When studying an infection it’s important to have access to a model for examining the progression of disease. In tuberculosis research, such model systems range from mice to guinea pigs to primates, with many species in between. Lalita Ramakrishnan has spent much of her career studying a more distinct (and less furry) model: Danio rerio, commonly known as the zebrafish. In this system, zebrafish are infected with the pathogen Mycobacterium marinum, a comparable relative of our own M. tuberculosis.
In a recent issue of Cell, Tobin and Ramakrishnan employed this model to identify a pathway which appears to play a role in determining susceptibility to mycobacterial infection (a study which took the cover of the journal). The authors used a genetic screen in which mutagenized zebrafish were subjected to M. marinum infection in order to identify host genes involved in the regulation of infection. Fish found to be hypersusceptible to bacterial growth were identified and characterized further. One such mutant contained a mutation in lta4h, a gene involved in the eicosanoid pathway. Lta4h catalyzes the conversion of leukotriene A4 (LTA4) into leukotriene B4 (LTB4), which promotes the recruitment of immune cells such as neutrophils.
The authors showed that reduced expression of lta4h in the mutant zebrafish resulted in reduced levels of LTB4. The supply of LTA4 was instead shunted to production of another eicosanoid, lipoxin A4 (LXA4). Ultimately, this shift resulted in reduced expression of tumor necrosis factor (TNF), a broadly pro-inflammatory molecule.
These data suggest that the lta4h locus may play an important role in determining susceptibility to infection in the zebrafish. This is all well and good for the fish, but the question, of course, remains—is this relevant for humans as well? Luckily, Tobin and colleagues are happy to oblige our curiosity, providing data from human populations in Vietnam and Nepal. They identified genetic differences in the LTA4H gene present in certain human individuals. Such variances are termed single nucleotide polymorphisms (SNPs). In the Vietnam cohort it was observed that heterozygosity for several SNPs in LTA4H were strongly associated with a reduced incidence of both pulmonary TB and TB meningitis, a highly serious and often fatal form of TB. Similar results were observed in leprosy patients in Nepal, where heterozygosity correlated with a less severe form of the disease.
The authors suggest that LTA4H regulates the balance of LTB4 and LXA4, with a shift toward LXA4 resulting in less TNF production. Lower levels of TNF (as seen in the zebrafish mutant) precipitate an inadequate inflammatory response, and rampant infection. Too much TNF, however, can cause collateral tissue damage in the lungs due to a hyperactive immune response, resulting in more severe disease. This corresponds well with the human data in this study, where heterozygosity (a polymorphism on only one allele, with the other allele being normal) was highly protective against mycobacteria-associated disease. It appears that, as Goldilocks found, inflammation has to be “just right” in order to effectively resolve mycobacterial infection. This research raises many possibilities for the treatment of TB, such as drugs which modulate the immune system in order to achieve a proper inflammatory balance. Additionally, a genetic test for the SNPs observed by the authors could be an important predictor of susceptibility to tuberculosis infection.
Can drugs which modulate the immune system be combined with current TB drugs or are better, more specific immunomodulators needed? Would immunomodulation be effective or harmful for all TB infected individuals including HIV infected or immunocompromised TB patients? Please share your thoughts and comments.