Reviewer 2's Review

-----

This is an important study from an outstanding group led by a highly respected
populations and infectious disease expert. Understanding predisposition to tuberculosis in human populations is a critical piece of knowledge that we must have. This study provides one of the important building blocks towards that goal. There is sufficient evidence (and we are talking abut huge datasets) to implicate TRL1-602 and TLR1-248S as associated with disease. Since we are talking about human populations and ethnic groups, I would check with the ethicist how to present this in the abstract, but certainly the data are precious and need to become public knowledge.

1. It would be important here or in the future to connect the polymorphisms with
more functional studies (is it a hyper- or hypo-active allele), as tuberculosis has
two sides – sometimes “too much’ reactivity is not a good thing. In that sense the
available information in the literature (p. 14) on TLR6 is in support of a
loss/reduced function. I would not hold the authors to carrying out more
functional experiments (although that would be great!).

2. In the above sense, the currently available information on TLR6 and MTB in the
murine systems is slightly underwhelming. The reference 45 used a dominant
negative TLR6 mutant, which is probably different from the human TLR6 alleles
described here. And all we know is that there was inhibition of signaling in
transfected cells. Again, I am not holding the authors to generate their own
functional data, but some additional and perhaps more careful (avoiding
advertisement of a concept) literature analysis would help. I feel that remaining
very cautious here is more important, both scientifically and otherwise. Last thing
we’d like to see that this falls into a lawyers or insurance company lap as an
“incontrovertible evidence”. So, many ifs and maybes need to be inserted in this
text.

3. Otherwise, I think that this is a great and important study and should be published.

-----

N.B. These are the general comments made by the reviewer when reviewing this paper in light of which the manuscript was revised. Specific points addressed during revision of the paper are not shown.