Deepe, G. S. | bioRxiv Science

bioRxiv2023

Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming

The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to early life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling. The p75 neurotrophic factor receptor (NTR) was an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" was long lasting in females and could be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/528015v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@117ad6eorg.highwire.dtl.DTLVardef@17b4188org.highwire.dtl.DTLVardef@10b4d9borg.highwire.dtl.DTLVardef@1142094_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Sialophorin is an essential host element for vaccine immunity against pulmonary fungal infections

The global burden of fungal infections is alarming, primarily due to the increasing immune-compromised population. The immuno-preventive/therapeutic measures, including vaccines, are necessary to prevent or control fungal diseases. Identifying a protective host element as a functional phenotypic marker is immensely valuable. We identified a host element, sialophorin, preferentially associated with antifungal memory T cells. We investigated its role in vaccine immunity using a mouse model of pulmonary fungal infection. We found that sialophorin was essential to bolster CD8+ T-cell responses to the vaccine by enhancing their differentiation and expanding cytokine-producing cells required for immunity. Using a gain-of-function approach, activating sialophorin using mAb augmented the CD8+ T cell responses, and sialophorin-sufficient CD8+ T cells were competitively superior in differentiation and expansion to the deficient cells. Sialophorin-mediated vaccine immunity was independent of the T cell trafficking effect. Finally, we show that sialophorin is a potential functional phenotypic marker of fungal vaccine-potency and immunity. Our study revealed that sialophorin is an essential host-target element to bolster vaccine responses and serves as a potential biomarker of fungal immunity. Author SummaryFungal infections have been rising in recent years due to increased immunocompromised individuals. Vaccination of at-risk individuals helps counter the infections. Thus, suitable vaccine platforms are needed with apt adjuvants, and a phenotypic marker of vaccine immunity will bolster the efforts. We identified a phenotypic marker, sialophorin, associated with T cell vaccine immunity to fungal infection. Our findings show an essential role of sialophorin for fungal immunity, as a target of adjuvanticity, and as a potential biomarker of vaccine immunity against many fungal infections.

immunology↗