Introduction

As a physician-scientist specializing in the field of Pediatric Infectious Diseases, my research agenda focuses on understanding mechanisms and consequences of immune dysregulation among highly vulnerable populations, including young infants, children living in low and middle income settings (LMIC), and individuals living with HIV-infection. My clinical experiences have also propelled my interest in improving diagnostic tools for common diseases impacting children, such as pediatric TB and severe pneumonia. My research training and expertise has allowed me to develop and lead studies focusing on how host-pathogen interactions lead to T cell and monocyte activation and differentiation, as well as the consequences of systemic inflammation on adaptive and innate immune function. My research funding is provided by the National Institute of Health, the Bill & Melinda Gates Foundation, the Friends of Doernbecher Foundation, and the Collins Medical Trust.

Current research program

The impact of naltrexone treatment on opioid-induced immune and viral dysregulation during HIV-infection

• Chronic opioid use among people living with HIV (PLHIV) is an on-going public health crisis. The interplay between opioids and HIV may accelerate HIV-associated immune dysregulation, chronic inflammation and coagulopathy, and predispose to AIDS and non-AIDS related mortality and morbidities. Published date from in vitro and animal models demonstrate that, in addition to their interactions with opioid receptors, opioids directly bind and activate Toll-like Receptor-4 (TLR-4), promote intestinal damage and microbial translocation, interfere with regulation of lipopolysaccharide (LPS)-induced inflammation, and facilitate HIV replication. Our own preliminary data support that opioid use is associated with advanced immune activation and dysregulated responses to LPS among PLHIV. We hypothesize that opioid exposure disrupts homeostatic anti-inflammatory miRNAs that normally limit TLR-4 mediated monocyte activation and dysfunction. We propose that opioid exposure will be associated with evidence of advanced intestinal permeability, HIV-associated T cell activation and exhaustion, coagulopathy, and compromised antiviral capacity. Working with Dr. Korthuis at OHSU, we will capitalize on access to longitudinal clinical samples from PLHIV who also suffer from opioid-use disorders who are participating in an independent phase IIB randomization clinical trial (CTN-067) to determine optimal management of combined HIV infection and OUD. Trial participants will receive antiretroviral therapy (ART) plus 6 months of OUD therapy with either 1) the long-acting opioid-antagonist extended release naltrexone (XR-NTX); or 2) treatment-as-usual (TAU) with opioid-agonists. Based on published findings from in vitro and animal models, we propose that XR-NTX will be associated with significant reductions in gut permeability, immune activation and exhaustion, coagulopathy, and gains in T cell anti-viral capacity; will restore miRNAs that normally regulate LPS-induced immune activation; and will promote early viral control and reduction of the inducible HIV reservoir. In addition to Dr. Korthuis, collaborators include: Dr. Marcel Culin at Oregon Health & Science University; Dr. Rafick Sekaly and Dr. Susan Pereira Ribeiro at Case Western Reserve University.

Immunologic and Nutritional Determinants of Failing versus Thriving Children following Severe Infection

• Undernutrition contributes to nearly 50% of all annual deaths in children under 5 years. Under nourished children are more vulnerable to infectious pathogens and more likely to die from infectious diseases; specifically, complications related to diarrhea, pneumonia, and measles. Although there has been some progress in reducing childhood undernutrition worldwide, children living in sub-Saharan Africa and Asia continue to bear the largest burden of morbidities and mortality associated with undernutrition. Undernutrition not only impacts growth and vulnerability to severe infection, but chronic undernutrition is highly associated with life-long cognitive delays. Thus, undernutrition deprives children from thriving to meet their full growth and cognitive potential, introducing disadvantages that persist into adulthood. Despite strong evidence of associations between undernutrition, infection and an increased risk of death among young children, the mechanisms driving this vulnerability are not understood. The Childhood Acute Illness & Nutrition Network (http://chainnetwork.org) is a group of investigators based at 9 international sites in LMIC in sub-Saharan Africa and SE Asia, who are working together to generate evidence and improved understanding of children with acute illness and undernutrition focusing in particular on the factors that result in their vulnerability, and working to identify targets of intervention which can help to avert the high mortality and poor outcomes within this group. Working with Dr. Ezekiel Mupere, a longtime collaborator, Dr. Lancioni serves as the Co-PI of the CHAIN site located in Kampala, Uganda, as well as the Co-lead of CHAIN sub projects focusing on the identification of immunologic determinants of survival outcomes following the hospitalization for acute illness among young infants, as well as the identification of novel diagnostic assays for TB in young infants.

Mechanisms governing TLR-2 mediated co-stimulation of neonatal CD4+ T cells

• Our research examines the ability of naïve CD4+ T cells from newborn infants to directly respond to molecules termed "Pathogen-Associated Molecular Patterns" (PAMPs) using "Toll-like Receptors)" (TLRs). Although TLRs have traditionally been described on innate antigen presenting cells, it is now recognized that T cells also use TLRs as co-stimulatory receptors. Dr. Lancioni determined that TLR-1/2 serves as a unique co-stimulatory receptor for naïve CD4+ T cells from newborn infants that allows them to become activated and differentiate into potent Th-1 effector cells productive of key pro-inflammatory cytokines, such as interferon-gamma. Currently, the laboratory is working to delineate the mechanisms governing TLR-1/2 mediated CD4+ T cell activation, with the hypothesis that TLR-1/2 signaling leads to epigenetic modifications that allow transcription of key pro-inflammatory genes.