HRV16 Impairs Macrophages Cytokine Response to a Secondary Bacterial Trigger

Human rhinovirus is frequently seen as an upper respiratory tract infection but growing evidence proves the virus can cause lower respiratory tract infections in patients with chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD). In addition to airway epithelial cells, macrophages are crucial for regulating inflammatory responses to viral infections. However, the response of macrophages to HRV has not been analyzed in detail. We used in vitro monocyte-derived human macrophages to study the cytokine secretion of macrophages in response to the virus. Our results showed that macrophages were competent at responding to HRV, as a robust cytokine response was detected. However, after subsequent exposure to non-typeable Haemophilus influenzae (NTHi) or to LPS, HRV-treated macrophages secreted reduced levels of pro-inflammatory or regulatory cytokines. This “paralyzed” phenotype was not mimicked if the macrophages were pre-treated with LPS or CpG instead of the virus. These results begin to deepen our understanding into why patients with COPD show HRV-induced exacerbations and why they mount a defective response toward NTHi

An additional taxon of the Kelisia guttula group from Central Italy: Kelisia italica (Auchenorrhyncha, Fulgoromorpha, Delphacidae).

Kelisia italica n. sp. found in high altitudes, between 1800-2200 m, in two mountain regions of the Central Italy (Monte Terminillo, Monte Velino) is described. It is closely related to K. guttula (Germar) sensu Wagner and K. sima Ribaut, but is easily distinguished from these species by the shape of the male genital segment (lobuliform projection of the caudal margin lateral of the anal tube) and the lack of the aedeagal lamella. In addition, it differs from K. vittipennis J. Sahlberg by the bigger spot on the genae, the lack of dark markings on the pronotum between eyes and scutum, and by the shape of the aedeagus, and from K. irregulata Haupt by its smaller size, the bigger spot on the genae and the male genital morphology. In the female genitalia there exists a very broad basal part of the “edeagal duct” not present in any other species of the K. guttula-group

Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke.

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5 °C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206 ± 105 vs. 63 ± 21 ng/ml; P = 0.0018 and 209 ± 100 vs. 46 ± 32 ng/ml; P<0.0001), IL-6 (144 ± 40 vs. 46 ± 20 pg/ml; P<0.001 and 184 ± 21 vs. 84 ± 54 pg/ml; P = 0.04), and IL-1β (27 ± 4 vs. 1.7 ± 2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1β and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 µg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling

HRV16 Impairs Macrophages Cytokine Response to a Secondary Bacterial Trigger

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Inhibition of HMGB1 activity protects mutant mice against the lethal effects of heatstroke.

<p>(<b>A</b>) SDS-PAGE analysis of the recombinant A-Box and GST control proteins expressed and purified from <i>E. coli</i> is shown. Increasing amounts of purified proteins were resolved by SDS-PAGE and stained with Coomassie blue; (<b>B</b>) Mutant mice were pretreated (i.p. injection) with A Box 600 µg/mouse; or GST control and heatstroke was induced by passive exposure to environmental heat until the core temperature reached 42.7°C. Pretreatment with A Box before heat stress protected the mutant mice against the lethal effects of heatstroke. *P = 0.04 Kaplan-Meier log-rank testing between the two groups.</p

Core body temperature response of mutant and wild mice type to environmental heat stress.

<p>Mice implanted intraperitoneally with radiotelemetric transmitters (Data Science International were allowed to recover for 2 weeks after surgery before subjected to heat stress or sham heat stress. (<b>A</b>) Core body temperature recorded in mutant and wild type mice at baseline (BL), and during sham heat exposure. (<b>B</b>) Core body temperature recorded in mutant and wild type mice at baseline, during cooling and recovery after heatstroke. Values represent median and IQR. *P<0.05 at T0+4 hours between the two groups tested by the generalized estimating equations model.</p

Thermal responses in Mutant and Wild-type mice subjected to heat stress.

<p>All values are median (25 and 75^th interquartile range). Statistical comparisons were made by Mann-Whitney test between mutant and wild-type mice.</p>*<p> = target core temperature that signals heatstroke onset.</p