. Laboratory studies have shown that Aedes Contrasting findings can be obtained even under aegypti (L.) is preferentially attracted to certain the same laboratory conditions when using gene- individuals more than others (Ribbands, 1949; ralist feeders such as A. aegypti or a very host- Brouwer, 1960 and Khan et al., 1965). specific species like A. gambiae s.s. Some mos- Furthermore, Rahm (1958) reported men to be quito species have very specific sites for landing more attractive than women to A. aegypti mos- and biting on the human body (Knols, 1996b). quitoes. Differences in human attractiveness have For instance, A. gambiae bites preferentially on been also related to ethnic groups. For example, feet and ankles (De Jong and Knols, 1995a), and Brown (1958) reported that Afroamericans were yet some studies have measured the responses of more attractive to A. aegypti mosquitoes than this species to human sweat isolated from the Caucasians or Asians. Age-related differences in forehead of Caucasian volunteers (Braks et al., human attractiveness, however are equivocal. For 2001). Experimental data may contain substantial instance, adults were reported to be more attrac- error if human sweat is not collected from the tive than children to Anopheles albimanus right places for certain mosquito species. Wiedemann (Muirhead-Thomson, 1951), and A. Field experiments have provided further evi- gambiae (Boreham et al., 1978; Port et al., dence that body odor is the primary factor invol- 1980). In contrast, Smith (1956) reported of chil- ved in mosquito attraction and discrimination. dren to be more attractive than adults to A. gam- Using experimental huts Lindsay et al. (1993) biae. In a group of adults ranging from 20 to 90 obtained a similar finding when studying A. gam-

252 Folia Entomol. Mex., 44(2) (2005) biae, Anopheles funestus Giles and Culex quin- chemical candidates is by not an easy task. Since quefasciatus Say. Similarly, it has been docu- the early reports by Howlett (1910) and Rudolfs mented that inter-individual human attractiveness (1922) that human sweat might be attractive to to the blackflies Simulium venustrum Say and Si- mosquitoes, our understanding of human attrac- mulium truncatum Lundstroem were maintained tants has been substantially advanced. Yet, the even after clothing, activity level and type of specific compounds contained in sweat from soap had been controlled among hosts (Schofield attractive subjects still remains a mystery. Acree and Sutcliffe, 1996). Brady et al. (1997) reported et al. (1968) isolated, tested and proved that L- that body odors was an essential factor behind lactic acid (hereafter referred only as lactic acid) differences between subjects in attractiveness to was attractive to A. aegypti. Others have ques- A. gambiae. Further evidence of the attractive- tioned the role of lactic acid as a mosquito attrac- ness of human odor to mosquitoes is provided tant (e.g. Eiras and Jepson, 1991, 1994). Skinner from the experiments of Knols et al. (1995), et al. (1965b) reported that lactic acid was a re- Mboera et al. (1997) and Costantini et al. (1996, pellent to A. aegypti. Smith et al. (1970) suggest- 1998). These works have relied on the use of ed that lactic acid could repell or attract depend- odor-baited entry traps (OBETS) (Costantini et ing upon the conditions. Regardless, these early al., 1993, 1996, 1998; Gibson, et al., 1997), or reports failed to convincingly describe what such baited traps (Knols et al., 1995; Mboera et al., conditions might be. Acree et al. (1968) and 1997), which consist of experimental huts baited Smith et al. (1970) mentioned that the effective- with human odors. The humans acting as bait are ness of lactic acid as mosquito attractant was either isolated inside the tent or in an under- enhanced by the addition of carbon dioxide. This ground pit dug beneath the tent. In this way, only synergistic effect was not observed by Stryker odors emanating from the body are presented as and Young (1970) or Canyon and Hii (1997) un- a stimulus to mosquitoes. Results from these stu- der field conditions. These studies have led to the dies convincingly show that human individuals conclusion that lactic acid is only a mild attrac- vary in body odor and that this essence is attrac- tant, (at least for A. aegypti) and that its effec- tive to mosquitoes. However, it has not yet been tiveness is due to the combined presence of car- shown that individuals attracting the most mos- bon dioxide. Field evidence with Ochleretatus quitoes were the ones bitten the most. taeniorhynchus (Wiedemann) showed an additive The quest for mosquito attractants. Currently