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Field-Deployable Treatments For Leishmaniasis: Intrinsic Challenges, Recent Developments and Next Steps
Thalia Pacheco-Fernandez1, Hannah Markle1, Chaitenya Verma2
1Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD, 20993, USA.
Abstract:
Leishmaniasis is a neglected tropical disease endemic primarily to low- and middle-income countries, for which there has been inadequate development of affordable, safe, and efficacious therapies. Clinical manifestations of leishmaniasis range from self-healing skin lesions to lethal visceral infection with chances of relapse. Although treatments are available, secondary effects limit their use outside the clinic and negatively impact the quality of life of patients in endemic areas. Other non-medicinal treatments, such as thermotherapies, are limited to use in patients with cutaneous leishmaniasis but not with visceral infection. Recent studies shed light to mechanisms through which Leishmania can persist by hiding in cellular safe havens, even after chemotherapies. This review focuses on exploring the cellular niches that Leishmania parasites may be leveraging to persist within the host. Also, the cellular, metabolic, and molecular implications of Leishmania infection and how those could be targeted for therapeutic purposes are discussed. Other therapies, such as those developed against cancer or for manipulation of the ferroptosis pathway, are proposed as possible treatments against leishmaniasis due to their mechanisms of action. In particular, treatments that target hematopoietic stem cells and monocytes, which have recently been found to be necessary components to sustain the infection and provide a safe niche for the parasites are discussed in this review as potential field-deployable treatments against leishmaniasis.
Insights
Leishmaniasis parasites hide in cellular niches, like hematopoietic stem cells and monocytes, to evade treatment. Targeting these safe havens offers new therapeutic strategies for this neglected tropical disease.
Area of Science:
- Parasitology and Tropical Medicine
- Immunology
- Drug Discovery
Background:
- Leishmaniasis is a neglected tropical disease with limited treatment options, often causing severe side effects.
- Current therapies are hampered by parasite persistence in host cellular niches.
- Existing treatments like chemotherapy and thermotherapy have limitations in efficacy and applicability.
Purpose of the Study:
- To review the cellular niches exploited by Leishmania parasites for host persistence.
- To discuss therapeutic strategies targeting these cellular niches and parasite survival mechanisms.
- To explore novel treatment avenues, including repurposed drugs and targeting specific host cells.
Main Methods:
- Literature review of recent studies on Leishmania parasite persistence.
- Analysis of cellular, metabolic, and molecular mechanisms of Leishmania infection.
- Exploration of potential therapeutic targets, including cellular safe havens and host-directed therapies.
Main Results:
- Leishmania parasites utilize specific cellular niches, such as hematopoietic stem cells and monocytes, to evade immune responses and chemotherapy.
- Understanding these niches reveals vulnerabilities for therapeutic intervention.
- Repurposing therapies like those targeting cancer or ferroptosis may offer new treatment options.
Conclusions:
- Targeting the cellular safe havens of Leishmania parasites is a promising strategy for developing novel treatments.
- Hematopoietic stem cells and monocytes are critical for parasite survival and represent key therapeutic targets.
- Further research into host-directed therapies could lead to field-deployable treatments for leishmaniasis.
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