In Columbus, Ohio, scientists have made significant strides in developing vaccines to combat leishmaniasis, a disfiguring skin disease, through animal studies.

In their latest research, the scientific team has uncovered how these vaccine candidates, created by altering disease-causing parasites using CRISPR gene editing, trigger molecular-level changes in host cells crucial for initiating an immune response. Findings were published in the journal iScience.

Despite using the same CRISPR technique for both vaccines, the two species of Leishmania parasites, the basis for these vaccines, produced vastly different effects. One of them facilitates the immune response by inhibiting a host metabolite that suppresses immune activity, while the other stimulates a chemical pathway that primes immune cells to combat pathogens.

The primary vaccine was created by modifying the genome of Leishmania major, responsible for causing cutaneous leishmaniasis in tropical and subtropical regions of the Eastern Hemisphere, while a backup vaccine was developed using Leishmania mexicana, a more virulent species found in South, Central, and North America.

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Leishmaniasis affects approximately 12 million people in 90 countries globally, yet no licensed human vaccine exists, and the existing drug treatment for skin lesions involves weeks of daily injections with unpleasant side effects. Visceral leishmaniasis, a more severe form that affects organs, can be fatal if untreated.

In their latest studies, researchers took a deeper dive into the effects of these vaccines by inoculating mouse ears with a normal parasite, a mutated parasite vaccine, or a placebo to simulate the bite of an infected sand fly, the mode of transmission for leishmania in both humans and animals. Mass spectrometry was used at the inoculation site to identify the most significant metabolites, including amino acids, vitamins, and other small molecules produced as a result of metabolism, which govern the body’s various chemical reactions.

The results revealed that the L. major vaccine induced a pro-inflammatory metabolic response in mice by utilizing the amino acid tryptophan to block signals from a molecule that suppresses immunity. In contrast, the L. mexicana vaccine enriched a series of metabolic reactions that activated the necessary pro-inflammatory functions of frontline immune cells.