effect of carbon dioxide and lactic acid (Kline et there is very little doubt that human attractiveness al., 1990). Braks et al. (2001) reported that after to mosquitoes is due to the overall body odour. the removal of lactic acid from sweat samples, Some authors like Hocking (1971) have stressed the samples were still attractive to A. gambiae. that: “Every imaginable part of the human body Healy and Copland (2000) also found no eviden- and its products must by now have been frac- ce to suggest that lactic acid is attractive to A. tionated in every possible way in the search for gambiae. Dekker et al. (2001a) reported that lac- a specific chemical attractant...While certain tic acid alone was not attractive to 5-14-day old attractive materials have been found...nothing mosquitoes in a Y-tube olfactometer. Its effect, proves to be as attractive as the intact man. This however was slightly enhanced when with carbon seems to suggest that blood-sucking arthropods dioxide was added. Interestingly, the amounts of recognize man for what he is, by his complex of lactic acid measured by Dekker et al. (2002) of effluvia and not by any specific indicator” (quo- skin rubbings from several vertebrates showed tation marks by Edman, 1989). Identification of that humans had the highest titre. Cow-skin

253 Rebollar-Téllez: Human body odor and mosquito bites rubbings were less attractive to A. gambiae s.s. soondar, 1994). Hand-washings using n-pentane than human-skin rubbings, but the differences also have been shown to be attractive to female were eliminated when 1.7 mmol/L lactic acid was L. longipalpis (Rebollar-Téllez et al., 1999; added to the cow-skin rubbings. In a similar se- Rebollar-Téllez, 2000). Human sweat samples ries of experiments, Steib et al. (2001) also from Burkina Faso were collected by Cork and showed that the addition of lactic acid (3.1 Park (1996) who analyzed them chemically and mg/min) to skin emanations of several domestic measured the electrophysiological responses to animals enhanced the attraction of female A. them in A. gambiae. These authors fractionated aegypti. Further, the response of A. aegypti to sweat samples into acid and non-acid com- unattractive human subjects could be reversed ponents. Analyses of dichloromethane extracts with the addition of lactic acid. At present, it is revealed 21 carboxylic acids eluted using gas- unclear why A. gambiae are not attracted to lactic chromatography/mass-spectometry (GC/MS), of acid alone, but are equally attracted to human- which only aliphatic carboxylic acids in the range skin rubbings or cow-skin rubbings with added of C18 to C carbon-chain length elicited greater lactic acid. Could this suggest that anthropophilic electroantennograph (EAG) recordings. Braks et A. gambiae recognize humans because of the al. (1999b) evaluated the attraction of C. quin- high levels of lactic acid present in human skin? quefasciatus to sweat samples taken from diffe- or that anthropophilic A. gambiae could poten- rent parts of the body. Some samples were more tially be diverted to bite cattle or other domestic attractive than the controls (ethanol), but the animals instead of humans by masking the freeze-dried concentrate was not as effective after amount of lactic acid released through human its reconstitution with ethanol. Sweat samples skin? It has been suggested that A. gambiae from human volunteers in Burkina Faso were possess innate preference for human-originated tested for A. gambiae responses in an olfactome- odours as shown in a dual-port olfactometer stu- ter (Braks et al., 1997). Unaltered (normal) sweat dies (Dekker et al., 2001b). This evidence may samples were tested and later either acidified or suggest that anthropophily habit in A. gambiae is alkalinized, with the result that the alkalinized genetically-programmed. samples were as effective as the normal samples An important discovery on mosquito attractants in eliciting mosquito responses. was reported by Schreck et al., (1981) who to Human skin wash extracts were obtained by isolated an unidentified material from human Geier et al. (1996) using ethanol-soaked hands. This extract was obtained by rinsing pre- pads. These authors found that one extract viously handled glass beads with organic GEM008, attracted A. aegypti in a Y-tube olfac- solvents. The attractant material could be collec- tometer. GEM008 attractiveness also was en- ted and transferred onto clean glass beads and hanced when lactic acid was added, but when lac- still lure A. aegypti. Schreck et al. (1992) under- tic acid was tested alone for attraction to A. aegy- took a similar experiment to evaluate