Journals

When less is more: primary immunodeficiency with an autoinflammatory kick.

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When less is more: primary immunodeficiency with an autoinflammatory kick.

Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):491-500

Authors: Giannelou A, Zhou Q, Kastner DL

Abstract

PURPOSE OF REVIEW: Next-generation sequencing is revolutionizing the molecular taxonomy of human disease. Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity.

RECENT FINDINGS: Whole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes. First, a phenotypic spectrum, including livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome, is caused by loss-of-function mutations in cat eye syndrome chromosome region, candidate 1 (CECR1), encoding adenosine deaminase 2. Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells, and a regulator of macrophage differentiation and endothelial development. Disease-associated mutations impair anti-inflammatory M2 macrophage differentiation. Second, patients presenting with cold-induced urticaria, granulomatous rash, autoantibodies, and common variable immunodeficiency, or with blistering skin lesions, bronchiolitis, enterocolitis, ocular inflammation, and mild immunodeficiency harbor distinct mutations in phospholipase Cγ2, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase Cγ2 autoinhibitory domain, causing increased or constitutive signaling.

SUMMARY: These findings underscore the power of next-generation sequencing, demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation, and suggesting a possible role for cat eye syndrome chromosome region, candidate 1 and phospholipase Cγ2 in common diseases.

PMID: 25337682 [PubMed - in process]

Mechanisms of immune regulation by IVIG.

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Mechanisms of immune regulation by IVIG.

Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):509-15

Authors: Ballow M

Abstract

PURPOSE OF REVIEW: In the past few years there have been many advances in our understanding of the mechanisms by which intravenous immune globulin (IVIG) modulates immune function in autoimmune disorders.

RECENT FINDINGS: Previous investigations have focused on the Fc domain of the IgG molecule, and the role of the FcγRIIB receptor and the sialylated Fc domain that have been show to mediate the anti-inflammatory effects in certain murine models of autoantibody-mediated diseases. More recent findings have implicated the F(ab’)2 domain in IVIG-induced immune modulation in T-cell-mediated autoimmune disease models in which upregulation of T-regulatory cells and downregulation of the Th17 pathways are important components of this mechanism. The prostaglandin E pathway may be playing a role in the IVIG-induced changes in the T-regulatory pathway.

SUMMARY: Many of the mechanisms proposed for the immune-modulating effects of IVIG demonstrate the complexity of immune effector functions in disease processes. Although controversy exists on the role of the FcγRIIB receptor and the importance of the sialylated Fc domain in human autoimmune disorders, probably no one single mechanism is responsible for the effects of IVIG in autoimmune and inflammatory diseases. The potential role of the prostaglandin E pathway may offer alternative treatments.

PMID: 25337683 [PubMed - in process]

Influenza Vaccine Prevents Medically-Attended Influenza-Associated Acute Respiratory Illness in Adults 50 Years or Older.

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Influenza Vaccine Prevents Medically-Attended Influenza-Associated Acute Respiratory Illness in Adults 50 Years or Older.

J Infect Dis. 2014 Oct 21;

Authors: Chen Q, Griffin MR, Nian H, Zhu Y, Williams JV, Edwards KM, Talbot HK

Abstract

BACKGROUND:  There are few estimates of influenza vaccine effectiveness in preventing serious outcomes in older adults.

METHODS:  Adults age ≥50 years who sought medical care for acute respiratory illness were enrolled. A nose/throat swab was tested for influenza by reverse-transcriptase polymerase chain reaction. Clinical and demographic data were collected, including verification of receipt of trivalent inactivated influenza vaccination (IIV-3). Adjusted ORs were estimated by multivariable logistic regression models with L1 penalty on all covariates except vaccination status (LASSO).

RESULTS:  1189 subjects were enrolled from November – April during five influenza seasons, 2006 through 2012, excluding the 2009-2010 season. Of those enrolled, 1064 (89%) had complete influenza testing, vaccination status, and demographic data obtained. Of 114 (9.5%) influenza positive patients, 63 (55%) were vaccinated. Of 950 patients influenza negative patients, 726 (76%) were vaccinated. Over 5 influenza seasons, IIV-3 was 61.9% (95% CI: 34.2, 72.3) effective for the prevention of medically-attended laboratory-confirmed influenza illness in adults ≥50 years and 55.2% (95% CI: 0.2, 77.3) effective in adults ≥65 years. When considering only hospitalizations, overall vaccine effectiveness was 58.4% in adults ≥50 years (95%CI: 37.0, 75.6).

CONCLUSIONS:  Influenza vaccine was moderately effective in preventing influenza-associated medical care visits in older adults.

PMID: 25336724 [PubMed - as supplied by publisher]

Clonal outbreak of Plasmodium falciparum in eastern Panama.

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Clonal outbreak of Plasmodium falciparum in eastern Panama.

