Tilston-Lunel, A. | bioRxiv Science

bioRxiv2026

Intestinal Barrier Loss Enables Microbiota-Mediated Purinergic Suppression During Malaria

The gut microbiota shapes malaria immunity and disease severity, but the mechanisms underlying these effects remain unclear. In a murine model, susceptibility to Plasmodium yoelii hyperparasitemia was associated with elevated regulatory T cells and diminished IFN-{gamma}. We demonstrate that the IgA-coated fraction of the microbiota is sufficient to transfer this susceptibility. Plasmodium infection disrupts the intestinal barrier regardless of microbiota composition. Mechanistically, barrier loss was associated with systemic adenosine persistence and an expansion of CD39+ plasmablasts in susceptible mice. Ugandan children with severe malaria exhibited a distinct purinergic immune signature compared to asymptomatic community children. Therapeutic reinforcement of the gut barrier or blockade of the downstream adenosine A2A receptor improved germinal centers and reduced disease severity in mice, independent of parasite burden, revealing a purinergic-dependent immunosuppression pathway that drives pathogenesis. This work defines an axis in which malaria-induced gut leakiness enables microbial-derived signals to trigger purinergic immunosuppression and severe disease.

immunology↗

bioRxiv2021

Inactivation of the Hippo Tumor Suppressor Pathway Promotes Melanoma

Human melanomas are commonly driven by activating mutations in BRAF, which promote melanocyte proliferation through constitutive stimulation of the MAPK pathway. However, oncogenic BRAF alone is insufficient to promote melanoma; instead, its expression merely induces a transient burst of proliferation that ultimately ceases with the development of benign nevi (i.e. moles) comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that induce this melanocytic growth arrest remain poorly understood. Recent modeling studies have suggested that the growth arrest of nevus melanocytes is not solely due to oncogene activation in individual cells, but rather due to cells sensing and responding to their collective overgrowth, similar to what occurs in normal tissues. This cell growth arrest is reminiscent of the arrest induced by activation of the Hippo tumor suppressor pathway, which is an evolutionarily conserved pathway known to regulate organ size. Herein, we demonstrate that oncogenic BRAF signaling activates the Hippo pathway in vitro, which leads to inhibition of the pro-growth transcriptional co-activators YAP and TAZ, ultimately promoting the growth arrest of melanocytes. We also provide evidence that the Hippo tumor suppressor pathway is activated in growth-arrested nevus melanocytes in vivo, both from single-cell sequencing of mouse models of nevogenesis and human tissue samples. Mechanistically, we observe that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome-doubling events, and that these two effects independently promote Hippo pathway activation. Lastly, we demonstrate that abrogation of the Hippo pathway, via melanocyte-specific deletion of the Hippo kinases Lats1/2, enables oncogenic BRAF-expressing melanocytes to bypass nevus formation, thus leading to the rapid onset of melanoma with 100% penetrance. This model is clinically relevant, as co-heterozygous loss of LATS1/2 is observed in [~]15% of human melanomas. Collectively, our data reveal that the Hippo pathway enforces the stable growth arrest of nevus melanocytes and therefore represents a critical and previously unappreciated barrier to melanoma development.

cancer biology↗