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Leishmaniasis Infection Severity Linked to Skin Microbiome-Related Host Immune Features

NEW YORK – Skin microbiome interactions with the host immune system appear to influence disease severity and delay healing times in individuals with cutaneous leishmaniasis infections caused by the sandfly-transmitted protozoa parasite Leishmania braziliensis, according to new research from investigators in the US and Brazil.

"The severity of cutaneous disease depends on the extent of parasite replication and the induction of immunopathologic responses," co-senior and co-corresponding authors Elizabeth Grice, a dermatology researcher at UPenn's Perelman School of Medicine, and Phillip Scott, a pathobiologist at UPenn, said in an email summary of the research. They noted that their team "has focused on defining the pathways that lead to severe inflammation in the disease in order to define host-directed therapies that might be given in conjunction with anti-parasitic drugs."

In their paper, published in Science Translational Medicine on Wednesday, Grice, Scott, and their colleagues relied on 16S ribosomal RNA amplicon sequencing, RNA sequencing, and clinical profiling to assess microbiome and host transcriptome patterns in lesion biopsies, lesion swabs, cultured lesions, or unaffected, contralateral skin samples from 62 individuals with L. braziliensis infections. Their results pointed to disease severity-associated skin microbiome and host immune features, which they then analyzed in more detail in mouse models.

"Using an integrative approach using clinical specimens and experimental murine infections, we directly demonstrate the microbiome's critical role in the outcome of leishmanial infection," the authors wrote in their paper, adding that their findings "highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis, and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences."

Along with an overall uptick in bacterial burdens in the microbiomes of individuals with more pronounced inflammation and slow healing, the team saw an overrepresentation of Staphylococcus aureus and other species from the Staphylococcus, Arcanobacterium, Streptococcus, Corynebacterium, and other genera in more severe leishmaniasis cases.

When the investigators used qPCR to quantify bacterial burden in skin biopsy samples, for example, they saw slower-than-usual healing rates in a group of 26 L. braziliensis-infected individuals with a high bacterial burden relative to 25 cases classified as having a low bacterial burden.

"[W]e found both qualitative and quantitative changes in the bacteria present in leishmanial lesions, and that high levels of bacteria in lesions, and specifically high levels of Staphylococcus aureus, are associated with treatment failure in Leishmania braziliensis patients," Scott and Grice explained in their email. "These results suggest that therapies that reduce the S. aureus burden in lesions might promote more rapid lesion resolution."

Among the 148 host genes showing enhanced expression in samples with a high bacterial burden, meanwhile, they saw an overrepresentation of neutrophil chemotaxis genes and genes from the IL-1 proinflammatory immune pathway. Likewise, members of the same team described lower-than-usual regulatory T-cell levels in skin samples from slow healing cutaneous leishmaniasis mouse models with enhanced levels of microbes such as S. aureus — work described in the Journal of Experimental Medicine earlier this month.

In the current study, the team also turned to mouse models to get a closer look at ties between L. braziliensis infection severity, S. aureus representation, and interleukin IL-1-beta levels, and demonstrated that the S. aureus influence on enhanced lesion size and delayed healing relies on IL-1-beta activity.

The study supports the notion that "a dysregulated skin microbiome is an additional pathway leading to increased disease dependent on IL-1-beta," the authors wrote, noting that the findings "provide a rationale for new therapies to influence the skin microbiome in patients, which might be accomplished by antibiotics, probiotics, and improved strategies for care of the leishmanial lesion."