Host genomics: lessons for infectious diseases

A complex field, host genomics research aims to identify genetic variants that might explain different individual responses to an infectious disease. 

A companion piece to our report, Host genomics: lessons for infectious disease, policy analyst and lead author of the report, Heather Turner, discusses the findings of the report and why host genomics matters for the health.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare. We discuss the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.
 
If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

If you have any questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: Welcome to 'Making science work for health', the PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. The progress being made by teams of scientists and researchers around the world is gaining more interest and attention. Many of the latest advances feature genomics and omics related technologies.

The field in which the PHG Foundation has more than 25 years of experience, helping policy makers get to grips with practical on the ground delivery. 'Making science work for health' aims to look behind the hype and explain what new science means for patients, health professionals, and members of society.

My name is Ofori Canacoo part of the communications team at the PHG Foundation and host of 'Making science work for health'. For this episode, we're discussing host genomics. A complex field, host genomics research aims to identify genetic variants that might explain different individual responses to an infectious disease.

This episode's discussion will be between Dr. Susan Mitchell, Director of External Affairs and Heather Turner, Policy Analyst in biomedical science at the PHG Foundation. Together they'll be discussing host genomics and why it matters. They'll also be talking about the Host Genomics Report, lead authored by Heather, released December, 2024.

Susan: Hi Heather. Welcome to the PHG podcast. I'm looking forward to our conversation around host genomics. We've obviously just launched a report recently, which you led on, so it'd be really good to have a conversation with you about what it's about and what we found.

I guess the first question is, what is host genomics?

Heather: So we know that people when exposed to the same pathogen have differences in response. Some people are resistant to infection, which basically means that they don't become infected, whereas others may be more susceptible to infection. So more at risk from the most severe consequences of the disease.

So host genomics is then exploring these differences in individual responses to identify the genetic factors that are involved in these different responses. 

Susan: And I think it's fair to say we looked at some different examples, didn't we, across the report? 

Heather: Our interest in host genomics was really sparked by the huge response seen during the COVID-19 pandemic, but we wanted to explore not just this research, but the wider research landscape in which COVID-19 would fit. Particularly we wanted to understand, kind of, this science better in context and to do this we looked across four diseases. These were COVID-19, hepatitis C virus, HIV, and tuberculosis. 

Susan: Thanks. And I guess it's interesting 'cause you've talked about HIV and you've talked about TB. Now, TB's obviously been a disease that's been in existence for a really long time.

Is there a sort of difference between perhaps the newer conditions such as HIV and even COVID compared to TB? Is there any inference or implications for host genomics from that perspective? 

Heather: In the report, we clearly found that across the four diseases, there are big differences in the research that's been undertaken and the findings that have come from that.

And I think there are two really important things that need to be understood. First of all, the resources that have gone into this research are quite wildly different. COVID, because this was a pandemic response, elicited far more resource than any host genomics research that had ever happened previously. Whereas with other diseases, they have been looked at over a long period of time, but not necessarily had the same volume of research delivered from the effort.

The second point is that the amount of time that these pathogens has been circulating is very different. COVID was a very recent pathogen, and therefore the impact on population evolution was very small, particularly when you then compare against TB, which has been circulating for at least 6,000 years and probably actually much longer.

So when we're understanding host genomics research in context, it's important to understand these factors and how that impacts on the research and also perhaps informs how research should be done going forward. 

Susan: Could you just give us a short overview of what are the kinds of questions that you might actually ask within host genomics research? 

Heather: Host genomics tends to focus on specific clinical phenotypes. So, a good way to think about this is through examples. So in COVID-19, a lot of the research focused on people who had a really severe response. Often people who were recruited from ICU. Other examples of this could be resistance. So tuberculosis we know from particular populations, when someone becomes infected, we can often through looking at family units, we can identify other people who've been exposed because they have that known exposure to someone who had active TB infection. And following up those individuals, you can then identify who did or didn't, elicit a response to TB. And those individuals can then tell us about innate resistance to tuberculosis or people who have greater control when infected with TB.

Susan: Okay, so the situation's a bit more complicated and perhaps less clear cut than, you know, we'd all aspire to something be really simple. So, yeah. Can you tell, you know, you've touched on that complexity. Are there any other aspects to host genomics, which are perhaps more complicated than you thought they would be when you started off with the work?

Heather: I think the key element is that most of host genomics results points to the immune system and the immune system is a very complex organ. It responds differently depending upon what pathogen is involved, and there are particularly complexities around understanding immune genetics and then transferring that into insights in terms of how that changes the immune response.

So a very good example of this is the HLA genes. So, HLA stands for human leukocyte antigens, and these are involved in antigen recognition. So this is when we're infected, this is different parts of the infection, and those get presented to the immune system and they initiate the immune response, particularly the adaptive immune response.

