Author response:
We thank the reviewers for their primarily positive comments and the critiques about where the manuscript could be improved. We agree with the vast majority of points raised. In our revised submission, we will:
<ul>
<li>Clarify some of the wording such as “unified mechanism” so that our intended meaning is clear to all readers</li>
<li>Completely change figure 2, as we accept the critique that an X-Y plot is not the logical way to present this concept</li>
<li>Amend the legends of figures 1 and 3 so that the disease pathways we are attempting to illustrate are clear for all readers</li>
<li>Expand on the genetic interactions between humans and TB and cite the manuscripts suggested</li>
<li>Add further discussion on multiple disease endotypes, and the immunological events that may lead to these distinct end points, along with how this may inform treatment stratification approaches</li>
<li>Extend the discussion about trained immunity</li>
<li>Make specific changes to address each of the reviewers’ points in the recommendations to authors</li>
<li>In the minority of cases where we feel a change is not necessary, we will justify this in our response to reviews</li>
</ul>

Bryan Bryson

Bavesh Kana

eLife Assessment
This Review Article explores the intricate relationship between humans and Mycobacterium tuberculosis (Mtb), providing an additional perspective on TB disease. Specifically, this review focuses on the utilization of systems-level approaches to study TB, while highlighting challenges in the frameworks used to identify the relevant immunologic signals that may explain the clinical spectrum of disease. The work could be further enhanced by better defining key terms that anchor the review, such as "unified mechanism" and "immunological route." This review will be of interest to immunologists as well as those interested in evolution and host-pathogen interactions.

anonymous

Reviewer #1 (Public review):
Summary:
This is an interesting and useful review highlighting the complex pathways through which pulmonary colonisation or infection with Mycobacterium tuberculosis (Mtb) may progress to develop symptomatic disease and transmit the pathogen. I found the section on immune correlates associated with individuals who have clearly been exposed to and reacted to Mtb but did not develop latent infections particularly valuable. However, several aspects would benefit from clarification.
Strengths:
The main strengths lie in the arguments presented for a multiplicity of immune pathways to TB disease.
Weaknesses:
The main weaknesses lie in clarity, particularly in the precise meanings of the three figures.
I accept that there is a 'goldilocks zone' that underpins the majority of TB cases we see and predominantly reflects different patterns of immune response, but the analogies used need to be more clearly thought through.

