Abstract
BackgroundBuruli ulcer is a severe human skin disease caused by Mycobacterium ulcerans. This disease is primarily diagnosed in West Africa with increasing incidence. Antimycobacterial drug therapy is relatively effective during the preulcerative stage of the disease, but surgical excision of lesions with skin grafting is often the ultimate treatment. The mode of transmission of this Mycobacterium species remains a matter of debate, and relevant interventions to prevent this disease lack (i) the proper understanding of the M. ulcerans life history traits in its natural aquatic ecosystem and (ii) immune signatures that could be correlates of protection. We previously set up a laboratory ecosystem with predatory aquatic insects of the family Naucoridae and laboratory mice and showed that (i) M. ulcerans-carrying aquatic insects can transmit the mycobacterium through bites and (ii) that their salivary glands are the only tissues hosting replicative M. ulcerans. Further investigation in natural settings revealed that 5%–10% of these aquatic insects captured in endemic areas have M. ulcerans–loaded salivary glands. In search of novel epidemiological features we noticed that individuals working close to aquatic environments inhabited by insect predators were less prone to developing Buruli ulcers than their relatives. Thus we set out to investigate whether those individuals might display any immune signatures of exposure to M. ulcerans-free insect predator bites, and whether those could correlate with protection.Methods and FindingsWe took a two-pronged approach in this study, first investigating whether the insect bites are protective in a mouse model, and subsequently looking for possibly protective immune signatures in humans. We found that, in contrast to control BALB/c mice, BALB/c mice exposed to Naucoris aquatic insect bites or sensitized to Naucoris salivary gland homogenates (SGHs) displayed no lesion at the site of inoculation of M. ulcerans coated with Naucoris SGH components. Then using human serum samples collected in a Buruli ulcer–endemic area (in the Republic of Benin, West Africa), we assayed sera collected from either ulcer-free individuals or patients with Buruli ulcers for the titre of IgGs that bind to insect predator SGH, focusing on those molecules otherwise shown to be retained by M. ulcerans colonies. IgG titres were lower in the Buruli ulcer patient group than in the ulcer-free group.ConclusionsThese data will help structure future investigations in Buruli ulcer–endemic areas, providing a rationale for research into human immune signatures of exposure to predatory aquatic insects, with special attention to those insect saliva molecules that bind to M. ulcerans.
Highlights
Buruli ulcer disease is the third most common mycobacterial disease in the world, behind tuberculosis and leprosy, and its incidence in Western African countries is among the highest in the world [1,2]
In contrast to control BALB/c mice, BALB/c mice exposed to Naucoris aquatic insect bites or sensitized to Naucoris salivary gland homogenates (SGHs) displayed no lesion at the site of inoculation of M. ulcerans coated with Naucoris SGH components
IgG titres were lower in the Buruli ulcer patient group than in the ulcer-free group. These data will help structure future investigations in Buruli ulcer–endemic areas, providing a rationale for research into human immune signatures of exposure to predatory aquatic insects, with special attention to those insect saliva molecules that bind to M. ulcerans
Summary
Buruli ulcer disease is the third most common mycobacterial disease in the world, behind tuberculosis and leprosy, and its incidence in Western African countries is among the highest in the world [1,2] This debilitating and progressive disease, characterized by skin lesions and sometimes localization in limb bones, is caused by Mycobacterium ulcerans, which produces a dermonecrotic toxin, a polyketidederived macrolide called mycolactone [3,4]. Buruli ulcer disease is a severe skin infection caused by Mycobacterium ulcerans, a bacterium related to those that cause tuberculosis and leprosy This poorly understood disease affects people living near slow-flowing or standing water in poor rural communities in tropical and subtropical countries. Bacteria inside these swellings produce a toxin that damages nearby soft tissues until eventually the skin sloughs off to leave a large open sore This usually heals but the resultant scar can limit limb movement. Most patients do not seek help until the later stages when the only treatment is to cut out the infection and do a skin graft, a costly and lengthy treatment
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