Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King M, Serhan CN, Ramakrishnan L. Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections. Cell. 2012 Feb 3; 148(3):434-446.
This week we have research out of the Ramakrishnan Laboratory that challenges thinking around tuberculosis treatment and considerations of host genotypes and responses. We interviewed Dr. Lalita Ramakrishnan and members of her team about efflux pumps and their role in development of drug resistance. The current article explores the genetics involved in the inflammatory response during TB infection, specifically a gene that effects the overproduction or underproduction of the inflammatory mediator TNF-alpha, and using this information to potentially factor into the TB treatment provided to a patient.
Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation causedby excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
Additional TB R&D News: