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Carozza, J.

Publications and source records attributed to Carozza, J..

2 recordsLinked to original sources

From protection to amplification: Imperfect chytridiomycosis prophylaxis increases infections in wild amphibians

Wildlife vaccination could become a powerful strategy to mitigate disease-induced biodiversity losses, yet many vaccines for wildlife diseases provide only limited protection. Notably, tools to control the fungal pathogen Batrachochytrium dendrobatidis (Bd) are urgently needed for amphibian conservation. Laboratory experiments have demonstrated that prophylactic exposure to Bd metabolites increases host resistance, significantly reducing infection intensity in amphibians subsequently challenged with live Bd. Because Bd metabolites are non-infectious and applied topically, this treatment has potential to be administered to waterbodies to vaccinate and protect amphibians. We developed an agent-based model that indicated imperfect vaccination could reduce or amplify Bd infections at the population level, depending on degree of enhanced resistance or tolerance. Utilizing a Before-After-Control-Impact design with ten years of data, we conducted an ecosystem-level trial where we applied low levels of Bd metabolites or a sham control treatment to ponds in California and subsequently quantified Bd prevalence and infection intensity in metamorphosing Pacific chorus frogs (Pseudacris regilla). Unexpectedly, infection intensity was significantly greater in treated ponds relative to control ponds following metabolite addition. Additional model simulations indicated that this could occur via two mechanisms: (1) if treatment greatly increased tolerance alone or in combination with smaller increases in resistance, or (2) if a deleterious environmental interaction caused the treatment to increase susceptibility, rather than promote resistance. Future research is needed to determine whether tolerance or environmental factors drove heightened Bd infection intensities in this field trial to identify contexts in which this treatment can be used as a conservation tool. Significance statementAlthough wildlife vaccination is increasingly explored as a strategy to mitigate disease-induced population declines, many available vaccines provide limited protection, requiring careful consideration to design successful conservation campaigns. Here, we use both an eco-epidemiological model and field manipulation experiment to assess the effectiveness of an imperfect prophylactic treatment (akin to a prototype vaccine) for chytridiomycosis, a disease implicated in the massive decline of amphibian biodiversity worldwide. We unexpectedly found that prophylaxis-treated ponds had higher pathogen loads relative to control populations and models suggest this could result from enhanced tolerance or an adverse environmental interaction.

ecology↗

Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP's role as an immunotransmitter

cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from that of ENPP1 and accounts for all remaining cGAMP hydrolysis activity in mice lacking ENPP1. Importantly, we also show that as with ENPP1, selectively abolishing ENPP3s cGAMP hydrolase activity results in diminished cancer growth and metastasis of certain tumor types. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work clearly shows that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a new target for cancer immunotherapy.

biochemistry↗