Reviewer #2 (Public review):
Summary:
This is a thought-provoking perspective by Reichmann et al, outlining supportive evidence that Mycobacterium tuberculosis co-evolved with its host Homo Sapiens to both increase susceptibility to infection and reduce rates of fatal disease through decreased virulence. TB is an ancient disease where two modes of virulence are likely to have evolved through different stages of human evolution: one before the Neolithic Demographic Transition, where humans lived in sparse hunter-gatherer communities, which likely selected for prolonged Mtb infection with reduced virulence to allow for transmission across sparse populations. Conversely, following the agricultural and industrial revolutions, Mtb virulence is likely to have evolved to attack a higher number of susceptible individuals. These different disease modalities highlight the central idea that there are different immunological routes to TB disease, which converge on a disease phenotype characterized by high bacterial load and destruction of the extracellular matrix. The writing is very clear and provides a lot of supportive evidence from population studies and the recent clinical trials of novel TB vaccines, like M72 and H56. However, there are areas to support the thesis that have been described only in broad strokes, including the impact of host and Mtb genetic heterogeneity on this selection, and the alternative model that there are likely different TB diseases (as opposed to different routes to the same disease), as described by several groups advancing the concept of heterogeneous TB endotypes. I expand on specific points below.
Strengths:
(1) The idea that Mtb evolved to both increase transmission (and possible commensalism with humans) with low rates of reactivation is intriguing. The heterogeneous TB phenotypes in the collaborative cross model (PMID: 35112666) support this idea, where some genetic backgrounds can tolerate a high bacterial load with minimal pathology, while others show signs of pathogenesis with low bacterial loads. This supports the idea that the underlying host state, driven by a number of factors like genetics and nutrition, is likely to explain whether someone will co-exist with Mtb without pathology, or progress to disease. I particularly enjoyed the discussion of the protective advantages provided by Mtb infection, which may have rewired the human immune system to provide protection against heterologous pathogens- this is supported by recent studies showing that Mtb infection provides moderate protection against SARS-CoV-2 (PMID: 35325013, and 37720210), and may have applied to other viruses that are likely to have played a more significant role in the past in the natural selection of Homo Sapiens.
(2) Modeling from Marcel Behr and colleagues (PMID: 31649096) indeed suggests that there are at least TB clinical phenotypes that likely mirror the two distinct phases of Mtb co-evolution with humans. Most of the TB disease progression occurs rapidly (within 1-2 years of exposure), and the rest are slow cases of reactivation over time. I enjoyed the discussion of the difference between the types of immune hits needed to progress to disease in the two scenarios, where you may need severe immune hits for rapid progression, a phenotype that likely evolved after the Neolithic transition to larger human populations. On the other hand, a series of milder immune events leading to reactivation after a long period of asymptomatic infection likely mirrors slow progression in the hunter-gatherer communities, to allow for prolonged transmission in scarce populations. Perhaps a clearer analysis of these models would be helpful for the reader.
Weaknesses:
(1) The discussion of genetic heterogeneity is limited and only discusses evidence from MSMD studies. Genetics is an important angle to consider in the co-evolution of Mtb and humans. There is a large body of literature on both host and Mtb genetic associations with TB disease. The very fact that host variants in one population do not necessarily cross-validate across populations is evidence in support of population-specific adaptations. Specific Mtb lineages are likely to have co-evolved with distinct human populations. A key reference is missing (PMID: 23995134), which shows that different lineages co-evolved with human migrations. Also, meta-analyses of human GWAS studies to define variants associated with TB are very relevant to the topic of co-evolution (e.g., PMID: 38224499). eQTL studies can also highlight genetic variants associated with regulating key immune genes involved in the response to TB. The authors do mention that Mtb itself is relatively clonal with ~2K SNPs marking Mtb variation, much of which has likely evolved under the selection pressure of modern antibiotics. However, some of this limited universe of variants can still explain co-adaptations between distinct Mtb lineages and different human populations, as shown recently in the co-evolution of lineage 2 with a variant common in Peruvians (PMID: 39613754).
(2) Although the examples of anti-TNF and anti-PD1 treatments are relevant as drivers of TB in limited clinical contexts, the bigger picture is that they highlight major distinct disease endotypes. These restricted examples show that TB can be driven by immune deficiency (as in the case of anti-TNF, HIV, and malnutrition) or hyperactivation (as in the case of anti-PD1 treatment), but there are still certainly many other routes leading to immune suppression or hyperactivation. Considering the idea of hyper-activation as a TB driver, the apparent higher rate of recurrence in the H56 trial referenced in the review is likely due to immune hyperactivation, especially in the context of residual bacteria in the lung. These different TB manifestations (immune suppression vs immune hyperactivation) mirror TB endotypes described by DiNardo et al (PMID: 35169026) from analysis of extensive transcriptomic data, which indicate that it's not merely different routes leading to the same final endpoint of clinical disease, but rather multiple different disease endpoints. A similar scenario is shown in the transcriptomic signatures underlying disease progression in BCG-vaccinated infants, where two distinct clusters mirrored the hyperactivation and immune suppression phenotypes (PMID: 27183822). A discussion of how to think about translating the extensive information from system biology into treatment stratification approaches, or adjunct host-directed therapies, would be helpful.

Reviewer #3 (Public review):
Summary:
This perspective article by Reichmann et al. highlights the importance of moving beyond the search for a single, unified immune mechanism to explain host-Mtb interactions. Drawing from studies in immune profiling, host and bacterial genetics, the authors emphasize inconsistencies in the literature and argue for broader, more integrative models. Overall, the article is thought-provoking and well-articulated, raising a concept that is worth further exploration in the TB field.
Strengths:
Timely and relevant in the context of the rapidly expanding multi-omics datasets that provide unprecedented insights into host-Mtb interactions.
Weaknesses (Minor):
(1) Clarity on the notion of a "unified mechanism". It remains unclear whether prior studies explicitly proposed a single unifying immunological model. While inconsistencies in findings exist, they do not necessarily demonstrate that earlier work was uniformly "single-minded". Moreover, heterogeneity in TB has been recognized previously (PMIDs: 19855401, 28736436), which the authors could acknowledge.
(2) Evolutionary timeline and industrial-era framing. The evolutionary model is outdated. Ancient DNA studies place the Mtb's most recent common ancestor at ~6,000 years BP (PMIDs: 25141181; 25848958). The Industrial Revolution is cited as a driver of TB expansion, but this remains speculative without bacterial-genomics evidence and should be framed as a hypothesis. Additionally, the claim that Mtb genomes have been conserved only since the Industrial Revolution (lines 165-167) is inaccurate; conservation extends back to the MRCA (PMID: 31448322).
(3) Trained immunity and TB infection. The treatment of trained immunity is incomplete. While BCG vaccination is known to induce trained immunity (ref 59), revaccination does not provide sustained protection (ref 8), and importantly, Mtb infection itself can also impart trained immunity (PMID: 33125891). Including these nuances would strengthen the discussion.

A co-evolutionary perspective on humans and Mycobacterium tuberculosis in the era of systems biology

Figures and data

Many routes can lead to TB via opposing immunological extremes.

Selection pressure of prolonged co-evolution favours individuals permissive to colonisation but resistant to active disease.

Escaping the human immune response from the pathogen’s perspective.

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