IL-10 Regulates Viral Lung Immunopathology during Acute Respiratory Syncytial Virus Infection in Mice

Interleukin (IL-) 10 is a pleiotropic cytokine with broad immunosuppressive functions, particularly at mucosal sites such as the intestine and lung. Here we demonstrate that infection of BALB/c mice with respiratory syncytial virus (RSV) induced IL-10 production by CD4(+) and CD8(+) T cells in the airways at later time points (e.g. day 8); a proportion of these cells also co-produced IFN-γ. Furthermore, RSV infection of IL-10(−/−) mice resulted in more severe disease with enhanced weight loss, delayed recovery and greater cell infiltration of the respiratory tract without affecting viral load. In addition, IL-10(−/−) mice had a pronounced airway neutrophilia and heightened levels of pro-inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid. Notably, the proportion of lung T cells producing IFN-γ was enhanced, suggesting that IL-10 may act in an autocrine manner to dampen effector T cell responses. Similar findings were made in mice treated with anti-IL-10R antibody and infected with RSV. Therefore, IL-10 inhibits disease and inflammation in mice infected with RSV, especially during recovery from infection

Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia

An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy

Bacteria isolated from lung modulate asthma susceptibility in mice

Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrial countries. This study evaluates the direct contribution of lung microbial components in allergic asthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to House Dust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection or increased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota, and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivable strains were screened for their immunoregulatory properties following their isolation from neonatal lungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development: the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969 had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life are critical for susceptibility to allergic asthma in young adults

Paving the way of systems biology and precision medicine in allergic diseases : the MeDALL success story Mechanisms of the Development of ALLergy; EUFP7-CP-IP; Project No: 261357; 2010-2015

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.Peer reviewe

The Helminth-derived immunomodulator AvCystatin reduces virus enhanced inflammation by induction of regulatory IL-10+ T cells

Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease

Energy expenditure and feeding practices and tolerance during the acute and late phase of critically ill COVID-19 patients

Background & aims: Different metabolic phases can be distinguished in critical illness, which influences nutritional treatment. Achieving optimal nutritional treatment during these phases in critically ill patients is challenging. COVID-19 patients seem particularly difficult to feed due to gastrointestinal problems. Our aim was to describe measured resting energy expenditure (mREE) and feeding practices and tolerance during the acute and late phases of critical illness in COVID-19 patients.  Methods: Observational study including critically ill mechanically ventilated adult COVID-19 patients. Indirect calorimetry (Q-NRG+, Cosmed) was used to determine mREE during the acute (day 0–7) and late phase (>day 7) of critical illness. Data on nutritional intake, feeding tolerance and urinary nitrogen loss were collected simultaneously. A paired sample t-test was performed for mREE in both phases.  Results: We enrolled 21 patients with a median age of 59 years [44–66], 67% male and median BMI of 31.5 kg/m2 [25.7–37.8]. Patients were predominantly fed with EN in both phases. No significant difference in mREE was observed between phases (p = 0.529). Sixty-five percent of the patients were hypermetabolic in both phases. Median delivery of energy as percentage of mREE was higher in the late phase (94%) compared to the acute phase (70%) (p = 0.001). Urinary nitrogen losses were significant higher in the late phase (p = 0.003).  Conclusion: In both the acute and late phase, the majority of the patients were hypermetabolic and fed enterally. In the acute phase patients were fed hypocaloric whereas in the late phase this was almost normocaloric, conform ESPEN guidelines. No significant difference in mREE was observed between phases. Hypermetabolism in both phases in conjunction with an increasing loss of urinary nitrogen may indicate that COVID-19 patients remain in a prolonged acute, catabolic phase

AvCystatin treatment in primary RSV infection.

<p>A) Schematic of the primary RSV model with AvCystatin treatment regimen: i.p. intraperitoneal; i.n. intranasal application. Neutrophil influx in the BAL was shown (B). RSV L gene copy numbers in the lungs (C) and viral load (D) measured 4 days post RSV/mock challenge. RSV-specific IgG2a detected in serum 8 days post infection (E). IFN-γ, TNFα, IL-6, CCL3, and CCL5 cytokine and chemokine production (F). Naïve (dark grey bars): mock infected and mock treated with PBS, RSV challenged day 0 (black bars); AvCystatin/RSV; AvCystatin treatment i.n. or i.p. on day -1 (white bars or light grey bars, respectively). Representative data of at least 2 independent experiments, 5 mice per group. Error bars indicate SEM. <i>P</i> values reflect Mann-Whitney t-test: * p<0.05, **p<0.01.</p

IL-10⁺ CD4⁺ T cell induction by AvCystatin conditioned macrophages.

<p>Lung and BAL CD4⁺ T cells detected by flow cytometry (A and D). Total number of IL-10 producing T cells determined by intracellular staining for IL-10 after restimulation with PMA/ionomycin for 3h in Lung and BAL (B and E). Number of CD4⁺ T cells positive for FoxP3 in lung (C) and BAL (F). Percentage of F4/80⁺CD11b⁺ cells infiltrating the lungs 24h post RSV challenge (G) and total cell number (H). Total cell number of CD4⁺ IL-10⁺ T cells infiltrating the BAL, 8 days post PEC transfer (I). Naïve (dark grey bars): mock infected and mock treated with PBS, RSV challenged day 0 (black bars); AvCystatin/RSV; AvCystatin treatment i.n. or i.p. on day -1 (white bars or light grey bars, respectively). Representative data of 2 experiments, 5 mice per group. Error bars indicate SEM. <i>P</i> values reflect Mann-Whitney t-test: * p<0.05, **p<0.01.</p

AvCystatin treatment reduced RSV-induced immunopathology in Th2-based models of viral lung eosinophilia.

<p>A) Schematic of the vvG RSV model: e.d. epidermabrasive; i.p. intraperitoneal; i.n. intranasal application. B) Weight loss in vvG RSV over an eight day period C) Eosinophil, neutrophil, and macrophage influx into BAL: total numbers in vvG RSV. D) RSV-specific serum immunoglobulin levels. E) L gene copy numbers in lungs, d4 after RSV/mock challenge. Naïve (light grey bars): mock infected and mock treated with PBS; vvG/RSV (black bars): scarified with vvG and challenged with RSV; vvG/AvCystatin/RSV (white bars): vvG/RSV plus intraperitoneal (d -14 and -7) and intranasal (d -2 and -1) injection of AvCystatin. Representative data from 2 independent experiments, 5 mice per group. Error bars indicate SEM. <i>P</i> values reflect Mann-Whitney t-test: * p<0.05, **p<0.01.</p