if odors re- pti, its effectiveness was only slight. GEM008 al- moved from different body sites were equally so proved to be as attractive to A. aegypti as hu- attractive to A. aegypti. They found that odors man hands. Unlike the hand-extracts obtained by collected from the head and hands were signi- Schreck et al. (1981, 1992), Eiras and Jepson ficantly more attractive than odors collected from (1994), Rebollar-Téllez et al. (1999), and Braks the trunk, arms, and legs. Hand odors have pro- et al. (1999b), no loss of biological activity was ven to be attractive to the sandfly Lutzomyia lon- seen in the extracts obtained by Geier et al. gipalpis (Lutz and Neiva) (Hamilton and Ram- (1996). Unfortunately, Geier et al. (1996) did not

254 Folia Entomol. Mex., 44(2) (2005) reveal the composition and/or polarity of the sol- pothesized that there was a connection between vents used to fractionate the ethanol-collected foot odor and . The similarity sweat samples. Skin extracts obtained with between these odor sources lies in the fact that ethanol were reported to be equally attractive to during the ripening of Limburger cheese, bacteria A. aegypti when compared with a human hand in such as are used. A Y-tube olfactometer (Geier and Boeckh, 1999). closely-related species, Brevibacterium epidermi- Healy et al. (2002) reported that A. gambiae dis, forms part of the microflora of human feet. were attracted to and landed on glass cylinders Analysis by gas-chromatography has shown that heated to 34/C and treated with aqueous solu- foot odors and those of ripe Limburger cheese tions of C38 to C oxo-carboxylic acids. More are similar in composition, with a predominance landings were seen with 2-oxopentanoic acid of carboxylic acids (Knols, 1996b). It was hypo-

(mw= 116). Human sweat is known to contain 2- thesized that malaria mosquitoes, A. gambiae re- oxopropanoic acid, 2-oxo-3-methylbutanoic acid, cognizes their favorite hosts (Homo sapiens) by 2-oxo-3-methylpentanoic and 2-oxo-4-methyl- odors emanating from the feet (Knols, 1996b). pentanoic acids, which elicit behavioral activity Limburger cheese extracts are attractive to A. in A. gambiae. gambiae as revealed by wind-tunnel trials and Microbiota and the production of body electrophysiological responses (Knols et al., odors. The very first insight that mosquitoes 1997). For A. aegypti, Limburger cheese was not might be attracted to chemicals produced by mi- as effective as a human hand or human-worn croorganisms inhabiting human skin was first in- in a dual-port olfactometer (Kline, 1998). vestigated by Schreck and James (1968), who no- Knols and Meijerink (1997) have hypothesized ticed that freshly-washed hands were less attrac- that the strain of bacteria used to mature Lim- tive than hands that had not been washed for burger cheese might have arisen from a human some time. Collection of bacteria from those un- origin; hence, it might be better said that “cheese washed hands yielded an isolate of Bacillus ce- smell like feet” rather than the opposite (quo- reus. In a dual-port olfactometer the responses of tation marks by Knols and Meijerink, 1997). This A. aegypti to volatiles from broth cultures of B. view may be supported by reports stating that cereus and a sterilized culture medium were com- strains of B. linens used in dairy activities are si- pared. The broth culture containing live B. cereus milar to those isolated from human skin (Sharpe was substantially more attractive than the sterili- et al., 1977). B. linens is known to be the major zed culture medium. The bacterial origin of component of the microflora of ripened attractive human odors has been confirmed by De such as Limburger, Roquefort, and Stilton, and Jong and Knols (1995a,b), who showed that that the flavor is attributable to the production of biting behavior of A. gambiae on a naked mo- methanethiol by the bacterium (Ferchichi et al., tionless human volunteer occurred mostly on the 1985). ankles and feet. If the, feet were washed with a Evidence for a microbial origin of human body bactericidal soap, then biting was diverted to odor has been strengthened by the work of Braks other body sites. and Takken (1999) who demonstrated that A. A remarkable story on the connection between gambiae were significantly more attractive to in- foot odor, malaria mosquitoes and Limburger cubated sweat samples than freshly-collected cheese was documented by Bart G. Knols (then sweat samples. This finding also has been con- at the Wageningen Agricultural University, The firmed by Meijerink et al. (2000) in bioassays ). Knols and De Jong (1996) hy- conducted in a dual-port olfactometer with An.

