Research Article: Protection against Mycobacterium ulcerans Lesion Development by Exposure to Aquatic Insect Saliva

Date Published: February 27, 2007

Publisher: Public Library of Science

Author(s): Laurent Marsollier, Estelle Deniaux, Priscille Brodin, Agnès Marot, Christelle Mbondji Wondje, Jean-Paul Saint-André, Annick Chauty, Christian Johnson, Fredj Tekaia, Edouard Yeramian, Pierre Legras, Bernard Carbonnelle, Gilles Reysset, Sara Eyangoh, Geneviève Milon, Stewart T Cole, Jacques Aubry, Françoise Portaels

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.

Partial Text: Buruli ulcer disease is now 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 polyketide-derived macrolide called mycolactone [3,4]. Understanding the life history traits of M. ulcerans within its natural aquatic ecosystems, and the preventive and therapeutic tools for reducing the incidence of the disease are still very limited [5–7]. Currently, there is no vaccine available against Buruli ulcer. Bacillus Calmette-Guérin (BCG) vaccination provides some protection against the most severe forms of Buruli ulcer, such as osteomyelitis [8], but does not prevent most of the skin-ulcerative disease cases [9]. Initial, limited clinical evidence suggests that a rifampicin-streptomycin combination may have some beneficial effects on preulcerative lesions [10]. However, late diagnosis often results in the need for surgery [6].

Using a previously developed mouse model [21,22], in this study we demonstrated (i) that preulcerative and ulcerative stages of Buruli ulcer at sites of inoculation of M. ulcerans are prevented if the mice have been bitten by M. ulcerans-free insects before being exposed to insects harbouring M. ulcerans, and (ii) that the presence of insect saliva–reactive antibodies in the mouse serum is an immune signature that correlates with this protective status. However, this protective status does not prevent M. ulcerans from establishing themselves and expanding, although the size of the bacterial population is one to two orders of magnitude lower than in control mice not previously exposed to insect bites and displaying a lesion at the site of inoculation.



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