Host-Directed Therapy (HDT) is a revolutionary way to boost a patient’s immune system in order to fight different diseases that modern medicine and medical procedures are having trouble with. In this current age, the creation and approval of drugs is an extremely difficult and long process, resulting in a shortage of drugs. Furthermore, most of the drugs currently available are simply modified versions of existing drugs. On the contrary, new diseases constantly appear and old ones mutate, many of which have become resistant to existing drugs. This problem poses a great challenge to physicians all around the world to provide the best patient care. Thus, scientist have found one solution to this problem and that is to target the host rather than the pathogen. This paper will explain the concept behind HDTs and its benefits, how different types of HDTs can improve care for patients with different types of diseases, as well as some of its limitations.
HDT is a series of treatments that is performed on a patient in order to enhance his/her immune system to attack threats inside the body [1]. This advancement was yielded by understanding the relationship between the host and pathogens. What is exciting about these treatments is the fact that it utilizes currently available drugs [2]. Meaning, by repurposing licensed drugs that are usually used for other diseases, such as cancer and cardiovascular diseases, as long as we figure out how to implement these therapies, it is not necessary to spend a huge amount of resources to invest in novel drugs.
HDT can impact a host’s internal biological condition in various ways: by inhibiting host-related factors that is required for diseases to grow, suppressing immune-suppressor cells that expands during infection, enhancing host’s immune response, suppressing the host’s harmful immune reactions such as hyperinflammation that cause diseases to exacerbate, and many others [3]. HDT approaches are also less prone to resistance in comparison to drugs that targets the pathogens. In order to combat drugs, pathogens only need to mutate minimally (i.e. to be resistant against rifampicin, bacteria should simply mutate its RNA polymerase beta subunit). However, to resist HDT, pathogens must use an alternative host factor to replicate. These host factors have been conserved over generations and evolutions. Therefore, in order to adopt resistance, more mutations must occur in the pathogens [2].
One disease that has attracted different researchers for the development of HDTs is tuberculosis. Tuberculosis (TB) is a disease caused by a bacterium called Mycobacterium tuberculosis. Treatments for this disease have posed problems in the past because these bacteria have grown resistant to multiple antibiotics. Moreover, as physicians start to cure patients using chemotherapy, they have yet again encounter problems: the treatments are expensive and takes a long time, which can lead to drug toxicities in patients [4]. These problems can be fixed using HDTs.
Recently, an experiment was performed on mice, which shows that the use of denileukin diftitox (DD), an agent that is commonly used to treat a type of immune system cancer, is an effective HDT for this disease [5]. The experiment was conducted by injecting tuberculosis-infected mice with different doses of DD. Then, to determine the effectiveness of the DD treatment on the tuberculosis bacteria, the scientists decided to count colony-forming units (CFU), which is the number of bacteria, found in both lung and spleen (common sites for TB). During a TB infection, cells that suppress our immune system arises and this facilitates higher rates of bacterial replication, promoting disease progression [5]. Two of these suppressor cells are called T-regulatory (Treg) and myeloid-derived suppressor cells (MDSC). This experiment was conducted on the basis that DD could deplete these immune-suppressor cells present during TB infections.
This experiment resulted in two important conclusions. The first states that injecting DD will inhibit the replication of the TB bacteria, as well as reduce the dissemination of the bacteria from the lungs to the spleen. As seen in Figure A, the number of CFU in treated mice are considerably lower than in those that are untreated. Meanwhile, in Figure B, it can be seen that the number of CFU in spleens of mice treated with DD is also considerably lower than untreated mice.
The second conclusion derived from this experiment is that injecting DD enhances current treatments for TB. By injecting the drug with and without protein toxin, a toxin involved in the standard treatment of TB, called RHZ. As seen in Figure C and D below, the level of CFU on RHZ+DD mice is lower in both the lungs and the spleen. This shows that when administered at the same time, DD HDT significantly increases the effectiveness of a standard RHZ tuberculosis therapy.
This experiment ultimately concludes that these promising results was due to DD’s ability to reduce Treg and MDSC frequencies in lungs and spleens during TB infections. This reduction in the frequency of immune suppressive cells that expands during infection reduces the ability of TB bacteria to replicate. The experiment indicates that “a single cycle of DD can result in a 7-fold decrease of TB bacteria CFU counts, a 70-fold reduction in lung-to-spleen dissemination, and significantly boosted the bacterial killing of current TB therapy” [5]. This experiment implicates that other suppressor cell–depleting therapies may be a useful form of adjunctive, host-directed therapies for TB.
Another intractable mycobacterium disease that can be aided by HDT is Mycobacterium Avium Complex (MAC). One HDT that can be used to battle MAC is adenosine triphosphate (ATP). This chemical is extremely common and is well-known for being the “energy currency of life” as it is in charge of facilitating chemical reactions necessary for survival. On the surface, ATP as a form of HDT is useful for three things: boosting our immune system to kill MAC bacteria, depriving bacteria of metal ions, as well as inducing the apoptosis, or cell death, of macrophages [4].
In boosting the host’s immune system, ATP targets macrophages, which are human white blood cells in charge of our immune system, and enhances its ability to kill mycobacterial organisms, like the MAC bacteria. ATP is also known to chelate metal ions, like Mg2+ and Mn2+. Metal ions are necessary for microorganisms to live and survive. During an infection, bacteria need to compete with other iron-chelating substances inside the hosts’ body. With the help of siderophores, a molecule secreted by bacteria which binds and transports iron, they are able to maintain sufficient iron levels for survival. Thus, by being able to exhibit high levels of iron-chelating activity, ATP is depriving the bacteria of these essential compounds, causing them to die. Furthermore, ATP also up-regulates apoptosis, or cell death, of macrophages, by inducing autophagy, a process of eliminating or recycling cellular components, such as damaged organelles, and creating new ones. Apoptosis is important because during an infection, after some time, macrophages can become a cellular source of immunosuppressing cells, which in turn will suppress its function to kill mycobacteria.
