How are life-saving drugs discovered?
Join DNDi researcher and series host Fanny Escudié to learn more about how scientists are using the most advanced technologies to improve the lives of millions of neglected patients around the world.
Episode 1
What are host-directed therapies – and how can they be used against neglected diseases?
Host-directed therapies (HDTs) are a promising alternative approach that DNDi is exploring to find new treatment options for patients affected by neglected infectious diseases.
Typically, drugs approved to treat infectious diseases stop infections by directly targeting the virus, parasite, or other microbe that causes the illness. These therapies, known as antimicrobials, have proven extremely successful over the years but are not always effective in treating all diseases.
Additional and complementary approaches are therefore needed.
Unlike antimicrobials, HDTs do not directly target microbes; instead, they target proteins of the human body (also known as ‘host factors’) that play an essential role in how diseases develop and affect patients.
Viruses and intracellular bacteria and parasites must enter and utilize host cells to infect, multiply, and persist in the body. HDTs can interfere with these steps by targeting the host factors that enable the microbe to survive and develop.
Developing such HDTs therefore requires a detailed understanding of the disease and its symptoms at both the cellular and molecular levels. Scientists must first identify the host proteins involved in the disease and then identify new or existing molecules that can ‘lock on’ to these proteins and modulate their activity.
HDTs can work in different ways
To explain some of these modes of action, let’s have a look at this graphic that shows possible reactions from the body’s immune system, which plays a critical role in eliminating invading microbes.
This is the ideal case, the ‘optimal’ immune response. The body’s immune system, including the white blood cells, naturally eliminates the microbes and fends off the infection. Tissues and organs heal. In this case, HDTs are not needed!
But sometimes, the immune response is too weak to eliminate the microbes, which can eventually lead to tissue and organ damage. In this situation, an appropriate HDT would boost the immune system. Such HDTs – usually called immunotherapies – have the potential to further reduce some microbial infections.
In other cases, for example, for some infectious diseases such as severe COVID-19 and severe dengue, disease symptoms can manifest or worsen late after the start of the infection, even as microbes are disappearing. These symptoms are usually the result of an excessive and uncontrolled inflammatory immune response. Initially triggered by the body to fight infections, such an immune response can sometimes persist and damage the tissues, and can even lead to death.
An appropriate HDT would therefore aim to reduce this exacerbated immune response.
That’s how some existing anti-inflammatory medicines, such as dexamethasone, were found to be effective against some cases of severe COVID-19 and then repurposed as treatments.
HDTs hold a lot of promise for treating neglected diseases. As one example, DNDi is researching whether they could also be used as a treatment to prevent progression to severe dengue.
Patients monitored in an improvised emergency care unit set up in Belo Horizonte, Brazil, to accommodate the massive influx of people in need of medical care during the 2024 dengue outbreak, the worst in Brazil's history.
Dengue outbreak in Brazil. April 2024
Dengue outbreak in Rio, Brazil. April 2024
Dengue outbreak in Brazil. April 2024
Dengue outbreak in Rio, Brazil. April 2024
Transmitted by mosquitoes and fuelled by climate change and rapid urbanization, dengue fever is one of the fastest-spreading infectious diseases worldwide. Reported cases have increased tenfold over the last two decades. As recently highlighted by The Lancet, dengue ‘is the only infectious disease for which annual mortality is rising’ – and still, no specific treatment exists.
Most people who contract dengue develop only mild, if any, symptoms, but some develop a severe and sometimes life-threatening form of the disease called severe dengue, which is associated with plasma leakage, bleeding, and organ dysfunction. Only symptomatic treatments and supportive therapies exist – for example, to help manage fluid levels in the body. Patients hospitalized with severe dengue require intense, round-the-clock monitoring by healthcare workers. Hospital wards can be quickly overwhelmed during intense dengue outbreaks, leading to increased mortality.
With rising cases and rising mortality, specific treatments to prevent the development of severe dengue are urgently needed.
Since the disease is probably caused not only by the dengue virus itself but also by a dysregulated host immune response, HDTs may be a viable solution.
As a starting point for identifying potential HDTs for dengue, DNDi drug discovery researchers are trying to better understand the biological processes involved in the progression to severe dengue.
We partnered with UK-based Benevolent AI to use AI technology to analyse all existing literature and data on dengue, including hundreds of thousands of scientific articles, to identify host factors that could be responsible for the severe form of the disease. The next step is to find a molecule that could home in on this target, attach to it perfectly like a key in a lock, and neutralize it, thus potentially preventing the development of severe symptoms.
HDTs could also be very effective in treating patients with other neglected diseases, such as Chagas disease and leishmaniasis.
Lesions to the skin caused by cutaneous leishmaniasis. Current treatment is very painful and, for many people, very difficult to access.
Current antimicrobial treatments for visceral leishmaniasis and cutaneous leishmaniasis are lengthy and associated with severe toxicities. We are exploring an immunotherapy approach that would help the immune system to better clear the pathogens and reduce tissue damage.
HTDs also show some promise for Chagas disease. The parasite responsible for the disease can stay dormant in the human body for extremely long periods. People with Chagas typically show no symptoms for many years, if not decades, but up to a third will suffer heart tissue damage that can lead to heart failure and sudden death.
Our researchers and partners are working to understand how the parasite can persist for so many years in the human body and escape its immune system. This foundational knowledge is critical to finding a molecule that could boost the immune defence system and help the body eliminate the parasite.
Identifying and developing HDTs requires a wide-ranging research and scientific expertise across different fields, which is why DNDi drug discovery researchers are collaborating with many different partners from all around the globe. As this is a relatively new area for DNDi that requires specific additional skills – e.g. in immunology, inflammation, and translation of host effects from lab to clinic – we welcome new connections and partnerships to explore these exciting opportunities.
Learn more about HDTs and DNDi’s work
- Host-directed therapies for infectious diseases: current status, recent progress, and future prospects - The Lancet Infectious Diseases
- Host-directed drug therapies for neglected tropical diseases caused by protozoan parasites - Frontiers in Microbiology
- Dengue: the threat to health now and in the future - The Lancet
- DNDi’s work on dengue
- DNDi's drug discovery programme
Photo credit: Xavier Vahed-DNDi, Swiss TPH, Fábio Nascimento-DNDi, Sydelle Willow Smith-DNDi
The Drugs for Neglected Diseases initiative (DNDi) is an international non-profit research and development organization that discovers, develops, and delivers safe, effective, and affordable treatments for neglected patients.
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