Identifying a Potential Therapeutic Host Target in Cutaneous Leishmaniasis

Area of Science:

• Immunology
• Dermatology
• Infectious Diseases

Background:

• Intracellular infectious agents can trigger autoimmune responses, worsening systemic illness.
• Cutaneous leishmaniasis (CL) involves severe immune responses leading to mucosal disease and ulceration.
• Previous research linked cytotoxic CD8+ T-cell responses to CL treatment failure.

Purpose of the Study:

• To investigate the efficacy of inhibiting granzyme B using a JAK1/3 inhibitor, tofacitinib, in managing CL.
• To assess the impact of tofacitinib on cutaneous lesion severity and immune responses in CL.
• To explore the potential of topical delivery for JAK inhibition in CL treatment.

Main Methods:

• Utilized a JAK1/3 inhibitor, tofacitinib, to block granzyme B activity.
• Evaluated the effect of tofacitinib on the severity of cutaneous lesions.
• Assessed the impact on T helper type 1 (Th1) signaling and parasite control.
• Investigated the feasibility of topical drug delivery.

Main Results:

• Inhibition of granzyme B with tofacitinib decreased the severity of cutaneous lesions.
• JAK inhibition did not attenuate T helper type 1 signaling.
• Parasite control was maintained despite granzyme B inhibition.
• Topical delivery of tofacitinib showed utility.

Conclusions:

• Janus kinase (JAK) inhibition, particularly targeting granzyme B, offers a potential therapeutic strategy for CL.
• Tofacitinib may reduce CL severity by modulating immunopathologic responses.
• JAK inhibition, combined with antiparasitic agents and topical delivery, presents a promising treatment approach for CL.