<i>Haemophilus ducreyi</i> Cutaneous Ulcer Strains Are Nearly Identical to Class I Genital Ulcer Strains

<div><p>Background</p><p>Although cutaneous ulcers (CU) in the tropics is frequently attributed to <i>Treponema pallidum</i> subspecies <i>pertenue</i>, the causative agent of yaws, <i>Haemophilus ducreyi</i> has emerged as a major cause of CU in yaws-endemic regions of the South Pacific islands and Africa. <i>H</i>. <i>ducreyi</i> is generally susceptible to macrolides, but CU strains persist after mass drug administration of azithromycin for yaws or trachoma. <i>H</i>. <i>ducreyi</i> also causes genital ulcers (GU) and was thought to be exclusively transmitted by microabrasions that occur during sex. In human volunteers, the GU strain 35000HP does not infect intact skin; wounds are required to initiate infection. These data led to several questions: Are CU strains a new variant of <i>H</i>. <i>ducreyi</i> or did they evolve from GU strains? Do CU strains contain additional genes that could allow them to infect intact skin? Are CU strains susceptible to azithromycin?</p><p>Methodology/Principal Findings</p><p>To address these questions, we performed whole-genome sequencing and antibiotic susceptibility testing of 5 CU strains obtained from Samoa and Vanuatu and 9 archived class I and class II GU strains. Except for single nucleotide polymorphisms, the CU strains were genetically almost identical to the class I strain 35000HP and had no additional genetic content. Phylogenetic analysis showed that class I and class II strains formed two separate clusters and CU strains evolved from class I strains. Class I strains diverged from class II strains ~1.95 million years ago (mya) and CU strains diverged from the class I strain 35000HP ~0.18 mya. CU and GU strains evolved under similar selection pressures. Like 35000HP, the CU strains were highly susceptible to antibiotics, including azithromycin.</p><p>Conclusions/Significance</p><p>These data suggest that CU strains are derivatives of class I strains that were not recognized until recently. These findings require confirmation by analysis of CU strains from other regions.</p>