Culture & Childhood Obesity: Investigating maternal experiences

<p>(A) Perivascular and (B) bronchial inflammation was recorded in mice exposed to cigarette smoke and RSV for 6 months and their corresponding controls. (C) Matrix accumulation was assessed with trichrome staining in each mouse group and quantified by the Ashcroft fibrosis score. Representative images of mice lungs from each group are presented here (scale bar = 20 µM; left panels). Fibrosis and inflammation scores were calculated for each treatment group (right panels where n = 12 animals/group). Each graph is represented as mean ± S.E.M. where each measurement was performed on 12 animals/group. p values shown, comparing both treatments connected by a line.</p

Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-Infected Malian Children

Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP) Malian children have age-dependent protection from malaria compared to matched schistosomiasis-negative (SN) children. Evidence of durable immunologic memory to malaria antigens is conflicting, particularly in young children and the effect of concomitant schistomiasis upon acquisition of memory is unknown. We examined antigen-specific B memory cell (MBC) frequencies (expressed as percentage of total number of IgG-secreting cells) in 84 Malian children aged 4–14 to malaria blood-stage antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1) and to schistosomal antigens, Soluble Worm Antigenic Preparation (SWAP) and Schistosoma Egg Antigen (SEA), at a time point during the malaria transmission season and a follow-up dry season visit. We demonstrate, for the first time, MBC responses to S. haematobium antigens in Malian children with urinary egg excretion and provide evidence of seasonal acquisition of immunologic memory, age-associated differences in MBC acquisition, and correlation with circulating S. haematobium antibody. Moreover, the presence of a parasitic co-infection resulted in older children, aged 9–14 years, with underlying S. haematobium infection having significantly more MBC response to malaria antigens (AMA1 and MSP1) than their age-matched SN counterparts. We conclude that detectable MBC response can be measured against both malaria and schistosomal antigens and that the presence of S. haematobium may be associated with enhanced MBC induction in an age-specific manner

Reduced T Regulatory Cell Response during Acute Plasmodium falciparum Infection in Malian Children Co-Infected with Schistosoma haematobium

Regulatory T cells (Tregs) suppress host immune responses and participate in immune homeostasis. In co-infection, secondary parasite infections may disrupt the immunologic responses induced by a pre-existing parasitic infection. We previously demonstrated that schistosomiasis-positive (SP) Malian children, aged 4-8 years, are protected against the acquisition of malaria compared to matched schistosomiasis-negative (SN) children.To determine if Tregs contribute to this protection, we performed immunologic and Treg depletion in vitro studies using PBMC acquired from children with and without S. haematobium infection followed longitudinally for the acquisition of malaria. Levels of Tregs were lower in children with dual infections compared to children with malaria alone (0.49 versus 1.37%, respectively, P = 0.004) but were similar months later, during a period with negligible malaria transmission. The increased levels of Tregs in SN subjects were associated with suppressed serum Th1 cytokine levels, as well as elevated parasitemia compared to co-infected counterparts.These results suggest that lower levels of Tregs in helminth-infected children correlate with altered circulating cytokine and parasitologic results which may play a partial role in mediating protection against falciparum malaria

Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice

Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression

Matrix Metalloproteinase 9 Exerts Antiviral Activity against Respiratory Syncytial Virus

<div><p>Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of <i>Mmp9</i> expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, <i>Mmp9</i>^-/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in <i>Mmp9</i>^-/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR.</p></div

MMP9 regulates cytokine/chemokine expression during RSV infection.

<p><i>Mmp9</i>^-/- mice and their FVB/NJ WT littermates were infected with 1x10⁶ pfu of RSV and animals were euthanized 7 dpi. (A) Cytokine gene expression in lung tissue and BALF levels of RANTES, IL-1β, SCF and G-CSF were determined in both mouse genotypes, 7 dpi. (B) BALF levels of CXCL5, IL-13, CXCL2, TNF-α, MCP-1, IL-17, IL-10 and CXCL1 were determined in both mouse genotypes, 7 dpi. Graphs are represented as mean ± S.E.M, where each measurement performed 3 times on 10 animals/group. p values shown, comparing both treatments connected by a line. All comparisons were determined by student t-tests.</p

MMP9 prevents RSV infectivity of human airway epithelial cells and mouse lungs.

<p>(A) SAE cells were treated with various concentrations of active and inactive human MMP9 and TCID₅₀ assays were performed 48 hours later. (B) RSV was treated with various concentrations of active and inactive MMP9 prior to infecting SAE cells. TCID₅₀ assays were performed to determine the quantity of virus following MMP9 treatment. * Represents a p value less than 0.05 comparing inactive to active MMP9 for each concentration. All comparisons were determined by student t-tests. (C) <i>Mmp9</i>^-/- mice and their FVB/NJ WT littermates were infected with 1x10⁶ pfu of RSV and animals were euthanized 1, 3, 5 and 7 dpi. Plaque assays and RSV N copy number, by qPCR (on 7 dpi), confirmed viral titers in lung tissue from all RSV-infected animals. Graphs are represented as mean ± S.E.M, with each measurement performed 3 times on 10 animals/group. Two-way ANOVA was used to compare the time-course curves and multiple comparisons were determined by the Bonferroni method (left panel). p value shown for qPCR (right panel) comparing both treatments connected by a line, determined by student t-tests.</p

Proposed pathway for MMP9 signaling during RSV infection.

<p>Proposed pathway for MMP9 signaling during RSV infection.</p