255 Rebollar-Téllez: Human body odor and mosquito bites gambiae. Braks et al. (2001) postulated that incu- abdomen is distended and eventually will dis- bated sweat samples are attractive to An. gam- appear as the blood is digested (Klowden, 1983). biae because ammonia is present. Braks et al. Inhibition of the blood-seeking behavior can also (1999a) discusses the fact that humans, unlike have a humoral basis. A mechanism called other apes, have significantly higher levels of tri- oöcyte-induced inhibition is initiated after a glycerides, which are subsequently broken down bloodmeal (> 48 h) and during this time the sen- into a plethora of short- and long-chain free fatty sitiveness of lactic acid-excited neurons to lactic acids by skin bacteria. This may be one of the acid in non-hostseeking females is approximately reasons why different persons have a unique 10-fold lower than that in host-seeking females odors. before a bloodmeal (Davis, 1984). The change in Vector responsiveness to chemical stimuli. sensitivity of lactic acid-excited neurons seems to Much of what has been described about human be associated with an inhibitor factor released by attractants to some extent focuses on ideal condi- the fat body (Klowden et al., 1987). The fat body tions for insect responses to certain stimuli. releases the inhibitor factor, triggered perhaps by There also are “unresponsive” periods in the a- one or more factors liberated by the ovaries 8-10 dult life of hematophagous insects. For instance, h post-feeding (Klowden, 1994). Neither the ova- newly emerged females in a number of blood- rian factor nor the fat body factor have yet been sucking insects do not engage actively in host- identified (Klowden, 1990). Research has shown seeking behavior due to several physiological and that during host inhibition behavior there is an in- internal limitations. Regulation of host-seeking crement in the head peptide Aea-HP-I, and that behavior includes maturation of host odor-sensi- injections of synthetic Aea-HP-I to non-oögenic tive receptors (Davis, 1996). In A. aegypti, for donor females (actively searching for a host) pro- example, lactic acid (LA)-sensitive neurons be- duced inhibition in host-seeking behavior (Brown come sensitive 96 h post-emergence (Davis, et al., 1994). Inhibition of host-seeking behavior 1984). Flight activity in certain mosquito species seems far to be terminated by unidentified ner- has been shown to be related to circadian rhy- vous signals associated with oviposition thms. Blood-seeking behavior of (Klowden, 1994). crepuscular/nocturnal species such as A. gam- Thus it is extremely important to be aware of biae, O. taeniorhynchus and C. quinquefasciatus the age and physiological status of experimental is thought to be related to an after-dusk oscillator mosquitoes as well as of the timing in which the (Jones and Gubbins, 1978; Nayar and Saverman, study should be conducted. Results obtained un- 1971; Jones, 1982). In contrast, flight activity der other conditions may lead to erroneous con- and hence blood-seeking behavior in diurnal A. clusions while searching for new mosquito attrac- aegypti seems to be related to an endogenous tants in human effluvia. rhythm promoted by light (Taylor and Jones, Epidemiological aspects of human attracti- 1969; Jones, 1981). Down-regulation of blood- veness and disease transmission. Vector-borne seeking behavior can also be due to abdominal parasites causing of human diseases have been distension in blood-fed females. Gwadz (1969) studied epidemiologically since the turn of the has shown that bloodmeal size is controlled by 20th century. MacDonald (1952) and Garrett- abdominal stretch receptors. In A. aegypti, it has Jones (1964) first advanced the concept of vecto- been shown that host-seeking inhibition occurrs rial capacity, which is defined as “The daily rate above a certain threshold of ingested blood. This at which future inoculations arise from a curr- inhibition however, will last only as long as the ently infective case” Transmission of parasites