J Infect Dis. 2014 Oct 21;

Authors: Obaldia N, Baro NK, Calzada JE, Santamaria AM, Daniels R, Wong W, Chang HH, Hamilton EJ, Arevalo-Herrera M, Herrera S, Wirth DF, Hartl DL, Marti M, Volkman SK

Abstract

Identifying the source of resurgent parasites is paramount to strategic and successful intervention for malaria elimination. Although malaria incidence in Panama is low, a recent outbreak resulted in a six-fold increase in reported cases. We hypothesized parasites sampled from this epidemic might be related and exhibit clonal population structure. We tested the genetic relatedness using informative single nucleotide polymorphisms and drug resistance loci. We found the parasites to be clustered into three clonal subpopulations and shared relatedness with parasites from Colombia. Two clusters of Panamanian parasites shared identical drug resistance haplotypes, and all clusters shared a chloroquine-resistance genotype matching the pfcrt haplotype of Colombian origin. Our findings suggest these resurgent parasite populations are highly clonal and likely resulted from epidemic expansion of imported or vestigial cases. Outbreak investigation using genetic tools can illuminate potential sources of epidemic malaria and guide strategies to prevent further resurgence in areas of malaria elimination.

PMID: 25336725 [PubMed - as supplied by publisher]

Diversity-Oriented Synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.

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Diversity-Oriented Synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.

J Infect Dis. 2014 Oct 21;

Authors: Lukens AK, Heidebrecht RW, Mulrooney C, Beaudoin JA, Comer E, Duvall JR, Fitzgerald ME, Masi D, Galinsky K, Scherer CA, Palmer M, Munoz B, Foley M, Schreiber SL, Wiegand RC, Wirth DF

Abstract

BACKGROUND:  The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways.

METHODS:  We screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds.

RESULTS:  We identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the reduction site of cytochrome b as its cellular target. Combination experiments with reduction and oxidation site inhibitors showed synergistic inhibition of the parasite.

CONCLUSIONS:  The cytochrome b oxidation center is a validated antimalarial target. We show that the reduction site of cytochrome b is also a druggable target. Our results demonstrating a synergistic relationship between oxidation and reduction site inhibitors suggests a future strategy for new combination therapies in the treatment of malaria.

PMID: 25336726 [PubMed - as supplied by publisher]

Cathelicidin augments epithelial receptivity and pathogenesis in experimental Escherichia coli cystitis.

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Cathelicidin augments epithelial receptivity and pathogenesis in experimental Escherichia coli cystitis.

J Infect Dis. 2014 Oct 21;

Authors: Danka ES, Hunstad DA

Abstract

BACKGROUND:  Cathelicidin is a proposed defender of the urinary tract via its antimicrobial properties, but its activity has not been delineated in a dedicated cystitis model.

METHODS:  Female C57Bl/6 mice, wild-type or deficient in CRAMP (ortholog of the sole human cathelicidin, LL-37), were infected transurethrally with the cystitis-derived uropathogenic Escherichia coli (UPEC) strain UTI89. Infection course was evaluated by bladder titers, intracellular bacterial community (IBC) quantification, and histology; immune responses and resolution were characterized through cytokine profiling, microscopy, and quantitation of epithelial recovery from exfoliation.

RESULTS:  CRAMP-deficient mice exhibited significantly lower bladder bacterial loads and fewer IBCs during acute cystitis. Though differences in bacterial titers were evident as early as 1 hour post infection, CRAMP-deficient mice showed no baseline alterations in immune activation, uroepithelial structure, apical expression of uroplakins (which serve as bacterial receptors), or intracellular bacterial growth rate. CRAMP-deficient hosts demonstrated less intense cytokine responses, diminished neutrophil infiltration, and accelerated uroepithelial recovery.

CONCLUSIONS:  Mice lacking the antimicrobial peptide cathelicidin suffered less severe infection than wild-type mice in a well-established model of cystitis. Though CRAMP exhibits in vitro antibacterial activity against UPEC, it may enhance UPEC infection in the bladder by promoting epithelial receptivity and local inflammation.

PMID: 25336727 [PubMed - as supplied by publisher]

Preexisting Neutralizing Antibody Responses Distinguish Clinically Inapparent and Apparent Dengue Virus Infections in a Sri Lankan Pediatric Cohort.

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Preexisting Neutralizing Antibody Responses Distinguish Clinically Inapparent and Apparent Dengue Virus Infections in a Sri Lankan Pediatric Cohort.

J Infect Dis. 2014 Oct 21;

Authors: Corbett KS, Katzelnick L, Tissera H, Amerasinghe A, de Silva AD, de Silva AM

Abstract

Dengue viruses (DENVs) are mosquito-borne flaviviruses that infect humans. The clinical presentation of DENV infection ranges from inapparent infection to dengue hemorrhagic fever and dengue shock syndrome. We analyzed samples from a pediatric dengue cohort study in Sri Lanka to explore whether antibody responses differentiated clinically apparent infections from clinically inapparent infections. In DENV-naive individuals exposed to primary DENV infections, we observed no difference in the quantity or quality of acquired antibodies between inapparent and apparent infections. Children who experienced primary infections had broad, serotype-cross-neutralizing antibody responses that narrowed in breadth to a single serotype over a 12-month period after infection. In DENV immune children who were experiencing a repeat infection, we observed a strong association between preexisting neutralizing antibodies and clinical outcome. Notably, children with preexisting monospecific neutralizing antibody responses were more likely to develop fever than children with cross-neutralizing responses. Preexisting DENV neutralizing antibodies are correlated with protection from dengue disease.

