Differences in virulence and immune response induced in a murine model by isolates ofMycobacterium ulceransfrom different geographic areas

Abstract

SummaryBuruli ulcer (BU) is the third most common mycobacterial disease in immunocompetent hosts. BU is caused by Mycobacterium ulcerans, which produces skin ulcers and necrosis at the site of infection. The principal virulence factor of M. ulcerans is a polyketide-derived macrolide named mycolactone, which has cytotoxic and immunosuppresive activities. We determined the severity of inflammation, histopathology and bacillary loads in the subcutaneous footpad tissue of BALB/c mice infected with 11 different M. ulcerans isolates from diverse geographical areas. Strains from Africa (Benin, Ghana, Ivory Coast) induced the highest inflammation, necrosis and bacillary loads, whereas the strains collected from Australia, Asia (Japan, Malaysia, New Guinea), Europe (France) and America (Mexico) induced mild inflammation. Subsequently, animals were infected with the strain that exhibited the highest (Benin) or lowest (Mexico) level of virulence in order to analyse the local immune response generated. The Mexican strain, which does not produce mycolactone, induced a predominantly T helper type 1 (Th1) cytokine profile with constant high expression of the anti-microbial peptides beta defensins 3 and 4, in co-existence with low expression of the anti-inflammatory cytokines interleukin (IL)-10, IL-4 and transforming growth factor (TGF)-b. The highly virulent strain from Benin which produces mycolactone A/B induced the opposite pattern. Thus, different local immune responses were found depending on the infecting M. ulcerans strain.

Evaluating decontamination protocols for the isolation of Mycobacterium ulcerans from swabs

“…This is as a result of intensive and extensive solution seeking investigations into a hitherto difficult situation. Investigations include (i) the extraction and use of mycolactone, the key virulent factor mediating Buruli ulcer disease for further research [7, 8], (ii) availability of information on drug susceptibility profiles of existing isolates to current antibiotics and potentially effective ones [9], (iii) M. ulcerans’ viability in BU lesions post antibiotic treatment, indicative of treatment successes or failures, (iv) molecular epidemiology of the disease [10] and (v) disease surveillance. Most of these investigations have relied on M. ulcerans isolates from culture; a method for growing isolates of viable M. ulcerans in-vitro .…”

Buruli Ulcer in Animals and Experimental Infection Models

“…The most comprehensive study on how the use of M. ulcerans strains from different geographical origin and with different cultivation history influences virulence and immune responses induced in experimentally infected mice was published in 2009 by Ortiz et al Eleven different M. ulcerans strains isolated from different parts of the world over a time span of 47 years were used to infect 6-8 weeks old male BALB/c mice in the foot pad. Subsequently, their ability to cause a productive infection was reported as well as a detailed characterization of the inflammation induced by the different strains [53]. The bacterial strains used in these experiments partially overlap with the set of strains which was regularly used in the laboratory of Jorge Pedrosa, the only other research group that systematically characterized murine infection caused by different strains of M. ulcerans [30,39,41,42,48,54].…”

“…With an estimated generation time of 3-4 days in the mouse foot pad [14], animal experiments with M. ulcerans often last for a long time. Depending on the infection dose and the virulence of the strain injected, development of a visible pathology only starts a few weeks after infection [14,53], with a typical lag time of 3-4 weeks. When foot pads are inoculated, the first visible signs are usually edema on the top of the foot pad, followed by reddening of the foot and ankle and swelling to the point where foot pads appear to be "leaky", so that cage bedding material starts to stick to the foot pad ( Fig.…”

Management of HIV Infected Patients with Active Buruli Ulcer in Tropical Regions in Africa, a New Therapeutic Challenge: A Review

“…Therefore, there is a significant potential for BU and HIV to occur in the only in a state of latency as reported for mycobacterium tuberculosis (MT). In addition, the study in mouse model histological analysis suggests that antibiotherapy leads to a shift in type of inflammatory infiltrate from neutrophils/macrophages-predominant to macrophages/ lymphocytes-predominant, associated with the enhancement of phagocytosis [16][17][18][19] . This immunological reaction is thought to be due to an exuberant reconstitution of the local immune response during the demise of MU bacilli under the influence of antibiotic therapy and mediated by immune-stimulators released from dying MU in areas of declining mycolactone concentration.…”