256 Folia Entomol. Mex., 44(2) (2005) within a susceptible host population is known as the quality of all available hosts, and ii) travel

the basic reproduction rate R0 (also referred as between hosts has no real costs to the vectors. the basic reproduction number). R0 can have two The value of R0 in the IFD model would be signi- possible outcomes: when R0 < 1, the number of ficantly different than that obtained with Garrett- new cases will eventually decline to zero. Con- Jones’ (1964) model; IFD is characterized by the

versely, if R0 > 1, then new cases will persist non-linearity of the effect of changing vector and within the host population producing outbreaks host densities (Kelly, 2001). (Woolhouse et al., 1997). The vectorial capacity The real epidemiological significance of a dis- mathematical model has several entomological tinct human attractiveness in endemic areas is components, including the biting rate on humans, that the actual outcome of disease (basic repro- which is the product of the number of vectors per duction rate) would be substantially different host (m) and the number of times the vector bites than expected in a situation where all persons are the host per day (a). Human-biting rate provides equally attractive. Practical consequences are that an estimated number of bites that a human indivi- costs involved in treatment of ill persons and dual would be exposed to during any given night. control of a vector population also might be nota- One of the flaws of the vectorial capacity model bly increased. Risk assessments in endemic areas is that it assumes that all persons would be bitten ought to consider “human attractiveness” as a with equal frequency by vectors. As seen from la- factor. This idea is not new and has been sugges- boratory and field studies, there is growing evi- ted in alternative mathematical models (e.g. Dye dence that different subjects may be bitten by and Hasibeder, 1986; Kingsolver, 1987; Burkot, blood-sucking insects more than others. Dye and 1988; Woolhouse et al, 1997) and more recently Hasibeder (1986) pointed out that vectors and by Kelly and Thompson (2000), and Kelly host are not homogeneously mixed in areas of (2001). According to the IFD model, its advan- transmission, resulting in a non-haphazard situa- tage over the other models is that it could incor- tion between vectors and hosts. Therefore, under porate measurable ecological data such as chan- this scenario certain individuals would be at ges in vector and host densities (Kelly, 2001). higher risk of being bitten by parasite-infected For most vector-borne diseases, the primary fac- mosquitoes and thereby acquiring the disease. tor influencing transmission is exposure to bites The prediction of vectorial capacity model is that of infected vectors. Thus, individual differences by increasing the human biting rate, the basic re- in attractiveness should be taken into account by production rate of disease will also rise (Garrett- vector control programs. Jones, 1964). A model for the basic reproduction number has been proposed based on the Ideal CONCLUDING REMARKS Free Distribution (IFD) (Kelly and Thompson, What makes an individual more attractive (or 2000; Kelly, 2001). This model assumes that less repellent?) to mosquito bites remains defini- feeding success of hematophagous vectors de- tively unanswered. Despite evidence of differen- pends almost entirely on the defensive behavior ces in attractiveness among people, little work of vertebrate hosts. In other words, the more de- has been undertaken to unravel why certain indi- fensive the host, the more likely it is that a feed- viduals are more attractive than others. It has ing insect will be interrupted before a full blood- been suggested that feeding behavior of hemato- meal had been taken (Kelly, 2001). Two funda- phagous insects is intrinsically linked to a host’s mental assumptions are the cornerstone of the defensiveness (Kelly, 2001). Under this scenario, IFD model; i) vectors possess a “knowledge” of vectors would feed preferentially on less defen-

