Friday, December 18, 2015

Both TNF-α and IL-1 are necessary for M. tuberculosis control

Both TNF-α and IL-1α are innate cytokines. For both cytokines there are FDA-approved biological drugs such as Humira® (TNF-α blocking) and Kineret® (IL-1RI blocking). Of note, anti-TNF-α, but not anti-IL-1RI blockers, carry specific FDA label regarding M. tuberculosis incidence as a drug side effect. 

So I was surprised to read new paper in journal Immunity where the authors showed that in mouse model of aerosol M. tuberculosis infection both TNF-α and IL-1 were required for efficient control of TB pathogen.

Of note, this article was under review for more than two years. I guess it took long time to convince editors to publish it. The study is based on analyses of bilateral bone marrow reconstituted knockout mice. Basically a descriptive study. I modified sequence of figures for clarity.  

In a first set of experiments the authors showed that mice deficient for IL-1α and IL-1β signaling on hematopoietic cells (DKO or IL-1RI KO) were highly susceptible to M. tuberculosis infection due to exaggerated, non-productive inflammatory response.

Follow up experiments with mice single deficient for IL-1α and IL-1β confirmed physiological significance of individual IL-1 molecules in host's defense against M. tuberculosis infection (the authors claim that IL-1β deficient hosts are less susceptible to M. tuberculosis infection, but overall survival trend is the same).

Significance of IL-1α in control of M. tuberculosis infection was supported by observation that transfer of stem cells expressing viral-encoded IL-1α under the control of CD11c promoter restored IL-1α KO host's resistance to M. tuberculosis infection (why the authors have not done the same experiment with IL-1β is unknown).
Next, the authors showed [or rather re-confirmed] that mice deficient for TNF-α signaling on hematopoietic as well as on non-hematopoinetic cells were susceptible for M. tuberculosis infection.

Additional experiments revealed that absence of signaling via both IL-1RI and TNF-R1 on non-hematopoietic cells [but not on hematopoietic cells] further diminished host's resistance against M. tuberculosis infection.

In summary, this study indicates that in mouse model of M. tuberculosis infection both TNF-α and IL-1 molecules play non-redundant role in host's defense. Interestingly, mice individually deficient for TNF-α or IL-1 signalling on hematopoinetic cells showed similar susceptible to M. tuberculosis infection (in contrast, only mice deficient for TNF-α, [but not IL-1] signalling on non-hematopoietic cells retain susceptibility to M. tuberculosis infection).

However, how these data fit with clinical studies with Humira® and Kineret® is another story altogether. Surprisingly, the authors failed to discuss it at all. That's a big problem.

David Usharauli

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