Recurrent infection transiently expands human tissue T cells while maintaining long-term homeostasis.

Chronic viral infections are known to lead to T cell exhaustion or dysfunction. However, it remains unclear if antigen exposure episodes from periodic viral reactivation, such as herpes simplex virus type-2 (HSV-2) recrudescence, are sufficient to induce T cell dysfunction, particularly in the context of a tissue-specific localized, rather than a systemic, infection. We designed and implemented a stringent clinical surveillance protocol to longitudinally track both viral shedding and in situ tissue immune responses in a cohort of HSV+ volunteers that agreed to avoid using anti-viral therapy for the course of this study.

Memory T cells possess an innate-like function in local protection from mucosal infection.

Mucosal infections pose a significant global health burden. Antigen-specific tissue-resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8+ T cells may also provide innate-like protection against antigenically unrelated pathogens independent of T cell receptor engagement.

The multitaskers of the brain: Glial responses to viral infections and associated post-infectious neurologic sequelae.

Many viral infections cause acute and chronic neurologic diseases which can lead to degeneration of cortical functions. While neurotropic viruses that gain access to the central nervous system (CNS) may induce brain injury directly via infection of neurons or their supporting cells, they also alter brain function via indirect neuroimmune mechanisms that may disrupt the blood-brain barrier (BBB), eliminate synapses, and generate neurotoxic astrocytes and microglia that prevent recovery of neuronal circuits. Non-neuroinvasive, neurovirulent viruses may also trigger aberrant responses in glial cells, including those that interfere with motor and sensory behaviors, encoding of memories and executive function.

Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination.

Background: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (TM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice.

IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state.

Innate immune responses to emerging RNA viruses are increasingly recognized as having significant contributions to neurologic sequelae, especially memory disorders. Using a recovery model of West Nile virus (WNV) encephalitis, we show that, while macrophages deliver the antiviral and anti-neurogenic cytokine IL-1β during acute infection; viral recovery is associated with continued astrocyte inflammasome-mediated production of inflammatory levels of IL-1β, which is maintained by hippocampal astrogenesis via IL-1R1 signaling in neural stem cells (NSC). Accordingly, aberrant astrogenesis is prevented in the absence of IL-1 signaling in NSC, indicating that only newly generated astrocytes exert neurotoxic effects, preventing synapse repair and promoting spatial learning deficits.

Cervicovaginal Tissue Residence Confers a Distinct Differentiation Program upon Memory CD8 T Cells.

Tissue-resident memory CD8 T cells (CD8 T) are critical for maintaining barrier immunity. CD8 T have been mainly studied in the skin, lung and gut, with recent studies suggesting that the signals that control tissue residence and phenotype are highly tissue dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B and TCF-1 To address if this phenotype is driven by CVT tissue residence, we used a mouse model to control for environmental factors.

Tissue-resident T cell-derived cytokines eliminate herpes simplex virus-2-infected cells.

The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CD8+ and CD4+ tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection; viral clearance always predominated within 24 hours of detection even when viral load exceeded 1 × 107 HSV DNA copies, and surges in granzyme B and IFN-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans.

Extracellular vesicles in human semen modulate antigen-presenting cell function and decrease downstream antiviral T cell responses.

Human semen contains trillions of extracellular vesicles (SEV) similar in size to sexually transmitted viruses and loaded with potentially bioactive miRNAs, proteins and lipids. SEV were shown to inhibit HIV and Zika virus infectivity, but whether SEV are able also to affect subsequent immune responses is unknown. We found that SEV efficiently bound to and entered antigen-presenting cells (APC) and thus we set out to further dissect the impact of SEV on APC function and the impact on downstream T cell responses.

Bacterial microbiome of breast milk and child saliva from low-income Mexican-American women and children.

Background: The childhood salivary microbiome, which plays an important role in healthy development, may be influenced by breast milk consumption. The composition of the milk microbiome and the role it plays in the establishment of the infant microbiome are not well understood.

Methods: Here, we sequenced the bacterial 16S rRNA gene to characterize microbial communities in breast milk and 5-year-old child saliva from 10 low-income, Mexican-American mother-child pairs with a high prevalence of obesity.

Sex differences in DNA methylation assessed by 450 K BeadChip in newborns.

Background: DNA methylation is an important epigenetic mark that can potentially link early life exposures to adverse health outcomes later in life. Host factors like sex and age strongly influence biological variation of DNA methylation, but characterization of these relationships is still limited, particularly in young children.

Methods: In a sample of 111 Mexican-American subjects (58 girls , 53 boys), we interrogated DNA methylation differences by sex at birth using the 450 K BeadChip in umbilical cord blood specimens, adjusting for cell composition.

Relationship between expression and methylation of obesity-related genes in children.

Epigenetic control of gene expression in children remains poorly understood, but new technologies can help elucidate the relationship between expression and DNA methylation. Here, we utilized the nCounter Analysis System to characterise the expression of 60 genes in 69 9-year-old children from a cohort with a high prevalence of obesity. nCounter expression levels ranged broadly (from 3 to over 10000 messenger RNA counts) and were divided into four categories: high (>2000 counts), moderate (200-1000 counts), low (100-200 counts) and marginal (<100 counts).

Ozone inhalation leads to a dose-dependent increase of cytogenetic damage in human lymphocytes.

Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we used a well-validated cytokinesis-block micronucleus Cytome assay.

Adiponectin and leptin trajectories in Mexican-American children from birth to 9 years of age.

Objectives: To address molecular mechanisms underlying obesity development, we examined patterns of critical metabolism-related hormones, adiponectin and leptin (adipokines), over childhood.

Subjects And Design: Plasma adiponectin and leptin were measured in 80 Mexican-American children at birth and again at 2, 5, and 9 years from the ongoing prospective cohort followed by the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We used a mixture modeling approach to identify patterns in adipokine trajectories from birth to 9 years.

Maternal bisphenol a exposure during pregnancy and its association with adipokines in Mexican-American children.

Bisphenol A (BPA) is a high volume production chemical that has been detected in 93% of the United States population. It is thought to have endocrine disrupting activity but human data are limited. In this study, we examined whether prenatal or concurrent urinary BPA concentrations are associated with key metabolism-related hormones, adiponectin and leptin (adipokines), in 9-year-old children.

Associations between perinatal factors and adiponectin and leptin in 9-year-old Mexican-American children.

What Is Already Known About This Subject: Mexican-American children are at particularly high risk of obesity. Features of the perinatal environment, including maternal nutrition, anthropometry, glucose tolerance and growth rate during infancy are implicated in programming of obesity in the offspring.

What This Study Adds: Greater rate of weight or length gain in the first 6 months of life is associated with lower 9-year child adiponectin levels, adjusting for 9-year child BMI.