Acetylcholine Regulates Pulmonary Pathology During Viral Infection and Recovery.

Introduction: This study was designed to explore the role of acetylcholine (ACh) in pulmonary viral infection and recovery. Inflammatory control is critical to recovery from respiratory viral infection. ACh secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation.

Immunosenescence in monocytes, macrophages, and dendritic cells: lessons learned from the lung and heart.

In the absence of an immune challenge, healthy, aged individuals have a significantly higher basal inflammatory state where circulating levels of cytokines, including IL-6, TNF-α and IL-1β, are elevated [1]. This progressive pro-inflammatory state, termed "inflamm-aging", affects the phenotype/function of cells present in the aged as well as renders the older individuals more susceptible to a poor prognosis after systemic insults. Although it is important to understand the mechanisms that underlie the progression of disease, most preclinical analyses of disease therapies are performed in young adult mice that have an intact, functional immune system.

A novel C5a-derived immunobiotic peptide reduces Streptococcus agalactiae colonization through targeted bacterial killing.

Streptococcus agalactiae (group B Streptococcus [GBS]) is a Gram-positive bacterium that colonizes the cervicovaginal tract in approximately 25% of healthy women. Although colonization is asymptomatic, GBS can be vertically transmitted to newborns peripartum, causing severe disease such as pneumonia and meningitis. Current prophylaxis, consisting of late gestation screening and intrapartum antibiotics, has failed to completely prevent transmission, and GBS remains a leading cause of neonatal sepsis and meningitis in the United States.

Innate immune induction and influenza protection elicited by a response-selective agonist of human C5a.

The anaphylatoxin C5a is an especially potent mediator of both local and systemic inflammation. However, C5a also plays an essential role in mucosal host defense against bacterial, viral, and fungal infection. We have developed a response-selective agonist of human C5a, termed EP67, which retains the immunoenhancing activity of C5a at the expense of its inflammatory, anaphylagenic properties.

Control of methicillin resistant Staphylococcus aureus infection utilizing a novel immunostimulatory peptide.

The emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a serious health concern worldwide that requires new therapeutic approaches that extend beyond the development and use of new antibiotics. In this study, a conformationally biased, response-selective agonist of human C5a, known as EP67, was used to induce host innate immunity as a therapeutic method of reducing CA-MRSA infections. Using a murine model of dermonecrosis we show that EP67 treatment effectively limits CA-MRSA infection by promoting cytokine synthesis and neutrophil influx.

A novel adjuvant for vaccine development in the aged.

A conformationally-biased, response-selective agonist of human C5a(65-74) (EP67) activated antigen presenting cells (APC) from aged C57Bl/6 mice in vitro and the generation of antigen (Ag)-specific antibody (Ab) responses in aged mice in vivo. EP67, induced the release of the pro-inflammatory cytokines IL-6, TNFα, and INFγ from splenic APCs obtained from both aged and young mice. Both aged and young mice produced high Ag-specific IgG Ab titers when immunized with EP67-containing vaccines to ovalbumin (OVA-EP67) and to a protein (rPrp1) from the cell wall of Coccidioides (rPrp1-EP67).

Age-associated changes in miRNA expression profiles in thymopoiesis.

During adult life, the thymus involutes and thymic output of mature T cells drastically declines. The molecular events underlying this process are not well understood. Here, we present evidence of the importance of miRNAs in regulating T cell differentiation in the aged.

Enhancement of in vivo and in vitro immune functions by a conformationally biased, response-selective agonist of human C5a: implications for a novel adjuvant in vaccine design.

A conformationally biased, agonist of human C5a(65-74) (EP67) was assessed for its adjuvant activities in vitro and in vivo. EP67 induced the release of the inflammatory (Th1) type cytokines from C5a receptor (CD88)-bearing antigen presenting cells (APC). EP67 did not induce the release of these cytokines from splenic APCs obtained from C5a receptor knockouts (CD88(-/-)).

A novel approach to thymic rejuvenation in the aged.

With advancing age, the mammalian thymus undergoes involution, a progressive loss of architectural integrity and lymphoid cellularity that results in reduced T lymphopoiesis. Thymic involution also is associated with extreme malnutrition and states of immune deficiency, such as active HIV infection, after chemotherapy, or during pregnancy. Immune recovery appears to require restoration of normal thymopoiesis.

IL-7 gene therapy in aging restores early thymopoiesis without reversing involution.

Thymic involution begins early in life and continues throughout adulthood, resulting in a decreased population of naive T cells in the periphery and a reduced ability to fight off newly encountered infectious diseases. We have previously shown that the first step of thymopoiesis is specifically blocked in aging. This block at the DN1 to DN2 transition and the subsequent loss of thymic output in old age mirrors the changes seen in IL-7-deficient mice, and it is hypothesized that decreased intrathymic IL-7 is involved in age-related thymic involution.