And we know across different populations, this is one of the areas where you see a really high degree of variability. Different populations have very different HLA profiles, and we still have a very limited understanding of translating some of those variants through to how that may actually impact on immune response, let alone how perhaps that impacts on specific infections in specific infectious responses.

Susan: This feels quite complicated. What can we do to make sense of it? 

Heather: Yes, the immune system is incredibly complex, but that's perhaps why host genomics is so important. It allows us to tie back specific elements of the host response to the immune system. And these insights have been really valuable for driving research.

Susan: You've mentioned that, obviously we're talking about infectious disease, where the burden isn't fairly distributed across the world and often we know that higher income countries spend more on research. Can you talk a bit about why is that an issue and what does that mean within the context of host genomics?

Heather: I think one of the fundamental challenges is that much of the infrastructure to deliver the researchers in high income countries, as you say, there's more resource available to inform research, but also there's more investment into the fundamental tools that researchers need to deliver research. So this could be your biobanks, this could be, clinical phenotyping data from having an electronic health record system.

And often these are resources that are not available in low middle income countries. And, therefore, for researchers who want to deliver this research, they will have to make strategic choices based upon the resources available to them, and that may lead to a higher volume of the research proportionately happening in high income countries.

Susan: Is that because therefore, inevitably that research might focus on aspects of host genomics, which are actually most relevant to those geographical populations, or is it that actually it's inappropriate for a high income country to be focusing on a condition that is actually much more prevalent elsewhere?

Heather: I suppose the questions you may ask are going to depend upon the disease. So HIV is a very good example of this, where in high income countries, the profile of people who are severely affected is very different to those in, for example, Sub-Saharan Africa. And this isn't then a problem that's specifically related to host genomics, but actually related to those questions that people may ask.

But then I suppose if you take an example like tuberculosis, where the burden of disease does much more fall on low and middle income countries, the scale of the research just becomes different. So it's not that TB doesn't occur in all countries across the world. It's more that the types of research you may deliver are then gonna differ depending upon the population and again, the resource available to the researchers.

Susan: We've touched on the work you've done has reviewed where we are from a kind of research perspective, and obviously from a PHG perspective we are really interested to think about how science benefits health. So what did you discover around the relevance of host genomics, probably within a clinical setting? Is there much we can say at this stage? 

Heather: So in terms of what has happened now, there are definitely examples of some therapeutics which host genomics research informed whether or not without host genomics, we may still have had these therapies is open to debate, but certainly thinking about type two inhibitors and Baricitinib to treat COVID-19, host genomics has definitely been pointed to by multiple researchers as an important source of information. Similarly, Maraviroc for HIV treatment, insights from host genomics definitely were informative for that drug, but other sources were also equally important. Beyond that, it's hard to say what the clinical impact of host genomics has been, but that's not to say that there isn't a lot of interest and opportunities that researchers have identified.

It's just at this stage, they're quite far from that translational research and particularly thinking about something like an actual product or clinical trials, testing, how that actually affects patient outcomes. 

Susan: So if you were gonna summarise kind of perhaps some of the key findings of our report, what would you say they were?

Heather: Host genomics is clearly an active field. We found a lot of different research just in the four diseases we studied. We did choose them because we knew they were active in terms of engagement with researchers, but there were other diseases we could have considered. What I think is really interesting is that the research in that landscape is not necessarily balanced.

So certainly some infectious diseases, particularly certain questions or phenotypes were disproportionately researched compared to others, and particularly then when thinking about the populations included in those studies, it was not necessarily clear how strategic those decisions were around which infectious disease, which question, which population, to study. 

Susan: Can you perhaps articulate why there would've been this lack of balance? 

Heather: I mean, for me, the main aspect that seems important is how difficult is a question to ask If you have a population that you know is suitable for a particular research question, particularly if there's already been engagement with that community, and therefore the opportunity is already there. I think that's attractive. So this partly would be your existing biobanks, but this could also be certain communities where there's been a particular event that make them a good... make them ideal, I suppose, for research, although any research will have nuances and difficulties to address, I think that fundamentally some questions are just more difficult to ask and the specifics of that are going to depend upon your disease and also upon the populations that have been affected. 

Susan: So, going back to our report findings what else would you say were the kind of key takeaways? 

Heather: Host genomics is one element that feeds into a much bigger landscape for infectious disease research. So one of the clear messages for me is considering host genomics within this larger context particularly because we do need these multiple types of evidence if we're to build that bigger picture. 

Susan: So when you talk about multiple types of evidence, what other... where else could host genomics pair up? Or, you know, who else could it ... what other branches of science could it be working with? 

Heather: I mean, we already know that it works with epidemiology. I think one area that was highlighted that's particularly of value could come from the synergies between pathogen genomics and host genomics. Where this is happening already, it enables a new relatively novel type of study called a genome to genome study.

