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Sex is a relevant infectious disease risk-factor, as males and females can have different probabilities of acquiring an infection and expressing clinical signs or symptoms of a disease (Roberts et al. 2001). In South America, cutaneous leishmaniasis (CL) is a zoonotic disease transmitted by sandflies (Phlebotominae), with a wide spectrum of clinical manifestations; the most typical are ulcerative skin lesions developed near or at the vector's bite site (Reithinger et al. 2007). Most epidemiological studies show that clinical CL is more frequent among men than women (e.g., Armijos et al. 1997; Davies et al. 2000; Wasserberg et al. 2002; Calvopiña & Hashiguchi 2004; Guerra et al. 2006; Guerra-Silveira & Abad-Franch 2013), and there is experimental evidence suggesting differential vulnerability of males and females to Leishmania spp. infection among laboratory animals (Travi 2002; Snider et al. 2009; Klein & Roberts 2010). In the present study, we investigated sex-biased vulnerability to clinical CL in human populations with differential patterns of gender-related exposure to vector habitats.
In central Amazonia and other humid-forest regions of Latin America in which CL is endemic, exposure to Leishmania vectors depends upon contact with forested habitats that maintain sandfly populations. Men are usually more exposed than women because they engage more often in forest-related activities such as hunting, logging or military training (Lainson 1988; Davies et al. 2000; Guerra et al. 2003). Additionally, androgens can partially suppress the immune response in males (Snider et al. 2009; Klein & Roberts 2010), and human population data show that infectious disease incidence (Guerra-Silveira & Abad-Franch 2013) as well as parasite-induced mortality (Owens 2002) is higher among men than women. Thus, there is evidence supporting both differential exposure and hormone-mediation as explanations for the higher incidence of parasitic infections in men than in women.
The relative importance of differential exposure and sex-related physiological factors in shaping CL incidence in human populations remains obscure. Here, we asked whether CL incidence is sex-biased even in the absence of differential exposure. We addressed this question by comparing clinical CL incidence in two populations, one with and one without gender-related differential exposure. Both populations occupied similar upland forest sites where Lutzomyia umbratilis is the principal CL vector (Killick-Kendrick 1990), and the vast majority of CL cases is caused by Leishmania (Viannia) guyanensis (Lainson et al. 1994). Our analyses tested the null hypothesis that, for both populations, male–female differences in incidence are solely due to differences in exposure.
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Our results added new information to previous clinical-epidemiological evidence of sex-biased CL incidence, with typically higher case frequency among males than among females (Weigle et al. 1993; Davies et al. 2000; Wasserberg et al. 2002; Calvopiña & Hashiguchi 2004; Guerra-Silveira & Abad-Franch 2013). After comparing two populations that differ in gender-related exposure, we suggested that incidence is male-biased in both, not just because the researchers showed a measurable, albeit relatively weak, effect of sex on incidence, but also because there was a strong interaction between sex and exposure time in this population. Therefore, both gender-related differential exposure and sex-related physiological factors likely contributed to male–female differences in the risk of clinical CL caused by Le. (V.) guyanensis.
The interpretation of our epidemiological data required consideration of two main issues. First, infection with Leishmania parasites does not always result in clinical CL symptoms; and second, geographic variation in the sandfly fauna could lead to differences in disease transmission between sites. As some Leishmania infections are asymptomatic, exposure to the parasites was likely higher than we perceived. Serological tests could provide a more precise assessment of exposure; however, we felt justified in using epidemiological information for two main reasons: 1) serology tests sometimes detect antibodies to Leishmania sp. in only 85% of patients clinically diagnosed with Le. (V.) guyanensis (Romero et al. 2005), and 2) serology tests can fail to detect an existing bias in clinical CL because they may respond to exposure to parasites even in the absence of clinical manifestation of the disease (Coimbra et al.1996; Guerra-Silveira & Abad-Franch 2013). We were particularly interested in male–female differences in the incidence of clinically evident CL, with cases defined by disease signs and/or symptoms.
As for geographic variation in vector fauna, the sandfly fauna of the BDFFP is likely to resemble that of Rio Pardo. Both sites are only about 75 km from each other and lie within the same eco-region – the Uatumã-Trombetas moist forests. Entomological surveys in Rio Pardo (W. Ramos, J.F. Medeiros, G.R. Julião, C.M. Rios - Velásquez, E.F. Marialva, S.J.M Desmouliere, S.L.B. Luz, F.A.C. Pessoa, unpublished data) showed that sandfly species composition was similar to what has typically been reported from the central Amazon region (Alencar 2007; Barbosa et al. 2008), particularly as regards the presence of the main local CL vector, Lu. umbratilis (W. Ramos, J.F. Medeiros, G.R. Julião, C.M. Rios - Velásquez, E.F. Marialva, S.J.M Desmouliere, S.L.B. Luz, F.A.C. Pessoa, unpublished data). Further research is needed to describe the sandfly fauna of BDFFP sites, but we had no reason to think that a local peculiarity would lead to a false impression of sex-biased incidence among researchers.
