Mechanisms of Bacterial Superinfection Post-influenza: A Role for Unconventional T Cells

Despite the widespread application of vaccination programs and antiviral drug treatments, influenza viruses are still among the most harmful human pathogens. Indeed, influenza results in significant seasonal and pandemic morbidity and mortality. Furthermore, severe bacterial infections can occur in the aftermath of influenza virus infection, and contribute substantially to the excess morbidity and mortality associated with influenza. Here, we review the main features of influenza viruses and current knowledge about the mechanical and immune mechanisms that underlie post-influenza secondary bacterial infections. We present the emerging literature describing the role of “innate-like” unconventional T cells in post-influenza bacterial superinfection. Unconventional T cell populations span the border between the innate and adaptive arms of the immune system, and are prevalent in mucosal tissues (including the airways). They mainly comprise Natural Killer T cells, mucosal-associated invariant T cells and γδ T cells. We provide an overview of the principal functions that these cells play in pulmonary barrier functions and immunity, highlighting their unique ability to sense environmental factors and promote protection against respiratory bacterial infections. We focus on two major opportunistic pathogens involved in superinfections, namely Streptococcus pneumoniae and Staphylococcus aureus. We discuss mechanisms through which influenza viruses alter the antibacterial activity of unconventional T cells. Lastly, we discuss recent fundamental advances and possible therapeutic approaches in which unconventional T cells would be targeted to prevent post-influenza bacterial superinfections

Natural Killer T Cells and Mucosal-Associated Invariant T Cells in Lung Infections

The immune system has been traditionally divided into two arms called innate and adaptive immunity. Typically, innate immunity refers to rapid defense mechanisms that set in motion within minutes to hours following an insult. Conversely, the adaptive immune response emerges after several days and relies on the innate immune response for its initiation and subsequent outcome. However, the recent discovery of immune cells displaying merged properties indicates that this distinction is not mutually exclusive. These populations that span the innate-adaptive border of immunity comprise, among others, CD1d-restricted natural killer T cells and MR1-restricted mucosal-associated invariant T cells. These cells have the unique ability to swiftly activate in response to non-peptidic antigens through their T cell receptor and/or to activating cytokines in order to modulate many aspects of the immune response. Despite they recirculate all through the body via the bloodstream, these cells mainly establish residency at barrier sites including lungs. Here, we discuss the current knowledge into the biology of these cells during lung (viral and bacterial) infections including activation mechanisms and functions. We also discuss future strategies targeting these cell types to optimize immune responses against respiratory pathogens

Identification of an IL-17–producing NK1.1neg iNKT cell population involved in airway neutrophilia

Invariant natural killer T (iNKT) cells are an important source of both T helper type 1 (Th1) and Th2 cytokines, through which they can exert beneficial, as well as deleterious, effects in a variety of inflammatory diseases. This functional heterogeneity raises the question of how far phenotypically distinct subpopulations are responsible for such contrasting activities. In this study, we identify a particular set of iNKT cells that lack the NK1.1 marker (NK1.1neg) and secrete high amounts of interleukin (IL)-17 and low levels of interferon (IFN)-γ and IL-4. NK1.1neg iNKT cells produce IL-17 upon synthetic (α-galactosylceramide [α-GalCer] or PBS-57), as well as natural (lipopolysaccharides or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi), ligand stimulation. NK1.1neg iNKT cells are more frequent in the lung, which is consistent with a role in the natural immunity to inhaled antigens. Indeed, airway neutrophilia induced by α-GalCer or lipopolysaccharide instillation was significantly reduced in iNKT-cell–deficient Jα18−/− mice, which produced significantly less IL-17 in their bronchoalveolar lavage fluid than wild-type controls. Furthermore, airway neutrophilia was abolished by a single treatment with neutralizing monoclonal antibody against IL-17 before α-GalCer administration. Collectively, our findings reveal that NK1.1neg iNKT lymphocytes represent a new population of IL-17–producing cells that can contribute to neutrophil recruitment through preferential IL-17 secretion

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

International audienceBackground: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.Discussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration: STRATEGIC-1 is registered a

Virtual delta-t mapping technique using a local interaction simulation approach for location of Acoustic Emission damage events for aerospace applications

Acoustic Emission (AE) is a promising technique for Structural Health Monitoring applications (SHM) and involves detecting the ultrasonic stress waves generated by damage initiation growth in a structure. One advantage of AE for SHM is the ability to locate AE sources. Delta-t mapping was developed to overcome the limitations of the conventional AE location technique. The disadvantage of the delta-t mapping is that it requires the manual collection of experimental training data. This paper explores the possibility of using local interaction simulation approach (LISA) to generate simulated training data for the algorithm. The results for locating a fatigue crack are presented for both the experimental and simulated training data and showed average errors in source location of 3mm and 8mm respectively. This demonstrates the potential of using simulated training data for the mapping technique which would ultimately reduce implementation of delta-t mapping on large scale structures

Process monitoring of fibre reinforced composites using a multi-measurand fibre-optic sensor

AbstractThis paper reports on the design, fabrication, characterisation and deployment of a multi-measurand optical fibre sensor (MMS) that is capable of simultaneously monitoring strain, temperature, refractive index and cross-linking chemistry. The sensor design is based on the extrinsic fibre Fabry–Perot interferometer. A feature of this sensor system is that a conventional multi-channel fibre-coupled near-infrared spectrometer is used to monitor the four independent parameters. The issues relating to the measurement resolution of the individual sensors and the associated interrogation equipment are discussed. The MMS was embedded in between the fourth and fifth plies of an eight-ply E-glass plain-weave fabric. A commercially available thermosetting epoxy/amine resin system was used to impregnate the fabric layers manually. The laminated preform was vacuum-bagged and cured in an autoclave. The following parameters were monitored: the depletion rates of the epoxy and amine functional groups in the resin system; the temperature in close proximity to the “chemical sensor”; the evolution of strain; and the refractive index of the resin system. The effect of post-processing on the output from the embedded optical fibre sensors is also considered

Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production

Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection