New tools to combat tuberculosis
Tuberculosis (TB) remains one of the leading infectious causes of illness and death world-wide, and was declared a Global Emergency by the World Health Organization in 1994.
Tuberculosis alone is responsible for 2 million deaths per year. Most of the tuberculosis burden occurs in the low income countries, particularly in those in South East Asia and Sub-Saharan Africa, where tuberculosis is often associated with HIV. Also in the countries of the former Soviet Union there is an alarming increase in the incidence of tuberculosis with emerging multi-drug-resistant disease.
Gunilla Källenius research group has for 20 years been working on, amongst other things, a easy, rapid diagnostic test for tuberculosis.
Molecular epidemiology and evolution of tuberculosis
Genotyping and molecular epidemiological methods are powerful tools for studying the epidemiology, evolution and spread of Mtb.
The aim of our studies is to contribute to more knowledge about the global spread and evolution of Mtb, and to identify genetic markers that can be used for identifying and exploring particular pathogenic clones/families/subtypes of Mtb.
In studies of drug resistant Mtb strains in Sweden we have found strains that are particularly prone to spread and/or disseminate. Of particular interest is the by us named cluster 49 outbreak, comprising the largest number of patients (n> 100), that is mainly spread in the Stockholm area. We are studying this cluster in more detail including whole genome sequencing.
In collaboration with other research partners we collect population based Mtb isolates from various parts of the world, with emphasis on Sub-Saharan Africa. A large number of isolates have already been analysed, contributing to the understanding of the global distribution of different strains/lineages of Mtb.
The highest diversity and strain variation of tubercle bacilli appears to occur in Africa. Yet the knowledge of the genetic variability is extremely scarce in most parts of Africa, where the burden of tuberculosis is highest. We have found that the majority of Mtb isolates from Guinea belong to a unique family of strains, the "Guinea Bissau family", originating and evolving in West Africa, which phylogenetically is close to the ancestor of the Mtb complex.
We hypothesize that the ancestor of the Mtb complex was an organism with a wide species tropism and that the Guinea Bissau strains represent an ongoing species adaptation between different hosts. By whole genome sequencing we hope to identify genes that are important for their host tropism and thereby contribute to a more rational design of a new efficient vaccine.
A rapid test for tuberculosis
One major problem hampering the battle with tuberculosis is the lack of reliable, simple, and inexpensive point of patient care (POC) diagnostic methods that would allow early detection of active tuberculosis disease. Culture-based diagnosis is time consuming since pathogenic mycobacteria grow slowly, requiring 3-4 weeks for development of visible colonies. The sensitivity of direct microscopy of sputum is very low.
We have shown that the mycobacterial cell wall component lipoarabinomannan (LAM) is excreted in the urine of patients having active tuberculosis, and have developed new diagnostic tests based on the identification of LAM in urine. These immunoassays are based on monoclonal anti-LAM antibodies prepared in our laboratory. A LAM-ELISA is intended for the use in laboratory settings and allowing quantification of mycobacterial antigen and a "dipstick" semi-quantitative format using antibodies coupled to a solid phase is being designed for field use. We are currently also working on the development of a POC test based on a lateral flow immunochromatographic platform
Towards a new tuberculosis vaccine
The protective efficacy of the only available vaccine against tuberculosis, bacille Calmette-Guerin(BCG) has been reported to vary considerably - from around 80% protection to none. The protective effect of BCG is mainly in neonates and children against non-infectious forms of primary disease, such as meningitis, but there is little or no protection against infectious, pulmonary tuberculosis in adolescents and adults.
The development of new efficient tuberculosis vaccines is complicated by the lack of understanding of the innate immunity to Mtb and how acquired immunity is mounted. It is an accepted view that a considerable part of the world´s population, perhaps as many as 30%, are infected with tubercle bacilli, but most, however, do not develop active disease.
Several new vaccine candidates have been prepared by our group and in preclinical tests shown to be highly immunogenic and protective in laboratory animals. These vaccine candidates include vaccines of the carbohydrate- protein conjugate type, consisting of oligosaccharides derived from the major Mtb cell wall lipoarabinomannan covalently bound to immunogenic carrier proteins. These vaccine candidates, when administered in mice, proved in preclinical tests to be as protective as the conventional BCG vaccine.
Our aim is to evaluate these vaccine candidates in phase I trials in Sweden, South Africa and Tanzania.
Helen Buteme, PhD student
Margarida Correia-Neves, Visiting professor
Beston Hamasur, PhD
Liudmyla Korshun, Associate professor
Gunilla Källenius, Research group leader
Sofia Omar Viegas, PhD
A sensitive urinary lipoarabinomannan test for tuberculosis.
PLoS ONE 2015 ;10(4):e0123457
Tuberculosis and HIV Coinfection.
Cold Spring Harb Perspect Med 2015 Feb;5(7):a017871
Mycobacterium tuberculosis Beijing genotype is associated with HIV infection in Mozambique.
PLoS ONE 2013 ;8(8):e71999
African 1, an epidemiologically important clonal complex of Mycobacterium bovis dominant in Mali, Nigeria, Cameroon, and Chad.
J. Bacteriol. 2009 Mar;191(6):1951-60
Mycobacterial glycoconjugates as vaccine candidates against tuberculosis.
Trends Microbiol. 2008 Oct;16(10):456-62