# Skin microbiome contributions to the pathogenesis of cutaneous leishmaniasis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $807,175

## Abstract

Project Summary
Leishmaniasis is a neglected tropical disease that occurs worldwide with ineffective anti-parasite drugs and
no vaccine. The disease severity is often due to an exaggerated immune response rather than uncontrolled
parasite replication. Our goal is to define the mechanisms promoting immunopathology in the disease in
order to develop new host-directed therapies. Our new data shows that the skin microbiome contributes to
the development of more severe disease in patients and experimental models. Qualitative and quantitative
changes in the bacteria present in leishmanial lesions, and high levels of Staphylococcus aureus, were
associated with delayed healing. Similarly, bacterial colonization of mice infected with Leishmania leads to
more severe disease without altering the parasite burden. Thus, our results indicate that disease outcome is
profoundly affected by the host response and the skin microbiome. We cultured S. aureus isolates from
patients and we will test the hypothesis that S. aureus promotes increased disease in a strain-specific
manner. Building on preliminary data that strain-level variation in S. aureus underlies differential
immunopathology in cutaneous leishmaniasis, we will use a comparative genomics approach combined with
host-directed phenotyping to identify S. aureus virulence factors that promote disease. We also found that
L. braziliensis patients had variable numbers of regulatory T cells (Tregs) in their lesions and that low
numbers of Tregs were associated with delayed healing. We recapitulated those findings in a mouse model,
showing that mice with low numbers of Tregs colonized with S. aureus and infected with L. braziliensis
develop severe disease with high levels of IFN-γ and S. aureus. We will use our murine models and in vitro
skin organoids to define the mechanisms leading to severe immunopathologic responses. The studies
defining qualitative differences in S. aureus and the immunopathologic responses associated with S. aureus
colonization will be used to identify potential targets for microbial- and host-directed therapies. Pentavalent
antimony is the standard of care for CL in Brazil, but it is often ineffective. Our findings strongly support the
concomitant use of host-directed therapies to improve outcomes. However, to ensure that such therapies do
not lead to an increase in S. aureus burden, we aim to develop therapies that limit host immunopathologic
responses while limiting S. aureus burden and virulence. To accomplish this, we will test a combination of
host-directed therapies with a consortium of skin commensal bacteria that directly inhibit S. aureus, and in
an alternative approach, test a pan-caspase inhibitor that blocks cell death but also controls S. aureus.
Together, these studies will uncover how S. aureus worsens disease caused by Leishmania, information
vital for developing new leishmaniasis treatments, and will also define how S. aureus, a major cause of skin
and soft tissue infectio...

## Key facts

- **NIH application ID:** 10978542
- **Project number:** 2R01AI143790-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth Anne Grice
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $807,175
- **Award type:** 2
- **Project period:** 2019-03-04 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978542

## Citation

> US National Institutes of Health, RePORTER application 10978542, Skin microbiome contributions to the pathogenesis of cutaneous leishmaniasis (2R01AI143790-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10978542. Licensed CC0.

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