A Community-engaged Curriculum at Alpert Medical School: Centering Patient Communities in Medical Education.

Background: Incorporating opportunities for community engagement into undergraduate medical education (UME) can help learners to identify and address social determinants of health (SDoH). Multiple challenges exist in operationalizing these experiences.

Methods: Using the Assessing Community Engagement (ACE) model, course directors at the Warren Alpert Medical School of Brown University (AMS) mapped community engagement initiatives to the four-year curriculum.

Predictors of COVID-19 severity: A literature review.

The coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving global emergency that continues to strain healthcare systems. Emerging research describes a plethora of patient factors-including demographic, clinical, immunologic, hematological, biochemical, and radiographic findings-that may be of utility to clinicians to predict COVID-19 severity and mortality. We present a synthesis of the current literature pertaining to factors predictive of COVID-19 clinical course and outcomes.

IL-10 mediated regulation of liver inflammation during acute murine cytomegalovirus infection.

Various cell types in both lymphoid and non-lymphoid tissues produce the anti-inflammatory cytokine interleukin (IL)-10 during murine cytomegalovirus (MCMV) infection. The functions of IL-10 in the liver during acute infection and the cells that generate this cytokine at this site have not been extensively investigated. In this study, we demonstrate that the production of IL-10 in the liver is elevated in C57BL/6 mice during late acute MCMV infection.

UNC93B1 mediates innate inflammation and antiviral defense in the liver during acute murine cytomegalovirus infection.

Antiviral defense in the liver during acute infection with the hepatotropic virus murine cytomegalovirus (MCMV) involves complex cytokine and cellular interactions. However, the mechanism of viral sensing in the liver that promotes these cytokine and cellular responses has remained unclear. Studies here were undertaken to investigate the role of nucleic acid-sensing Toll-like receptors (TLRs) in initiating antiviral immunity in the liver during infection with MCMV.

Regulation of inflammatory monocyte/macrophage recruitment from the bone marrow during murine cytomegalovirus infection: role for type I interferons in localized induction of CCR2 ligands.

Monocytes/macrophages are critical early innate immune responders during murine CMV (MCMV) infection. It has been established that inflammatory monocyte/macrophages are released from the bone marrow and into the peripheral blood before entry into infected tissue sites. We previously reported a role for IFN-alpha/beta in promotion of CCR2-mediated recruitment of monocyte/macrophages into the liver in response to MCMV infection.

IFN-alphabeta-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection.

Chemokine responses critical for inflammation and promotion of effective innate control of murine CMV (MCMV) in liver have been shown to be dependent on immunoregulatory functions elicited by IFN-alphabeta. However, it remains to be determined whether upstream factors that promote viral sensing resulting in the rapid secretion of IFN-alphabeta in liver differ from those described in other tissues. Because plasmacytoid dendritic cells (pDCs) are known producers of high levels of systemic IFN-alpha in response to MCMV, this study examines the in vivo contribution of pDCs to IFN-alpha production in the liver, and whether production of the cytokine and ensuing inflammatory events are dependent on TLR9, MyD88, or both.

CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL.

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation.

CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection.

Innate inflammatory events promoting antiviral defense in the liver against murine cytomegalovirus (MCMV) infection have been characterized. However, the mechanisms that regulate the selective recruitment of inflammatory T lymphocytes to the liver during MCMV infection have not been defined. The studies presented here demonstrate the expression of monokine induced by gamma interferon (IFN-gamma; Mig/CXCL9) and IFN-gamma-inducible protein 10 (IP-10/CXCL10) in liver leukocytes and correlate their production with the infiltration of MCMV-specific CD8 T cells into the liver.

The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system.

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1.

Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver.

IFN-alpha/beta-mediated functions promote production of MIP-1alpha (or CCL3) by mediating the recruitment of MIP-1alpha-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-gamma delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-alpha/beta and/or play intermediary roles in supporting macrophage trafficking.

Calling in the troops: regulation of inflammatory cell trafficking through innate cytokine/chemokine networks.

The recruitment of immune effector cells to localized sites of infection is crucial for the effective delivery of innate immune mechanisms. Under the conditions of infections with murine cytomegalovirus (MCMV), a herpesvirus with pathogenic potential, early immune functions are essential in the control of virus replication and virus-induced pathology. Our studies have demonstrated that the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) is critical for natural killer (NK) cell inflammation and delivery of interferon (IFN)-gamma to mediate downstream protective responses against MCMV infection in liver.

TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.

Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice.

Dendritic cell responses to early murine cytomegalovirus infection: subset functional specialization and differential regulation by interferon alpha/beta.

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-alpha/beta in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV).

Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection.

NK cell cytotoxicity, IFN-gamma expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets.

Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1alpha delivery to the liver.

Macrophage inflammatory protein 1alpha (MIP-1alpha, CCL3) is critical for liver NK cell inflammation and delivery of IFN-gamma to mediate downstream protective responses against murine cytomegalovirus (MCMV) infections. This system was used to evaluate the upstream contribution of the type 1 IFNs, IFN-alpha/beta, in promotion of MIP-1alpha production. Mice deficient in IFN-alpha/beta functions, as a result of mutation in the receptor for these cytokines (IFN-alpha/betaR(-)), were profoundly deficient in MIP-1alpha expression and accumulation of NK cells and macrophages in the liver and had increased sensitivity to MCMV infection.

Promotion of alpha/beta interferon induction during in vivo viral infection through alpha/beta interferon receptor/STAT1 system-dependent and -independent pathways.

Viruses and viral components can be potent inducers of alpha/beta interferons (IFN-alpha/beta). In culture, IFN-alpha/beta prime for their own expression, in response to viruses, through interferon regulatory factor 7 (IRF-7) induction. The studies presented here evaluated the requirements for functional IFN receptors and the IFN signaling molecule STAT1 in IFN-alpha/beta induction during infections of mice with lymphocytic choriomeningitis virus (LCMV).

Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo.

Interferon (IFN)-alpha/beta and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8alpha(+)Ly6G/C(+)CD11b(-) phenotype.