And this compares within a particular area, a particular strain of an infectious disease to the local population that have been affected and tries to identify whether or not there are actually relationships between particular genotypes that are involved in the disease compared to the local population.

And this can be really insightful, particularly if you're trying to identify people who are particularly susceptible because this relates to the selective pressure that the population applies potentially to your disease, and I think this is really interesting, particularly when you are thinking about something like tuberculosis where we know that there are particular strains that are circulating in particular populations, and this is about then taking that research up another level enabled by these new innovations.

Susan: Is it fair to say then that what you've discovered through this report is that actually there's a huge variation in the role of host genomics within different infectious diseases? 

Heather: For sure. I think that just reflects the natural history of different diseases. It isn't possible for a one size fits all with any of these research questions.

You need to start with the infectious disease and the impact it has on local populations. Otherwise the questions won't necessarily make sense. That doesn't mean that there aren't common questions across the diseases, it's just that some questions are more relevant in some settings than others. 

Susan: And I guess that reflects some of the complexity in this topic, that actually, as you said, there isn't a one size fits all. It has to be bespoke and reflect that particular population and the particular infectious disease that you're looking at. 

Heather: Exactly, I think also one useful thing to point out is that these diseases don't happen in isolation. So one of the ongoing questions and evolving areas is around some of the syndemics that we are seeing, particularly between HIV and tuberculosis, hepatitis C virus and other diseases that are endemic in the same regions.

HIV because it has such a major consequence for the immune response, has a significant role in increasing consequence of these other diseases. So, particularly with TB, people are walking around not realising that they have TB and when they become infected with HIV, that can lead them to progress to active TB disease, which they may not have otherwise had.

Susan: That's really fascinating that almost they are. Adding on top of each other and sort of strengthening the overall impacts. 

Heather: Exactly, and I think this is always one of the concerns when trying to address any public health mission around any of these infectious diseases is you need to have an understanding of not just the one disease, but this wider context and the relationships, and it's why such ongoing and concerted effort is needed to address these infectious diseases. 

Susan: What would you say are the recommendations that we've concluded from the report about what needs to happen next to actually address some of the challenges and opportunities that you've described? 

Heather: I think what's very clear for me is that the value from host genomics comes from the biological insights.

These are going to leap the opportunities that hopefully with time and effort can lead to improved outcomes for patients and populations. I think key to this is understanding that host genomics isn't happening in isolation and it needs that integrated, that holistic perspective. It is that broader view and that interconnectedness of different infectious diseases, populations, and interdisciplinarity that will lead to the value that we want to see.

In terms of recommendations then, it came down to three kind of main areas. The first is that currently the landscape of host genomics research is quite fragmented, and there is value perhaps in developing a strategy which would allow greater coordination of research, and that this should be informed not just by host genomics research, but by the infectious disease researchers and experts in this area, to perhaps take a step back and think about how this research can provide the greatest value, and this can then guide decisions around ongoing research.

The second recommendation from the report was thinking about how her ceramics may be complemented by advances in new technologies and through better aligning the goals of host genomics and infectious disease research.

So I think a key area is around robust infrastructure. There are initiatives, particularly thinking about in Africa, there are efforts to establish a biobank for Africa, and I think this would go a long way to supporting this research. The other element is around functional studies. So I think this is about recognising that while you funded host genomics research, it's also important to fund functional studies, which then take the research and take it to the next level because it's through these insights leading to my third recommendation that we can facilitate translation of research into practice. We need to think more precisely about this pipeline where you have discovery research and the need to then support translational research and that hopefully then would lead to implementation. Each of these elements are distinct, but would work best when considered as a whole. 

Susan: And I guess that's where it comes back to that first recommendation about a research strategy, because that actually could underpin all of it. And I guess, you know, we are making these recommendations, but recognising that it is probably for research funders to make some of these decisions.

They have the power to incentivise this research and direct it. So we are really keen to see research funders think about this and think about the opportunities that might arise if they can incorporate host genomics strategically into the research they fund. 

Heather: I think that's completely true.

I also think, there are wider synergies between host genomics research and some of the other goals that we have around genomics research as a whole. So particularly thinking about the fact that many of the global majority populations are underrepresented in our genomics databases, and there are a number of different initiatives which are aimed to address this data gap.

Host genomics predominantly should be focused on the infectious diseases that are affecting these global majority populations. And I think that there is opportunities for synergies where we can address both this data gap that we've found with these global majority populations, and also address the diseases that are also most relevant to these populations through host genomics research.

Susan: Thanks, Heather. I think that was a really good way of summing-up what we want to see going forward. Thank you. Good to chat with you. 

Heather: Thanks Susan. 

Ofori: And that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description.

You can also find additional information on our website, www.phgfoundation.org, and if you have any further questions about the topic, then you can email us at intelligence@phgfoundation.org. Thank you for listening, and we look forward to bringing you a new topic in the next episode.