Our modelling results provided support for a combined effect of sex and exposure time as CL risk factors: first, the average odds of reporting CL were more than two times higher for males than for females in both populations (Table 1), and, second, our models estimated a relatively strong, negative effect of the interaction between male sex and time of exposure to sand fly habitats (Table 3). Sex-related differences in the clinical manifestations of Leishmania spp. infections can be at least partially explained by endocrine–immune interactions (Roberts et al. 2001; Snider et al. 2009; Klein & Roberts 2010). Protective immunity against parasites of the genus Leishmania critically depends on effective T helper (Th)1-type cellular responses (Alexander et al. 1999; Roberts et al. 2001; Alexander & Bryson 2005). As oestrogen upregulates Th1-type responses, females can potentially mount more efficient immunity against these parasites (Snider et al. 2009). Male hamsters experimentally infected with Le. (V.) guyanensis presented increased occurrence and severity of cutaneous lesions, supporting the role of sex hormones in immune modulation (Travi 2002).
Based on evidence implying an enhanced protective immune response in female hosts, we suggested that sex and vector exposure determined the higher risk of clinical development of CL among men. Our BDFFP results suggested that, at low levels of exposure, endocrine–immune interactions resulted in more effective responses in women; yet, this extra protection tended to wane under long-lasting exposure, perhaps because repeated infection events overwhelm cellular immunity. This would explain why male BDFFP researchers had higher probability of reporting CL than their female counterparts particularly at short exposure. On the other hand, the stronger male bias among settlers was likely the result of male-biased exposure and, to a lesser extent, higher overall male susceptibility.
Another important finding of our study was that according to the odds ratio obtained from our model parameters, Rio Pardo settlers were about 11 times less likely to report CL as BDFFP researchers (odds ratio = 0.09; see Table 2). Most settlers had a long history of exposure to sandfly bites, whereas most researchers were probably first bitten by sandflies during fieldwork. It has been shown experimentally that mice treated with proteins found in vector saliva were less vulnerable to Leishmania (Viannia) braziliensis infection, suggesting a protective effect of sandfly bites (Oliveira et al. 2008). Prior exposure of mice to bites of uninfected Phlebotomus papatasi, an Old World CL vector, resulted in some degree of immunity against Leishmania major (Kamhawi et al. 2000). However, the immune response induced by sandfly saliva can lead to either infection aggravation or resistance, depending on the parasite species and on the salivary proteins to which the hosts are exposed (Gomes et al. 2008; Oliveira et al. 2008; Collin et al. 2009). Whatever the precise mechanism, there is evidence that previously non-exposed human populations in Amazonia had a higher probability of developing CL than long-term residents of endemic areas (Lainson & Rangel 2005). Additionally, researchers may be more intensely exposed to sandfly habitats than rural settlers because of the contrasting dwelling conditions in the BDFFP sites vs. the settlement area. BDFPP researchers slept in open-walled premises immediately adjacent to forest environments that support sandfly populations, whereas most rural settlers lived in wooden-walled houses surrounded by crops or deforested areas where Lu. umbratilis is rarer than in nearby forest or forest edges (W. Ramos, J.F. Medeiros, G.R. Julião, C.M. Rios - Velásquez, E.F. Marialva, S.J.M Desmouliere, S.L.B. Luz, F.A.C. Pessoa, unpublished data).
Finally, we believe that a deeper understanding of genetic variability among parasites, vectors, and hosts would help foster understanding of CL epidemiology. The diversity of Le. (V.) guyanensis genotypes in the study area is unknown, yet different parasite lineages can result in specific disease manifestations (Nolder et al. 2007; Doudi et al. 2010). Genetically divergent sandfly populations can differ in their vector competence (Scarpassa & Alencar 2012), contributing to inter-population differences in CL incidence. We did not take into account genetic variation in our study populations, which included individuals from different geographic and ethnic origins who may have differed in immune competence against Leishmania infections, but we hope that our results will motivate further work on the mechanisms underlying CL epidemiological patterns. A consistent identification of higher-risk population groups and an improved understanding of the mechanisms driving CL incidence will provide a robust background for planning effective prevention strategies and reducing disease burden.