257 Rebollar-Téllez: Human body odor and mosquito bites sive hosts, promoting natural selection for vec- tected with modern instrumental capabilities. tors to respond to cues associated with less de- The afore-mentioned problems are likely what fensive hosts (Kelly, 2001). Although the final has prevented many researchers from unraveling outcome of biting rate among humans by vectors chemical profiles of attractive and non-attractive would be explained in terms of the relative attrac- individuals. Testing every single chemical in hu- tiveness and defensiveness of the host (Kelly and man effluvia for mosquito responses will undoub- Thompson, 2000, and Kelly, 2001). On the other tedly be an overwhelming project. An interesting hand, Knols and Meijerink (1997) have proposed recent development in research on mosquito that some persons emanate significantly higher attractants is linkage of coupled GC/MS to elec- amounts of attractive chemicals either as normal troantennographs (EAG) or single-cell recordings skin products or as by-products of microbial (SCR) of mosquito antennae. This strategy identi- decomposition. The balance between attrac- fies those chemicals producing electrical respon- tion/repulsion to mosquitoes may be due to the ses (measured as action potential spikes) in mos- equilibrium of naturally occurring skin chemicals quito neurons (Cork and Park, 1996). Candidate (Skinner et al., 1965b, 1968; Costantini et al., compounds then could be evaluated for beha- 1998). Skinner et al. (1965b) found certain frac- vioral responses using the extracts and synthetic tions of skin lipids to repell A. aegypti. Further chemicals. Single-cell recordings in hematopha- analysis of those lipids yielded three different gous insects is a state-of-the-art technique to fractions; one was identified as lactic acid while identify new attractive molecules and it is expec- the other two could not be identified (Skinner et ted that major breakthroughs will come up in the al., 1965a). The presence or absence of these near future to shed new light on this area. Elec- chemicals may partially explain why some indi- trophysiological responses of olfactory cells in viduals are more or less attractive to mosquitoes. several Anopheles mosquitoes and zoophilic spe- The final response of blood-sucking insects to cies (e.g. A. quadriannulatus Theobald) have humans might be results of a “push-pull system” provided outstanding findings (Van den Broek of attractive and repellent components (Cos- and den Otter, 1999; Meijerink and Van Loon, tantini et al., 1998). The push-pull model has 1999; Meijerink et al., 2000, 2001, Qiu et al., been strengthened by recent evidence suggesting 2004). Anopheles may have unique peripheral that some long-range chemicals may inhibit the receptors “tuned” to certain stimuli of different upwind flight of A. gambiae mosquitoes (Cos- hosts. This would agree with Dekker et al. tantini et al., 2001). Whether this inhibition oc- (2001a) regarding the innate preferences of ano- curs in other mosquito species remains unknown. pheline mosquitoes. In comparison, little research It also is unclear how this inhibitory chemical(s) has been conducted on sandflies, blackflies and relates to the levels of lactic acid reported by biting midges (other than host odors and phero- Dekker et al. (2002). mones) (Gibson and Torr, 1999). Confirmation or rejection of the push-pull An exciting new avenue of research dealing theory is complicated by the staggering number with mosquito olfaction and chemical attractants, of compounds emanating from the human body. is based on the genes encoding odor-binding pro- Sastry et al. (1980) highlighted the difficulties in- teins (OBPs), which are thought to be highly spe- volved in the study of human odors. First, not all cific to the olfactory receptor cells (ORCs) (re- chemicals produced by the human body are vola- viewed by Hildebrand and Shepherd, 1997). This tile, and this limits use of the GC/MS technique. approach focuses on identifying attractant odor Second, not all chemicals can be isolated and de- molecules based on the specific genes linked to

