Identification of the fungal ligand triggering cytotoxic PRR-mediated NK cell killing of Cryptococcus and Candida.

Natural killer (NK) cells use the activating receptor NKp30 as a microbial pattern-recognition receptor to recognize, activate cytolytic pathways, and directly kill the fungi Cryptococcus neoformans and Candida albicans. However, the fungal pathogen-associated molecular pattern (PAMP) that triggers NKp30-mediated killing remains to be identified. Here we show that ß-1,3-glucan, a component of the fungal cell wall, binds to NKp30. We further demonstrate that ß-1,3-glucan stimulates granule convergence and polarization, as shown by live cell imaging. Through Src Family Kinase signaling, ß-1,3-glucan increases expression and clustering of NKp30 at the microbial and NK cell synapse to induce perforin release for fungal cytotoxicity. Rather than blocking the interaction between fungi and NK cells, soluble ß-1,3-glucan enhances fungal killing and restores defective cryptococcal killing by NK cells from HIV-positive individuals, implicating ß-1,3-glucan to be both an activating ligand and a soluble PAMP that shapes NK cell host immunity.

Cerebrovascular and ventilatory responses to acute isocapnic hypoxia in healthy aging and lung disease: effect of vitamin C.

Acute hypoxia increases cerebral blood flow (CBF) and ventilation (V̇e). It is unknown if these responses are impacted with normal aging, or in patients with enhanced oxidative stress, such as (COPD). The purpose of the study was to 1) investigate the effects of aging and COPD on the cerebrovascular and ventilatory responses to acute hypoxia, and 2) to assess the effect of vitamin C on these responses during hypoxia. In 12 Younger, 14 Older, and 12 COPD, we measured peak cerebral blood flow velocity (V̄p; index of CBF), and V̇e during two 5-min periods of acute isocapnic hypoxia, under conditions of 1) saline-sham; and 2) intravenous vitamin C. Antioxidants [vitamin C, superoxide dismutase (SOD), glutathione peroxidase, and catalase], oxidative stress [malondialdehyde (MDA) and advanced protein oxidation product], and nitric oxide metabolism end products (NOx) were measured in plasma. Following the administration of vitamin C, vitamin C, SOD, catalase, and MDA increased, while NOx decreased. V̄p and V̇e sensitivity to hypoxia was reduced in Older by ∼60% (P < 0.02). COPD patients exhibited similar V̄p and V̇e responses to Older (P > 0.05). Vitamin C did not have an effect on the hypoxic V̇e response but selectively decreased the V̄p sensitivity in Younger only. These findings suggest a reduced integrative reflex (i.e., cerebrovascular and ventilatory) during acute hypoxemia in healthy older adults. Vitamin C does not appear to have a large influence on the cerebrovascular or ventilatory responses during acute hypoxia.

Increased ventilatory response to carbon dioxide in COPD patients following vitamin C administration.

Patients with chronic obstructive pulmonary disease (COPD) have decreased ventilatory and cerebrovascular responses to hypercapnia. Antioxidants increase the ventilatory response to hypercapnia in healthy humans. Cerebral blood flow is an important determinant of carbon dioxide/hydrogen ion concentration at the central chemoreceptors and may be affected by antioxidants. It is unknown whether antioxidants can improve the ventilatory and cerebral blood flow response in individuals in whom these are diminished. Thus, we aimed to determine the effect of vitamin C administration on the ventilatory and cerebrovascular responses to hypercapnia during healthy ageing and in COPD. Using transcranial Doppler ultrasound, we measured the ventilatory and cerebral blood flow responses to hyperoxic hypercapnia before and after an intravenous vitamin C infusion in healthy young (Younger) and older (Older) subjects and in moderate COPD. Vitamin C increased the ventilatory response in COPD patients (mean (95% CI) 1.1 (0.9-1.1) versus 1.5 (1.1-2.0) L·min-1·mmHg-1, p<0.05) but not in Younger (2.5 (1.9-3.1) versus 2.4 (1.9-2.9) L·min-1·mmHg-1, p>0.05) or Older (1.3 (1.0-1.7) versus 1.3 (1.0-1.7) L·min-1·mmHg-1, p>0.05) healthy subjects. Vitamin C did not affect the cerebral blood flow response in the young or older healthy subjects or COPD subjects (p>0.05). Vitamin C increases the ventilatory but not cerebrovascular response to hyperoxic hypercapnia in patients with moderate COPD.