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

Autophagy-independent role for Atg5 in M. tuberculosis infection

This is a second paper about neutrophils in Nature this week (advanced online publication). Quite interesting and surprising. It showed that autophagy molecule Atg5 has unique [autophagy-independent] role in protecting against neutrophil-driven immunopathology during M. tuberculosis lung infection.

Initially, the authors showed that myeloid cell-specific deletion of Atg5 (LysM-Cre Atg5^fl/fl) made mice highly susceptible to M. tuberculosis infection (that was expected based on earlier studies).

Unexpectedly and surprisingly, however, mice singly deficient for other autophagy components showed normal response to M. tuberculosis infection, implying unique, autophagy-independent role for Atg5 during M. tuberculosis infection.    

Indeed, LysM-Cre Atg5^fl/fl mice showed more severe M. tuberculosis-associated immunopathology and neutrophil infiltration (even though LysM-Cre Atg5^fl/fl mice did not harbor substantially more M. tuberculosis).

Furthermore, LysM-Cre Atg5^fl/fl mice depleted of neutrophils were protected from lung pathology during M. tuberculosis infection.

Finally, neutrophil-specific deletion of Atg5 (MRP8-Cre Atg5^fl/fl mice) confirmed pathological role of Atg5-deficient neutrophils during M. tuberculosis infection. 

In summary, this study provides evidence for autophagy-independent role of Atg5 deficiency in neutrophils during M. tuberculosis infection. It appears that neutrophils recruited to the sites of M. tuberculosis infection contribute to tissue pathology rather than provide protection in absence of Atg5. Earlier it was assumed that Atg5 played a protective role during infection purely via its involvement in autophagy formation. However, this new study point to a more complex role of Atg5.

David Usharauli