258 Folia Entomol. Mex., 44(2) (2005) these molecules. Once the specificity of OBPs nally, entomological and epidemiological studies and their ligands are established, it would be po- ought to consider individual differences in attrac- ssible to manipulate the vector genome to create tiveness when assessing risk of transmission of a “non-responsive” mosquito line to human odors tropical parasite-caused diseases. Even if this and thereby reduce biting rates in endemic areas. “attractiveness” factor is not incorporated into Molecular studies in other insect groups have mathematical models, it should be considered shown that OBPs may be involved in selecting, when interpreting on the frequency of mosquito transporting and presenting odors to specific ol- landings on humans in a given population center. factory receptors and thereby conferring spe- cificity to insect pheromones (Field et al., 2000). ACKNOWLEDGEMENTS Five candidate odor receptor genes have been The conducted experiments on human odours identified in A. gambiae: AgOr1, AgOr2, AgOr3, and sandfly responses during a PhD program AgOr4 and AgOr5 (Fox et al., 2001, 2002). In supported by the National Council of Science and addition molecular studies of head and antenna Technology (Conacyt, Mexico) at the University palp extracts of A. gambiae have revealed three of Keele, UK. My special gratitude is extended to peptides that may be important in olfactory pro- Dr. Laurence J. Zwiebel (Vanderbilt University, cesses (Ricci et al., 2002). However, this area of USA) for reading an early draft of this paper, and research is still young and has been limited to A. for his multiple observations on basic things I gambiae. had overlooked. Thanks also to Dr. Bart G. J. The ultimate goal of identifying human mosqui- Knols (ICIPE, Kenya) for reading and to attractants is to develop odor-based control commenting on particular points included herein. strategies of disease transmission. The design of Thanks also to Dr. David W. Kelly (Oxford a “synthetic human fragrance” will face one com- University, UK) for clarifying some points on the plication; different mosquito species may have Ideal Free Distribution. The final manuscript was different thresholds of response to different che- kindly edited by Dr. Hugo Delfín-González micals. For example, Knols et al. (1995) (in: (University of Yucatán, México) and by one Takken and Knols, 1999) described one person anonymous reviewer. in was found to be significantly more attractive to A. funestus than other subjects, yet REFERENCES the same person was the least attractive to A. ACREE, F., R. B. TURNER, H. K. GOUCK, M. BEROZA AND N. squamosus Theobald. Nonetheless, effort in- SMITH. 1968. L-lactic acid: A mosquito attractant isolated from humans. Science, 161: 1346-1347. vested to develop odor-baited traps using syn- BALASHOV, Y. S. 1984. Interaction between blood-sucking thetic human odors will be useful. These efforts arthropods and their hosts, and its influence on vector will provide insight on how mosquitoes dis- potential. Annual Review of Entomology, 24: 137-156. criminate between individuals and will contribute BENOHANIAN, A. 2001. Antiperspirants and Deodorants. Clinics in Dermatology, 19: 398-405. to the discovery of new blends of attractive BERNIER, U. R., D. L. KLINE, D. R. BARNARD, C. E. SCHRECK and/or repellent chemicals. Evidence reported by AND R. A. YOST. 2000. Analysis of human skin emanations Costantini et al. (2001) suggests than some indi- by gas chromatography/mass spectrometry. 2. Identification viduals may actually be repellent to certain mos- of volatile compounds that are candidate attractants for the yellow fever mosquito (Aedes aegypti). Analytical quito species. How these odors evolved in hu- Chemistry, 72: 747-756. mans and how the same odors influence the bi- BOREHAM, P. F. L, J. A. CHANDLER AND J. JOLLY. 1978. The ting behavior of other hematophagous insects are incidence of mosquitoes feeding on mothers and babies at Kisumu, Kenya. Journal of Tropical Medicine and Hygiene, two questions that deserve future attention. Fi-

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