Matthias Wabl, PhD

Professor
Department of Microbiology and Immunology
+1 415 476-6036

Antibodies in tuberculosis therapy

Approximately one third of the world’s population is at risk for developing tuberculosis (TB) because at some point in their lives they have been infected with the disease-causing bacteria. Progression to debilitating, life-threatening “active disease” occurs in 5 to 10% of infected people for reasons that are often not clear. Between one and two million people die every year from TB.

TB is most prevalent in the developing world, but is nonetheless present across the globe, with a substantial presence in Europe. The spread of the disease is readily impacted by changes in socio-economic circumstances and population migration patterns. 

Antibiotic-resistant TB (“multi-drug resistant TB”; MDR-TB; and extensively drug-resistant TB, XDR-TB) has become a major global problem. Its rise in prevalence can be directly attributed in large part to obvious inadequacies of current antibiotic regimens, particularly their toxicity and long duration, with the associated compliance issues these naturally present. In some countries, MDR-TB now accounts for more than a quarter of TB cases. MDR-TB places considerable strain on national health care budgets—particularly in developing countries—because it is much more expensive to treat than conventional drug-sensitive TB and is associated with higher morbidity and mortality.

Recent advances during the last decade have clarified the fact that active TB disease is a consequence of immunological dysfunction and a failure of the mechanisms that normally keep the TB bacteria in check in the majority of infected people. A well-characterized immunological defense system is at the center of this dysfunction, namely the type I interferon response. Whereas this system helps protect humans from diverse infections, it is also harmful in some circumstances, as, for example, in lupus, and particularly now in TB. 

The increase in prevalence of MDR-TB and XDR-TB calls for new therapies. While there are a few anti-biotics in development—for example, a nucleoside-analog inhibitor of bacterial RNA polymerase may be promising—the power of specific antibodies has been neglected in TB therapy. This power can be har-nessed to redirect the human immune system, as is being done so successfully in cancer immuno-therapy. Or the antibodies can be directed at Mycobacterium tuberculosis, the causative agent of TB.

The tubercle bacterium is considered an archetypal intracellular pathogen, and as such is thought to be immune to direct antibody attack. However, the bacterium also divides extracellularly, and it is the extracellular bacterial population—especially the one present in the lung cavity—that clinicians aim to eliminate. This actively dividing population in the lung cavity is most responsible for the person-to-person transmission of tuberculosis and provides the reservoir for drug-resistant mutants.

The challenge of antibody therapy exceeds the capacity of one person or a small academic lab, but can be explored in a larger setting; please see austrianni.com.

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Virology & Microbial Pathogenesis
Research Summary: 
Immunotherapy of tuberculosis

Websites

Publications: 

Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice.

The Journal of general virology

Beck-Engeser GB, Ahrends T, Knittel G, Wabl R, Metzner M, Eilat D, Wabl M

APOBEC3 enzymes restrict marginal zone B cells.

European journal of immunology

Beck-Engeser GB, Winkelmann R, Wheeler ML, Shansab M, Yu P, Wünsche S, Walchhütter A, Metzner M, Vettermann C, Eilat D, DeFranco A, Jäck HM, Wabl M

Insertional hypermutation in mineral oil-induced plasmacytomas.

European journal of immunology

Knittel G, Metzner M, Beck-Engeser G, Kan A, Ahrends T, Eilat D, Huppi K, Wabl M

Gene expression profiling of murine T-cell lymphoblastic lymphoma identifies deregulation of S-phase initiating genes.

Leukemia research

Dabrowska MJ, Ejegod D, Lassen LB, Johnsen HE, Wabl M, Pedersen FS, Dybkær K