Authors: Babak Javid (currently at Tsinghua University, Beijing, China but moving shortly to UCSF, CA, USA)
Emerging evidence has suggested that B cells and humoral immunity could modulate the immune response to intracellular pathogens, including Mycobacterium tuberculosis, despite a previous focus on T cell-mediated immunity in this field. In this interview we speak to Babak Javid (currently at Tsinghua University, Beijing, China but moving shortly to UCSF, CA, USA), about his research on this topic and the importance of learning about immune factors in order to develop vaccination strategies and to understand latent TB.
First, could you just introduce yourself and give a brief summary of your career to-date?
I am a physician–scientist and I trained in the UK predominantly; I studied medicine at Cambridge and after medical school I did my residency training in London. That’s when I became fascinated by infectious diseases and I also became interested in a career in academic medicine. So, I went back to Cambridge to do a PhD with Paul Lehner (Cambridge Institute for Medical Research). This was in immunobiology, so, very fundamental science – it was fantastically rigorous training, a lot of hard work but a lot of fun! At the end of it I realized that as much as I loved it, I really wanted to focus on a disease that I was passionate about and that’s when I became interested in TB. TB is interesting partly because it is a fascinating disease and partly because it affects the most disenfranchised populations in the world; they are people who don’t have a voice, even within their own countries, and that was something I cared a lot about.
So, I finished my infectious disease specialist training and then I got a fellowship to go to Harvard (MA, USA) to work with Eric Rubin studying mycobacterial genetics. I did my postdoc there and after 4 years, I was thinking about where to set up my group and my wife and I thought “Let’s just have an adventure!” So, I set up my group at Tsinghua University, where I’ve been for the last 8 years. That has been a fantastic experience – and I would do it again in a heartbeat – but actually in the next couple of months I will be relocating to the University of California San Francisco (CA, USA), and I am excited about this new chapter.
What role does humoral immunity play in defense against TB?
There is no easy answer to this question because this field is still very controversial. What I can say is that until recently, humoral immunity had mostly been dismissed as playing any role at all and for reasonably good reasons. For example, in animal models, cell-mediated immunity is really important in defense against TB, whereas if you knock out B cells the phenotype is pretty modest.
However, in the last few years a few groups, including my own, decided that we should just go straight to humans and look at human antibody-mediated immunity. And although each group used slightly different methods – slightly different ways of trying to answer the same question – we all came to roughly the same conclusion, which is that is that some individuals make antibodies that protect against TB. Now, the question is how dominant is antibody-mediated immunity? It doesn’t seem to be important for everybody; so, is it protecting some people, but not others? Those are really open questions at the moment, and no one really knows.
The other thing I would say is that, unlike viral infections, in a TB infection it is not simple neutralization that is at play; in TB there seems to be a much more complex interaction of the immune system. So, for example, in our own work, we showed that T cells are important for antibody-mediated immunity in ways that we still don’t understand.
Could immune factors influence TB susceptibility?
Absolutely. So, we have known for a long time from both animal models, and also, for example, the natural history of HIV infection, that if you have too little immunity this appears to increase susceptibility to infection, and definitely increases the chance of latent TB reactivating. We know that depleting CD4-positive T cells for HIV, giving anti-TNF drugs for treating rheumatoid arthritis can all really increase the chance of TB reactivation and possibly increase the chance of getting new disease as well. TB is an unusual disease in that some people can have a latent infection where they don’t have any symptoms at all for possibly decades, and then it can reactivate and cause disease.
However, what has emerged in the last few years is that too much immunity is also very bad for you. For example, there have been some really nice studies showing that immune checkpoint inhibitors, which have transformed cancer treatment, can actually predispose to life-threatening TB reactivation. So, it seems that there is a very fine balancing act in the immune system; too little immunity but also too much immunity can drive immunopathology and disease.
Do you think the reactivation pathway and the new infection pathway are very different, or do you think that there are similarities?
That is a good question that I honestly don’t know the answer to. My suspicion is that they are different but in almost all animal models we either study one or the other and rarely both in the same animal model, so, it is difficult to say.
Focusing on the bacteria, and why are the translational apparatus in mycobacteria really unique?
This is another major interest in my lab and actually I would say that the more truthful answer is that the mycobacterial translation apparatus is not particularly unique, however, almost everything we know about bacterial translation comes from E. coli, which is actually the exception to the rule. The mycobacterial translation process is more similar to other bacteria, but these bacteria are all different from E. coli.
One example I would give is that a really essential part of eukaryotic translation, which also happens to be essential in E. coli translation, is missing in mycobacteria and most other bacteria. This means that in translation of certain codons, mycobacteria have a really high error rate – tens or hundreds of times higher than in E. coli or in eukaryotic systems. That in itself is interesting, but what’s more interesting is that the bacteria seem to prefer it that way. We have shown in our lab that this high error rate leads to proteomic innovation and that protects the bacteria from hostile environments, such as drugs or the immune system. It is an adaptive response – the term we have coined in our lab is ‘adaptive mistranslation’.
Could understanding host–pathogen interactions lead to new approaches for TB?
Well, I would hope so. One thing I think that is certainly true in the TB field, and probably most other fields, is that there is a lot of dogma in the field and that has driven a lot of technology but this hasn’t turned out to be as useful as we predicted. Having said that, in the last year we’ve been stunned that there have been two new vaccines candidates that seemed to have worked. So, I certainly think we need to understand the host–pathogen interaction for being able to improve on those vaccines in a rational way.
I think the other thing I would say is that understanding the host–pathogen interaction could be an avenue to target host-directed therapies as a new treatment modality, and also to look at anti-virulence strategies. So, instead of conventional antibiotics that aim to suppress growth of the bacteria, for anti-virulence strategies we need to understand what drives disease and try to target that. I think we really need to understand the host–pathogen interaction properly to be able to do rational design for these new treatment avenues.
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