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Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with and that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.
Copyright © 2018 by The American Association of Immunologists, Inc.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no single organism has emerged as being definitively involved in NEC pathogenesis. In this review, the authors summarize the literature on infectious causes of NEC.
Copyright © 2015 Elsevier Inc. All rights reserved.
New strategies to treat antibiotic-resistant infections are urgently needed. We serendipitously discovered that stem cell conditioned media possessed broad antimicrobial properties. Biochemical, functional, and genetic assays confirmed that the antimicrobial effect was mediated by supra-physiological concentrations of transferrin. Human transferrin inhibited growth of gram-positive (Staphylococcus aureus), gram-negative (Acinetobacter baumannii), and fungal (Candida albicans) pathogens by sequestering iron and disrupting membrane potential. Serial passage in subtherapeutic transferrin concentrations resulted in no emergence of resistance. Infected mice treated with intravenous human transferrin had improved survival and reduced microbial burden. Finally, adjunctive transferrin reduced the emergence of rifampin-resistant mutants of S. aureus in infected mice treated with rifampin. Transferrin is a promising, novel antimicrobial agent that merits clinical investigation. These results provide proof of principle that bacterial infections can be treated in vivo by attacking host targets (ie, trace metal availability) rather than microbial targets.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
BACKGROUND - Introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease of oral manifestations (OMs). The profile and risk factors for OM in those individuals initiating HAART remain understudied in the Southeast of the United States, region of increasing HIV prevalence.
OBJECTIVE - To determine clinical, socio-demographic, and laboratory characteristics associated with the presence of OM among patients initiating HAART.
METHODS - Retrospective review of electronically captured data from patients initiating HAART at a Southeastern US clinic. Prevalence was determined, and risk factors for overall OM, oropharyngeal candidiasis (OPC), and all other OM were evaluated using logistic regression.
RESULTS - In our sample (n = 744), majority of individuals were males (75 percent), African-American (50 percent), mean age of 39 years, 42 percent of which reported sex with men (MSM). Two hundred sixty-six had some type of OM. Compared with those without any OM, patients with OM had a lower mean baseline CD4+ T cells count (CD4 count) (331 ± 260 versus 179 ± 244 CD4 cells/mm(3) ) and higher mean baseline HIV-1 RNA viral load (4.0 ± 1.34 log(10) versus 4.6 ± 1.30 log(10) ) (P < 0.01). In the logistic regression models seeking to determine factors associated with an increased risk of OM and OPC, the only characteristic associated with the outcome was baseline CD4 value. Being male, African-American, and heterosexual showed a protective role for OM other than OPC.
CONCLUSION - OM continues to be common despite HAART. General OM and OPC were closely associated with a low baseline CD4 count. Knowledge of risk factors for OM can potentially help clinicians target oral evaluation of HIV-positive individuals.
© 2011 American Association of Public Health Dentistry.
Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) (PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.
Candida albicans is the most common opportunistic fungal pathogen and causes local and systemic disease in immunocompromised patients. Alveolar macrophages (AMs) are pivotal for the clearance of C. albicans from the lung. Activated AMs secrete 5-lipoxygenase-derived leukotrienes (LTs), which in turn enhance phagocytosis and microbicidal activity against a diverse array of pathogens. Our aim was to investigate the role of LTB(4) and LTD(4) in AM antimicrobial functions against C. albicans and the signaling pathways involved. Pharmacologic and genetic inhibition of LT biosynthesis as well as receptor antagonism reduced phagocytosis of C. albicans when compared with untreated or WT controls. Conversely, exogenous LTs of both classes augmented base-line C. albicans phagocytosis by AMs. Although LTB(4) enhanced mainly mannose receptor-dependent fungal ingestion, LTD(4) enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C-δ (PKCδ) and PI3K but not PKCα and MAPK activation. Both LTs reduced activation of cofilin-1, whereas they enhanced total cellular F-actin; however, LTB(4) accomplished this through the activation of LIM kinases (LIMKs) 1 and 2, whereas LTD(4) did so exclusively via LIMK-2. Finally, both exogenous LTB(4) and LTD(4) enhanced AM fungicidal activity in an NADPH oxidase-dependent manner. Our data identify LTB(4) and LTD(4) as key mediators of innate immunity against C. albicans, which act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.
