To date smallpox is the only infectious disease of humans
To date, smallpox is the only infectious disease of humans that has been eradicated. A biological factor that favored smallpox eradication is the lack of a nonhuman reservoir. In pppa to smallpox, a yaws-like disease has been documented in various species of nonhuman primates (NHPs) that reside in areas of Africa where yaws may be present in humans (). Knauf et al. reported a disease that caused skin lesions in baboons at Lake Manyara National Park (LMNP) in Tanzania (). These investigators demonstrated the presence of in the affected baboons\' tissues using immunohistochemistry and showed with molecular techniques that the spirochetal agent is very closely related to . Although humans can be experimentally infected with a baboon strain (i.e., Fribourg-Blanc) () that is highly similar to , it is unclear if baboons can serve as a reservoir for human infection and, if so, how yaws could be transmitted from baboons to humans. Knauf et al. hypothesized that insects might function as a mechanical vector for interspecies transmission of in areas where there is a high prevalence of -induced skin ulcerations in NHPs (). The possibility that insects (i.e., flies) act as a vector for yaws merits renewed consideration based on the results of observational and experimental studies that were conducted several decades ago in the pre-molecular era. In 1907, Castellani, who identified as the etiologic agent of yaws (), noted that non-biting flies “eagerly crowd” on the lesions of yaws patients and “sucking with avidity the secretion” may afterward alight on the broken skin of others, purportedly enabling the transmission of yaws (). Castellani demonstrated that flies that fed on yaws patients\' lesions could transmit yaws to monkeys whose skin had been scarified. Later, Lamborn succeeded in transmitting yaws to a human using as the vector (). In 1953, Satchell and Harrison reported that and that fed on yaws lesions for 5min or less picked up on their mouthparts (). Microscopic analysis revealed that motile were present for up to 2h in the flies\' crop, but that these spirochetes were rarely present in the flies\' gut contents. Although the early studies of Castellani and Lamborn showed that flies can act as a vector for yaws in an experimental setting, confirmation of the role of flies as a vector for yaws in a natural setting remained elusive. An essential criterion to incriminate flies in the transmission of yaws is the demonstration that flies from a yaws-endemic setting harbor viable . In their study published in this issue of EBioMedicine, Knauf et al. report the results of molecular interrogation of wild-caught flies from LMNP and Tarangire National Park (TNP) for the presence of -like strains (). Knauf et al. detected DNA in 17–23.5% of 207 flies based on PCR amplification of two or more genomic loci. Interestingly, , which has been shown to transmit yaws in an experimental setting, was one of two fly species at both LMNP and TNP that was disproportionately PCR positive for DNA. Phylogenetic analysis of the polymorphic locus showed that 23 of 26 sequences from the flies cluster with sequences from human strains and from baboon strains (i.e., Fribourg-Blanc and LMNP). Nineteen of the 23 sequences from the flies were identical to -like sequences from the -infected LMNP baboons (). Furthermore, three sequences from the flies cluster with sequences from human and subsp. (i.e., endemic syphilis) strains, suggesting that different subsp. are present in the baboon population or possibly that flies had contact with -infected humans. The intriguing results of Knauf et al. could have important implications for yaws eradication efforts, but several questions remain (). For example, what is the source of the fly-associated DNA (e.g., infected baboons or humans)? Are fly-associated viable and present in sufficient numbers for interspecies transmission? Do humans living in villages that border LMNP and TNP have clinical and/or serological evidence of yaws? If so, does fly control have an effect on the incidence/prevalence of yaws in these villages? Some of these questions may be difficult to address because of the fragile, not-yet-cultivable nature of the subsp. However, the use of molecular tools and epidemiological methods should facilitate further studies to elucidate the potential role of flies in the transmission of yaws. Clearly, a better understanding of yaws transmission is necessary for the development of suitable control strategies that are critical to achieve WHO\'s 2020 goal of yaws eradication.