Intrinsic Programming of Alveolar Macrophages for Protective Antifungal Innate Immunity Against Pneumocystis Infection

Invasive fungal infections, including Pneumocystis Pneumonia (PcP), remain frequent life-threatening conditions of patients with adaptive immune defects. While innate immunity helps control pathogen growth early during infection, it is typically not sufficient for complete protection against Pneumocystis and other human fungal pathogens. Alveolar macrophages (AM) possess pattern recognition molecules capable of recognizing antigenic and structural determinants of Pneumocystis. However, this pathogen effectively evades innate immunity to infect both immunocompetent and immunosuppressed hosts, albeit with differing outcomes. During our studies of mouse models of PcP, the FVB/N strain was identified as unique because of its ability to mount a protective innate immune response against Pneumocystis infection. In contrast to other immunocompetent strains, which become transiently infected prior to the onset of adaptive immunity, FVB/N mice rapidly eradicated Pneumocystis before an adaptive immune response was triggered. Furthermore, FVB/N mice remained highly resistant to infection even in the absence of functional T cells. The effector mechanism of innate protection required the action of functional alveolar macrophages, and the adoptive transfer of resistant FVB/N AMs, but not susceptible CB.17 AMs, conferred protection to immunodeficient mice. Macrophage IFNγ receptor signaling was not required for innate resistance, and FVB/N macrophages were found to display markers of alternative activation. IFNγ reprogrammed resistant FVB/N macrophages to a permissive M1 biased phenotype through a mechanism that required direct activation of the macrophage IFNγR. These results demonstrate that appropriately programmed macrophages provide protective innate immunity against this opportunistic fungal pathogen, and suggest that modulating macrophage function may represent a feasible therapeutic strategy to enhance antifungal host defense. The identification of resistant and susceptible macrophages provides a novel platform to study not only the mechanisms of macrophage-mediated antifungal defense, but also the mechanisms by which Pneumocystis evades innate immunity

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Cellular composition of BAL fluid^* from SSZ- and PBS-treated IRIS mice.

*<p>BAL fluid was isolated from one-half of the lung.</p>a<p>days post-immune reconstitution.</p>b–o<p>P<0.05 as compared with uninfected mice and SSZ-treated mice at the same time point, n≥18/time point/group, data is pooled from three independent experiments.</p

SSZ reduces inflammatory chemokine and cytokine production during PcP-related IRIS.

<p>Pc-infected SCID mice were immunologically reconstituted, and then treated with PBS or SSZ. (A, B, C, and D) MCP-1, RANTES, TNF-α, and IFN-γ levels were measured in the BAL fluid. Values are mean ±1 SEM (n≥15/time point/group). ** and #, P<0.05 as compared to uninfected mice at the same time point. *, P<0.05 as compared to SSZ treated mice at the same time point. Mean represents combined data from three independent experiments.</p

SSZ reduces pulmonary inflammation during PcP-related IRIS.

<p>Pc-infected SCID mice were immunologically reconstituted, and then treated with PBS (Panels A–C) or SSZ (Panels D–F) beginning at day 1 post-reconstitution. Lung sections from mice at days 13 (A, D), 18 (B, E) or 25 (c, F) post-reconstitution were stained with Hematoxylin and Eosin. Representative pictures were taken by microscopy under 40× magnification. Arrows denote peribronchiolar regions in each section, while asterisks denote alveolar regions.</p

SSZ treatment reduces the severity of PcP-related IRIS.

<p>Pc-infected SCID mice were immunologically reconstituted and then treated with PBS or SSZ beginning at day 1 post-reconstitution. (A and B) Body weight and respiratory rates were monitored non-invasively. (C, D, E) Dynamic lung compliance, lung resistance and BAL albumin content were measured at 13, 18, and 25 days post-reconstitution. Values are mean ±1 standard error measurement (SEM) (n≥15 for day 13, n≥37 for day 18, and n≥15 for day 25). ** and #, P<0.05 as compared to uninfected mice at the same time point. *, P<0.05 as compared to SSZ treated mice at the same time point. Mean represents combined data from eight independent experiments.</p