Complications of liver transplantation are not limited to acute and chronic rejection, and recurrence of original disease, but include surgical complications, most commonly hepatic artery occlusion, infections, and development of de novo malignancies. In the early posttransplantation period, procurement/preservation injury, non-immunologic injury to the graft during harvesting and implantation, is manifested by centrilobular hepatocyte pallor and cholestasis but rarely leads to significant graft dysfunction. Ischemic complications, such as hepatic artery thrombosis, are more serious complications and may lead to early graft loss or biliary stricture. Infectious complications generally occur in the mid-to-late period after transplantation; cytomegalovirus (CMV) remains a common pathogen. Human herpes 6 virus infection has been implicated in allograft dysfunction, but is usually seen in the setting of co-infection with CMV. De novo malignancies are emerging as a significant cause of mortality after liver transplantation; risk is cumulative, and increases with time posttransplantation. Development of such malignancies in the setting of solid organ transplantation is multifactorial, and is related to individual and regional predispositions to malignancy, pre-transplantation disease states, recipient viral status, and use and intensity of immunosuppression regimens.
BACKGROUND - Substantial morbidity and mortality rates are associated with infections in the first year after pediatric lung transplantation. To understand better the clinical significance of bloodstream infections (BSIs), we evaluated systematically the epidemiologic features of BSIs in the first year after transplantation.
METHODS - A retrospective case-cohort study of pediatric primary lung transplant recipients was performed. The frequency of BSIs and the organisms isolated were determined through medical and laboratory record review. We assessed variations in causative organisms and rates of BSIs in 3 time periods after transplantation, ie, early (0-30 days), intermediate (31-90 days) and late (91-365 days).
RESULTS - Between July 1990 and November 2000, 190 pediatric patients received primary lung transplants. Twenty-six percent (49 of 190) of recipients had at least 1 BSI. The most commonly isolated organisms were coagulase-negative Staphylococcus (n = 25, 28.4%), Pseudomonas aeruginosa (n = 14, 16.0%) and Candida spp. (n = 9, 10.2%). The overall rate of BSIs was 2.1 episodes per 1000 catheter-days. The highest rate of BSIs occurred in the early period, compared with the intermediate and late periods (5.5, 1.3 and 1.6 episodes per 1000 catheter-days, respectively; P = 0.21). Early BSIs were associated with death in the first year after transplantation (relative risk, 3.9; 95% confidence interval, 1.6-9.4; P = 0.002).
CONCLUSIONS - BSIs occur frequently after primary pediatric lung transplantation, with the highest rate being in the first 30 days after transplantation. Early BSIs are associated with death in the first year after transplantation.
Trichomoniasis, bacterial vaginosis (BV) and candidiasis are reproductive tract infections (RTIs) of the vagina. We conducted a cross-sectional study in 4 prenatal clinics in Kingston, Jamaica, to estimate the prevalence of these infections and the risk factors that may facilitate their transmission among pregnant women. Of the 269 women studied, 18.0% had culture-positive trichomoniasis, 44.1% had BV (Nugent score > or = 7) and 30.7% were positive for candidiasis by wet mount. A multiple logistic regression analysis showed that having a malodorous discharge was associated with trichomoniasis (odd ratios [OR]=3.9, confidence intervals [CI]=1.04-14.7) and BV (OR=3.4, CI=1.3-8.7). Women who took action to prevent HIV infection had lower BV prevalence (OR=0.34, CI=0.12-0.98). Women who were employed were less likely to have any of the infections (OR=0.61, CI=0.36-1.03). The strong association of a symptomatic presentation with trichomoniasis and BV suggests the merit of considering syndromic management of vaginitis in this population.