PMID: 25336728 [PubMed - as supplied by publisher]

Relapse or reinfection with tuberculosis: a whole genome sequencing approach in a large population-based cohort with high HIV prevalence and active follow-up.

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Relapse or reinfection with tuberculosis: a whole genome sequencing approach in a large population-based cohort with high HIV prevalence and active follow-up.

J Infect Dis. 2014 Oct 21;

Authors: Guerra-Assunção JA, Houben RM, Crampin AC, Mzembe T, Mallard K, Coll F, Khan P, Banda L, Chiwaya A, Pereira RP, McNerney R, Harris D, Parkhill J, Clark TG, Glynn JR

Abstract

BACKGROUND:  Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain.

METHODS:  In a population-based study in northern Malawi, tuberculosis patients diagnosed from 1996-2010 were actively followed after the end of treatment. Whole genome sequencing with approximately 100X coverage was carried out on all available cultures. IS6110 RFLP was available on cultures up to 2008.

RESULTS:  Based on our data, a single nucleotide polymorphism (SNP) difference of ≤10 SNPs was used to define relapse, and >100 SNPs for reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 relapse, 20 reinfection, unclassified for 64. Almost all relapses occurred in the first two years. HIV was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was over-represented and lineage-1 under-represented among the reinfecting strains (p=0.004).

CONCLUSIONS:  While some of the factors determining recurrence depend on the patient and their treatment, differences in the M.tuberculosis genome appear to have a role in both relapse and reinfection.

PMID: 25336729 [PubMed - as supplied by publisher]

Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing CS & ME-TRAP Against Controlled Human Malaria Infection in Malaria Naïve Individuals.

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Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing CS & ME-TRAP Against Controlled Human Malaria Infection in Malaria Naïve Individuals.

J Infect Dis. 2014 Oct 21;

Authors: Hodgson SH, Ewer KJ, Bliss CM, Edwards NJ, Rampling T, Anagnostou NA, de Barra E, Havelock T, Bowyer G, Poulton ID, de Cassan S, Illingworth JJ, Douglas AD, Mange PB, Collins KA, Roberts R, Gerry S, Berrie E, Moyle S, Colloca S, Cortese R, Sinden RE, Gilbert SC, Bejon P, Lawrie AM, Nicosia A, Faust SN, Hill AV

Abstract

BACKGROUND:  Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors ChAd63-MVA is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the pre-erythrocytic antigen insert ME-TRAP. We hypothesised that ChAd63-MVA containing CS may result in significant, clinical protective efficacy. Methods. We conducted an open-label, two-site partially randomized sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP. The study was registered at: www.clinicaltrials.gov (NCT01623557).

RESULTS:  1/15 (7%) vaccinees receiving ChAd63-MVA CS and 2/15 (13%) vaccinees receiving ChAd63-MVA ME-TRAP were sterilely protected post-CHMI. 3/15 (20%) vaccinees receiving ChAd63-MVA CS and 5/15 (33%) vaccinees receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment compared to unvaccinated controls. In qPCR analyses, ChAd63-MVA CS was estimated to reduce liver parasite burden by 69-79%, compared to 79-84% for ChAd63-MVA ME-TRAP.

CONCLUSIONS:  ChAd63-MVA CS does result in a reduction in liver parasite burden but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller, but biologically important differences in vaccine efficacy that can influence future vaccine development.

PMID: 25336730 [PubMed - as supplied by publisher]

Distinct patterns of B-cell activation and priming by natural influenza infection versus inactivated influenza vaccination.

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Distinct patterns of B-cell activation and priming by natural influenza infection versus inactivated influenza vaccination.

J Infect Dis. 2014 Oct 21;

Authors: He XS, Holmes TH, Sanyal M, Albrecht RA, García-Sastre A, Dekker CL, Davis MM, Greenberg HB

Abstract

BACKGROUND:  The human B-cell response to natural influenza infection has not been extensively investigated at the polyclonal level.

METHODS:  The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (pH1N1) was analyzed by determining the acute reactivity of plasmablast-derived polyclonal antibodies (PPAb) to influenza proteins. Recipients of inactivated influenza vaccine containing the same pH1N1 strain were studied for comparison.

RESULTS:  During acute infection robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza nuclear protein and to heterovariant and heterosubtypic hemagglutinins in comparison to responses to the inactivated pH1N1 vaccine. In the pH1N1 vaccinees, the presence of baseline serum neutralizing antibodies against pH1N1, suggesting previous exposure to natural pH1N1 infection, did not affect the plasmablast response to vaccination; whereas repeated immunization with inactivated pH1N1 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses.

CONCLUSIONS:  Natural pH1N1 infection and inactivated pH1N1 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza strains.

PMID: 25336731 [PubMed - as supplied by publisher]