Parasite-induced Lipoxin A4 Is an Endogenous Regulator of IL-12 Production and Immunopathology in Toxoplasma gondii Infection

The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-γ–dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently, we demonstrated that lipoxin (LX)A4, an eicosanoid mediator that depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on dendritic cell IL-12 production triggered artificially by a T. gondii extract. We now formally establish the physiological relevance of this pathway in the systemic control of IL-12 production induced by live T. gondii infection and demonstrate its function to be distinct from that of IL-10. Thus, T. gondii–exposed wild-type, but not 5-LO–deficient animals, produced high levels of serum LXA4 beginning at the onset of chronic infection. Moreover, 5-LO−/−, in contrast to wild-type mice, succumbed during the same period displaying a marked encephalitis. The increased mortality of the 5-LO−/− animals was also associated with significant elevations of IL-12 and IFN-γ and was completely prevented by the administration of a stable LXA4 analogue. Together, these findings demonstrate a new pathway involving the induction of host LXs for the in vivo regulation of proinflammatory responses during microbial infection

C5aR1 Activation Drives Early IFN-gamma Production to Control ExperimentalToxoplasma gondiiInfection

Toxoplasma gondii (T. gondii) is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) senseT. gondiithrough TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-gamma as an essential mechanism for early parasite control. Further, C3 can bind toT. gondiiresulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritonealT. gondiiinfection. We found thatC5ar1(-/-)animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection inC5ar1(-/-)mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-gamma. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1 alpha, IL-6, and TNF-alpha, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-gamma production was associated with diminishedIfngmRNA expression in the spleen and the brain, reduced frequency of IFN-gamma+NK cells in the spleen, and decreasedNos2expression in the brain ofC5ar1(-/-)mice. Mechanistically, DCs from the spleen ofC5ar1(-/-)mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulationin vivoandin vitro. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-gamma production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acuteT. gondiiinfection

Early administration of the first antimicrobials should be considered a marker of optimal care of patients with community-acquired pneumonia rather than a predictor of outcomes

Summary Background The effect of time of the first antimicrobial dose (TFAD) on the outcomes of community-acquired pneumonia (CAP) remains a controversy. Methods This was an observational, retrospective study of consecutive adult patients hospitalized with CAP. TFAD was defined as the time in hours from arrival at the emergency department to the intravenous infusion of antimicrobial. All patients received appropriate antibiotic therapy according to available Infectious Diseases Society of America/American Thoracic Society guidelines during the time of our study. Multivariable analysis and a propensity score adjusted methodology were used to measure the association of TFAD with mortality, time to clinical stability (TCS), and length of stay in the hospital (LOS). Results Data of 372 patients with CAP were studied. A total 29 (8.4%) patients died within 30 days of hospitalization. Our propensity-adjusted logistic regression model did not show a significant association between TFAD and mortality ( p =0.148). Patients who died received antimicrobials significantly earlier than survivors: 5.7h vs. 7.5h, respectively ( p =0.04). The LOS and TCS were not significantly affected by the TFAD; the LOS hazard ratio was 0.996 (95% confidence interval 0.97–1.02; p =0.774) and the TCS hazard ratio was 1.01 (95% confidence interval 0.98–1.03; p =0.604). Conclusions TFAD does not seem to be associated with the clinical outcome of patients with CAP. Early TFAD should be considered as an important marker of optimal care of patients with CAP rather than as a factor predicting outcomes

Diacylglycerol kinase ζ regulates microbial recognition and host resistance to Toxoplasma gondii

Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mφ) and dendritic cells. DGKζ deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor α production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKζ negatively controls the phosphatidylinositol 3–kinase (PI3K)–Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKζ-deficient Mφ. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKζ promotes TLR responses via a pathway involving inhibition of PI3K

Do Antiplatelet Medications Prevent Poor Clinical Outcomes in Patients With Community-Acquired Pneumonia? Results From the Community-Acquired Pneumonia Organization International Cohort Study

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Short Duration of Antibiotic Therapy in Hospitalized Patients with Community-Acquired Pneumonia: Results from the CAPO International Cohort Study

Introduction: Experts suggest a short duration of antibiotic therapy (DOT) in responding patients with community-acquired pneumonia (CAP). The aim of this study was to evaluate clinical outcomes after hospital discharge among patients treated with short-course antibiotic therapy (SCT) vs. long-course antibiotic therapy (LCT) for CAP. Methods: A secondary analysis of the Community-Acquired Pneumonia Organization (CAPO) database from January 2007 to June 2013 was performed, including hospitalized CAP patients who reached clinical stability within 5 days. Two groups were identified: patients who were treated with antibiotic therapy for a total duration of 5 days or less (SCT Group) vs. longer than 5 days (LCT Group). Rehospitalization and mortality were evaluated at 30 days after discharge. Results: 1,849 patients were enrolled (58% males; median age: 65 years), 179 (10%) were included in the SCT and 1,670 (90%) in the LTC group. Median DOT was 5 days in the SCT and 10 days in the LTC group, p Conclusions: A duration of antibiotic therapy of ≤ 5 days does not adversely impact clinical outcomes at 30-days after discharge compared to \u3e5 days in patients who reached early clinical stability