High genetic diversity among Mycobacterium tuberculosis complex strains from Sierra Leone

<p>Abstract</p> <p>Background</p> <p>Among tuberculosis (TB) high incidence regions, Sub-Saharan Africa is particularly affected with approx. 1.6 million new cases every year. Besides this dramatic situation, data on the diversity of <it>Mycobacterium tuberculosis </it>complex (MTBC) strains causing this epidemic in this area are only sparsely available. Here we analyzed the population structure of strains from Sierra Leone with a special focus on the prevalence of <it>M. africanum</it>.</p> <p>Results</p> <p>A total of 97 strains isolated from smear positive cases registered for re-treatment in the Western Area and Kenema districts in years 2003/2004 were investigated by susceptibility testing (first line drugs) and molecular typing (IS<it>6110 </it>fingerprinting, spoligotyping, and MIRU-VNTR typing).</p> <p>Among the strains analyzed, 32 were resistant to isoniazid, and 11 were multidrug resistant (at least resistant to isoniazid and rifampin). The population diversity was high with two previously described <it>M. africanum </it>lineages (West African-1, n = 6; West African-2, n = 17) and seven <it>M. tuberculosis </it>lineages (Haarlem, n = 14; LAM, n = 15; EAI, n = 4; Beijing, n = 4; S-type, n = 4, X-type, n = 1; Cameroon, n = 4). Furthermore, two new <it>M. tuberculosis </it>genotypes Sierra Leone-1 (n = 7) and -2 (n = 10) were found. Strain classification according to a 7 bp deletion in pks1/15 revealed that the majority of <it>M. tuberculosis </it>strains belonged to the Euro American lineage (66 out of 74).</p> <p>Conclusion</p> <p>Resistance rates in Sierra Leone have reached an alarming level. The population structure of MTBC strains shows an intriguing diversity raising the question of possible consequences for TB epidemic and for the introduction of new diagnostic tests or treatment strategies in West Africa.</p

Mycobacterium avium subsp. paratuberculosis Infection in a Patient with HIV, Germany

Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne disease in ruminants, has been incriminated as the cause of Crohn disease in humans. We report the first case of human infection with MAP in a patient with HIV; infection was confirmed by obtaining isolates from several different specimen types

Mycobacterium bovis Isolates with M. tuberculosis Specific Characteristics

Our study is the first report of exceptional Mycobacterium bovis strains that have some characteristics of M. tuberculosis. The strains were isolated from 8 patients living in Kazakhstan. While molecular markers were typical for M. bovis, growth characteristics and biochemical test results were intermediate between M. bovis and M. tuberculosis

Worldwide Emergence of Extensively Drug-resistant Tuberculosis

Mycobacterium tuberculosis strains are becoming resistant to not only the most powerful first-line drugs but also many second-line drugs

Multidrug-Resistant Tuberculosis Treatment Outcomes in Karakalpakstan, Uzbekistan: Treatment Complexity and XDR-TB among Treatment Failures

BACKGROUND: A pilot programme to treat multidrug-resistant TB (MDR-TB) was implemented in Karakalpakstan, Uzbekistan in 2003. This region has particularly high levels of MDR-TB, with 13% and 40% among new and previously treated cases, respectively. METHODOLOGY: This study describes the treatment process and outcomes for the first cohort of patients enrolled in the programme, between October 2003 and January 2005. Confirmed MDR-TB cases were treated with an individualised, second-line drug regimen based on drug susceptibility test results, while suspected MDR-TB cases were treated with a standardised regimen pending susceptibility results. PRINCIPAL FINDINGS: Of 108 MDR-TB patients, 87 were started on treatment during the study period. Of these, 33 (38%) were infected with strains resistant to at least one second-line drug at baseline, but none had initial ofloxacin resistance. Treatment was successful for 54 (62%) patients, with 13 (15%) dying during treatment, 12 (14%) defaulting and 8 (8%) failing treatment. Poor clinical condition and baseline second-line resistance contributed to treatment failure or death. Treatment regimens were changed in 71 (82%) patients due to severe adverse events or drug resistance. Adverse events were most commonly attributed to cycloserine, ethionamide and p-aminosalicylic acid. Extensively drug resistant TB (XDR-TB) was found among 4 of the 6 patients who failed treatment and were still alive in November 2006. CONCLUSIONS: While acceptable treatment success was achieved, the complexity of treatment and the development of XDR-TB among treatment failures are important issues to be addressed when considering scaling up MDR-TB treatment

Pulmonary Tuberculosis due to Mycobacterium bovis in Captive Siberian Tiger

We report the first case of pulmonary tuberculosis caused by Mycobacterium bovis subsp. caprae in a captive Siberian tiger, an endangered feline. The pathogen was isolated from a tracheal aspirate obtained by bronchoscopy. This procedure provided a reliable in vivo diagnostic method in conjunction with conventional and molecular tests for the detection of mycobacteria

Tuberculosis Recurrence and Mortality after Successful Treatment: Impact of Drug Resistance

BACKGROUND: The DOTS (directly observed treatment short-course) strategy for tuberculosis (TB) control is recommended by the World Health Organization globally. However, there are few studies of long-term TB treatment outcomes from DOTS programs in high-burden settings and particularly settings of high drug resistance. A DOTS program was implemented progressively in Karakalpakstan, Uzbekistan starting in 1998. The total case notification rate in 2003 was 462/100,000, and a drug resistance survey found multidrug-resistant (MDR) Mycobacterium tuberculosis strains among 13% of new and 40% of previously treated patients. A retrospective, observational study was conducted to assess the capacity of standardized short-course chemotherapy to effectively cure patients with TB in this setting. METHODS AND FINDINGS: Using routine data sources, 213 patients who were sputum smear-positive for TB, included in the drug resistance survey and diagnosed consecutively in 2001–2002 from four districts, were followed up to a median of 22 months from diagnosis, to determine mortality and subsequent TB rediagnosis. Valid follow-up data were obtained for 197 (92%) of these patients. Mortality was high, with an average of 15% (95% confidence interval, 11% to 19%) dying per year after diagnosis (6% of 73 pansusceptible cases and 43% of 55 MDR TB cases also died per year). While 73 (74%) of the 99 new cases were “successfully” treated, 25 (34%) of these patients were subsequently rediagnosed with recurrent TB (13 were smear-positive on rediagnosis). Recurrence ranged from ten (23%) of 43 new, pansusceptible cases to six (60%) of ten previously treated MDR TB cases. MDR M. tuberculosis infection and previous TB treatment predicted unsuccessful DOTS treatment, while initial drug resistance contributed substantially to both mortality and disease recurrence after successful DOTS treatment. CONCLUSIONS: These results suggest that specific treatment of drug-resistant TB is needed in similar settings of high drug resistance. High disease recurrence after successful treatment, even for drug-susceptible cases, suggests that at least in this setting, end-of-treatment outcomes may not reflect the longer-term status of patients, with consequent negative impacts for patients and for TB control

Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains

The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype −261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52–0.84, Pnominal 0.0009, Pcorrected 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70–1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49–0.81, Pnominal 0.0004, Pcorrected 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants −261C and −261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM −261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population