Another important bacterial infection that can be inhibited by HDT is sepsis [2]. Sepsis is the leading cause of death in ICUs in industrialized countries. The majority of deaths caused by sepsis happens when this disease evolves into its highly immunosuppressive state. Here, HDT can be used to restore host immunity and improve survival. This type of HDT is called IFNγ, a type of cytokine, which are substances secreted from immune cells. In a recent study of patients in the immunosuppressive state of sepsis, treating them with this HDT reduced duration of mechanical ventilation as well as ICU stays. Patients also have fewer infection-related deaths. Another highly-promising cytokine-based HDT for the treatment of sepsis is IL-7. This HDT is important in making sure essential immune cells, called CD4+ and CD8+ T cells, survive. The depletion of these immune cells is the pathophysiological hallmark of the sepsis disease. What makes IL-7 exciting is the fact that it does not only reactivate those important immune cells, it also increases the surface expression of cell adhesion molecules that facilitates the trafficking of immune cells to infection site for faster immune response.
In addition to bacterial infections, HDT can also aid in the mitigation of viral infections [2]. Viruses are considered parasites since they are required to infect a host cells in order to replicate and survive. This is why viral infections usually begin when viruses attach itself to the host cell. This attachment requires an interaction between proteins on the virus’ surface with receptors on the cell membrane of the host cell. Since viruses are highly dependent on multiple host cell factors in order to survive and replicate, each of the host dependency factor (HDF), host factors that viruses need, is a potential target for HDT. Additionally, HDT that inhibits the binding of virus particle with the host cell receptor is also extremely promising. These types of HDT has been proven successful in the treatment of life-threatening viruses like the Hepatitis B virus (HBV) and the human immunodeficiency virus (HIV).
An HDT that prohibits entry of HBV virus is called myrcludex B [2]. This peptide (a chain of amino acids), binds to the cell surface receptor, which is essential for productive HBV infection and thus blocks viral entry. Apart from entry inhibitors, HDTs that inhibits replication are also attractive forms of therapies. An example of an HDT relevant for the mitigation of hepatitis virus are Cyp A inhibitors. CypA is a primary HDF for the replication of hepatitis virus. In its early stages of development, researches encounter troubles since CypA is also essential in the activation of T-cells, which is our body’s immune system. However, since then, scientists have managed to create non-immunosuppressive CypA drugs, which warrants this a safe HDT.
For HIV, the novel HDT is called Maraviroc [2]. This drug locks the HIV entry receptor, CCR5, and therefore dampen its function. If the receptor is not working, then the HIV will have more trouble entering the cell. Furthermore, as expected for an HDT, resistance to Maraviroc is low, and given the importance of CCR5 in HIV infection, Maraviroc has become an important HDT for HIV therapy. This implicates that targeting entry molecules can really inhibit viral infections. Recently, there has been the identification of entry molecules in different diseases like, NPC1 for Ebola virus, LAMP1 for Lassa virus and PLA2G16 for picornaviruses [2]. This obviously provides a starting point for the development of HDTs against these viruses through entry inhibitors.
However, despite all these positive implications of HDT, there are still some limitations of using these therapies. In general, HDT entails high cost, and since it is host-specific, as human populations exhibit significant diversity in their immune responses to different diseases, this presents a complication for HDTs [4]. Due to multiple genetic differences in some host, it might have strong side effects and only minimal efficacy in potentiating host defense against pathogens. There are also multiple specific negative implications of different HDTs. For instance, HDTs that inhibits an HDF important in viral replication called microRNA are concerning. Though microRNA does promote replication of viruses, it also acts as a tumor suppressor, so inhibiting it comes at a cost [2]. Major limitations of cytokine-based therapies are numerous side effects that includes influenza-like symptoms, depression, bone marrow suppression, exacerbated autoimmunity [2]. Furthermore, multiple HDT requires a precise typing of the disease (i.e. HIV with an X4 strain is different than HIV with an R5 strain), this can delay the onset of treatment and can cause therapy failure [2].
All in all, researches around the world have established that HDT is a revolutionary way of curing current problematic diseases. It has an abundance of uses and advantages for physicians globally. However, they do have some limitations that have yet to be resolved. Even so, being in its infancy, HDT still has room for constant growth which will result in discoveries that can help save millions of lives. For instance, by utilizing HDT together with a close study on patient’s genetic traits, we would be able to identify novel ways of personalized medicine.
Works cited
[1] Alam, Zahidul (2019). A Novel Way to Fight Drug-Resistant Bacteria. Scientific American Blog Network. https://blogs.scientificamerican.com/observations/a-novel-way-to-fight-drug-resistant-bacteria/.
[2] Kaufmann, Stefan H, Dorhoi A, Hotchkiss RS, Bartenschlager R (2017). Host-Directed Therapies for Bacterial and Viral Infections. Nature. https://www.nature.com/articles/nrd.2017.162.
[3] Hawn TR, Shah JA, Kalman D (2015). New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics. Immunol Rev. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571192/
[4] Tomioka H (2015). Host-Directed Therapeutics: ATP as an Immunoadjunctive Agent for Chemotherapy against Mycobacterial Infections. Hiroshima, Japan.
[5] Gupta S, Cheung L, Pokkali S, Winglee K, Guo H, Murphy J, Bishai W (2017). Suppressor Cell–Depleting Immunotherapy with Denileukin Diftitox is an Effective Host-Directed Therapy for Tuberculosis. The Journal of Infectious Diseases, Volume 215, Issue 12:1883–1887.