It benefits modern microbiology by the invention of new diagnostic techniques including the dental pulp study, the suicide PCR and the Multiple Spacer Sequencing Typing and changes in infectious disease paradigms, including that bovines were not source of prehistorically human tuberculosis. Therefore, paleomicrobiology opens the way for the elucidation of controversies concerning different past infections, such as the plague, influenza and tuberculosis. For a long time, the history of the plague was surrounded by many questions concerning the etiologic agent. Based on the description of outbreaks associated with bubonic lesions, 3 devastating plague pandemics have been identified: the Justinian plague, the medieval Black Death and the current pandemic starting in 1855. Dental pulp is an important source of DNA that has been used in different studies and showed to be more efficient that bone samples. Here, we describe for the first time the adaptation of iPCR for the detection of the Y. pestis antigen in dental pulp extracted from Nilotinib monohydrochloride monohydrate ancient teeth. The detection limit that was obtained by iPCR when testing the Y. pestis antigen in PBS indicated an improvement by a factor of 70 over the detection limit of the classical ELISA. One of the major drawbacks of iPCR is the presence of high background and nonspecific binding. However, in our study, a specificity of 100% was determined using a predetermined cut-off. Among the 34 historically positive teeth that were collected from 5 different archeological sites, 41% were detected positive by iPCR, compared to 29% by PCR with Y. pestis confirmed in 14 teeth by previous detection of DNA by PCR and antigenic proteins detection by iPCR. Protein-based methods are considered more suitable for detecting the plague in historical samples because proteins are more resistant to environmental degradation than DNA. The impact of the environment on DNA conservation has been demonstrated by Hoss et al., who demonstrated inverse correlations between both the average temperature of the archeological site and the humidity Tulathromycin B levels and DNA retrieval. In addition, the impact of tooth storage in soil has been investigated, demonstrating a decrease in extractable DNA by 90% after only 6 weeks of storage. In summary, we successfully adapted for the first time an iPCR method to detect pathogen-derived antigens in ancient samples. Our results suggest that DNA and antigen-based methods are complementary.