Modulating arbovirus infection via mosquito saliva – an interview with Daniella Lefteri

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Arboviruses constitute a major public health problem. In addition, with our changing climate, mosquito-borne viruses – including dengue, chikungunya and Zika – are expanding in vector range and posing an increasing threat.

In this interview we speak to Daniella Lefteri about her presentation at the Microbiology Society’s Annual Conference (8–11 April, Belfast, UK) where she outlined her research on modulating arbovirus infection by targeting mosquito saliva, and what avenues this could present for new antiviral treatments.

First, could you introduce yourself and give a brief summary your career to date?

So, I originally did my undergraduate degree at the University of Leeds (UK) and I did a BSc in biology. Then I moved to London and did my Masters at Imperial College London (UK), in Virology. I worked for Qiagen for a little while before I started my PhD in Clive McKimmie’s group at the University of Leeds. Our research is based on the virus–host interactions between arboviruses and the mammalian host.

Could you outline the research you’re presenting here?

It has been well established that arbovirus infection of mammals is enhanced by the presence of a mosquito bite, compared with simply injecting the virus in the absence of a bite in a purely experimental setting. This has been shown by a number of different groups using a number of different arboviruses. We also know that mosquito saliva experimentally injected in the absence of a bite enhances infection, which suggests that there is something about mosquito saliva that is responsible for triggering a specific host response that helps the virus spread.

However, it remains unclear which host responses are responsible and it also remains unclear which specific factors in the mosquito saliva are responsible for triggering the host responses. And that is what we are trying to establish. We have evidence that aspects of the host response to saliva inadvertently enhances virus infection. We now need to work out which responses are key for helping the virus.

How important is the inflammatory response in modulating infection?

So, we have discovered that mosquito saliva does not act directly on cells to enhance infection, because when we tried to investigate this in vitro using cell culture, we see that we cannot observe arbovirus enhancement. This suggests that systemic host responses are required, such as inflammation, for enhancement of infection to occur.

We therefore think that the inflammatory response is key in facilitating this. Not only do we see that saliva doesn’t act directly on the virus or on the cells, previous work has also shown that by inhibiting specific inflammatory responses we can reduce inflammation to the mosquito bite, and that this occurs with a reduction in the ability of a bite to enhance infection. Specifically, we think that this infection enhancement is reliant on the influx of inflammatory leukocytes to the site of inflammation, but we are only just beginning to define which aspect of the host inflammatory responses to saliva are responsible.

Is this infection enhancement universal across mosquito species?

Interestingly we have discovered that not all mosquito species are able to enhance infection. This discovery that not all mosquito species are able to enhance arbovirus infection was important as we could then start comparing the differences in host responses with mosquito species that enhance viral infections, such as Aedes aegypti, to that of a mosquito species that doesn’t, such as Anopheles gambiae. This enabled us to define which host responses are required for arbovirus enhancement. For example, via this comparison we observed that Aedes aegypti bites trigger significant amounts of oedema (i.e. that’s fluid accumulation at the site of inflammation), whilst Anopheles gambiae bites do not. This led us to think that perhaps oedema is responsible for viral enhancement.

We tested this by experimentally inducing oedema in absence of any mosquito factors by injecting purified histamine and observed a similar enhancement of infection as we do with the mosquito bites, suggesting that oedema is important in facilitating arbovirus enhancement. So hypothetically, by inhibiting the formation of oedema we can then prevent viral enhancement from occurring in the first place.

Why does the saliva from different species mosquitoes have a differing impact on infection?

The short answer is we don’t really know! But we think it depends on distinct factors that are present in some mosquito’s saliva which can vary between different species. We also believe that several factors need to be present for this enhancement to occur. We have observed that several species enhance infections such as Aedes aegypti, Aedes albopictus, Culex pipiens, but when it comes to the Anopheles mosquitoes, we have discovered that this mosquito species is unable to enhance viral infection.

This is quite interesting as the Anopheles mosquitoes have been shown to be very inefficient vectors of most arboviruses. Even though scientists have been able to detect viral RNA from arboviruses in these mosquitoes, there is no evidence that they can transmit them, with the exception of one, which is called O’nyong’nyong’ virus (ONNV). Currently, no one really understands why they are able to transmit this arbovirus but none of the other ones, however, we think that this phenomenon could help us explain the vector competence of these mosquitoes. For example, we have actually shown that this virus is able to infect mice regardless of the presence of a mosquito bite, unlike most other mosquito-borne viruses that require mosquito saliva to efficiently infect the mammalian host. So, we believe that ONNV has evolved not to rely on enhancement of arbovirus infection mechanism by mosquito saliva, and that this enables it to be spread via a different mosquito species that lacks this inflammation-inducing salivary component.

Could understanding how mosquito saliva modulates infection help to develop future treatments?

We believe that investigating how saliva enhances virus infection will help us develop a treatment, it blocking arbovirus enhancement from occurring in the first place could prevent more serious disease and illnesses associated with these virus infections. This would be quite revolutionary as this would result in a much broader treatment covering a large number of different arboviruses. We know from other work in our lab that it is possible to supress arbovirus infection via the use of an anti-viral topical treatment (keep a look out for our new paper), which suggests that we can alter clinical outcome to infection by manipulating events at the bite site. The idea of developing alternatives that directly target saliva enhancement isn’t improbable.

What are the advantages of an approach that targets many infections simultaneously via targeting mosquito saliva?

There are so many genetically different arboviruses and many of which are largely unheard of and poorly studied. Given the unpredictable nature of the emergence and re-emergence of these viruses, a universal treatment would be of a huge advantage as it could be used without prior need to diagnose the virus infection – something that is very hard during outbreaks of infection. Also, currently there is a very limited number of vaccines available and there are currently no licensed antivirals available for most of these arboviruses, so it would be a very important step if we could develop a broadly acting therapeutic.

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