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Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen.

ABSTRACT: Pathogen-associated molecular patterns (PAMPs) are known to be fundamental in instigating immune responses, but their role in influencing these responses beyond their initiation is less well understood. Here, using the protozoan parasite Trypanosoma cruzi, which is deficient in strong PAMPs, we demonstrate a requirement for the continuous expression of PAMPs for optimal anti-pathogen immunity. Although co-inoculating with, temporary anchoring of and transgenic expression of exogenous PAMPs all result in enhanced early adaptive immune responses, only the continuous expression of bacterial PAMPs on transgenic T. cruzi sustains these responses, resulting in enhanced pathogen clearance. These findings demonstrate that PAMPs function to potentiate adaptive immune responses well beyond their initiation and may determine the efficiency of control of pathogens capable of long-term persistence.

SUBMITTER: Kurup SP

PROVIDER: S-EPMC4161029 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen.

Kurup Samarchith P SP Tarleton Rick L RL

Nature communications 20130101

Pathogen-associated molecular patterns (PAMPs) are known to be fundamental in instigating immune responses, but their role in influencing these responses beyond their initiation is less well understood. Here, using the protozoan parasite Trypanosoma cruzi, which is deficient in strong PAMPs, we demonstrate a requirement for the continuous expression of PAMPs for optimal anti-pathogen immunity. Although co-inoculating with, temporary anchoring of and transgenic expression of exogenous PAMPs all r ...[more]

PMID: 24149620

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Project description:BackgroundBlood cultures, and molecular diagnostic tests that directly detect pathogen DNA in blood, fail to detect bloodstream infections in most infected patients. Thus, there is a need for a rapid test that can diagnose the presence of infection to triage patients, guide therapy, and decrease the incidence of sepsis.MethodsAn Enzyme-Linked Lectin-Sorbent Assay (ELLecSA) that uses magnetic microbeads coated with an engineered version of the human opsonin, Mannose Binding Lectin, containing the Fc immunoglobulin domain linked to its carbohydrate recognition domain (FcMBL) was developed to quantify pathogen-associated molecular patterns (PAMPs) in whole blood. This assay was tested in rats and pigs to explore whether it can detect infections and monitor disease progression, and in prospectively enrolled, emergency room patients with suspected sepsis. These results were also compared with data obtained from non-infected patients with or without traumatic injuries.ResultsThe FcMBL ELLecSA was able to detect PAMPS present on, or released by, 85% of clinical isolates representing 47 of 55 different pathogen species, including the most common causes of sepsis. The PAMP assay rapidly (<1h) detected the presence of active infection in animals, even when blood cultures were negative and bacteriocidal antibiotics were administered. In patients with suspected sepsis, the FcMBL ELLecSA detected infection in 55 of 67 patients with high sensitivity (>81%), specificity (>89%), and diagnostic accuracy of 0·87. It also distinguished infection from trauma-related inflammation in the same patient cohorts with a higher specificity than the clinical sepsis biomarker, C-reactive Protein.ConclusionThe FcMBL ELLecSA-based PAMP assay offers a rapid, simple, sensitive and specific method for diagnosing infections, even when blood cultures are negative and antibiotic therapy has been initiated. It may help to triage patients with suspected systemic infections, and serve as a companion diagnostic to guide administration of emerging dialysis-like sepsis therapies.

Project description:BackgroundThe current outbreak of novel coronavirus disease 2019 has caused a serious disease burden worldwide. Vaccines are an important factor to sustain the epidemic. Although with a relatively high-vaccination worldwide, the decay of vaccine efficacy and the arising of new variants lead us to the challenge of maintaining a sufficient immune barrier to protect the population.MethodA case-contact tracking data in Hunan, China, is used to estimate the contact pattern of cases for scenarios including school, workspace, etc, rather than ordinary susceptible population. Based on the estimated vaccine coverage and efficacy, a multi-group vaccinated-exposed-presymptomatic-symptomatic-asymptomatic-removed model (VEFIAR) with 8 age groups, with each partitioned into 4 vaccination status groups is developed. The optimal dose-wise vaccinating strategy is optimized based on the currently estimated immunity barrier of coverage and efficacy, using the greedy algorithm that minimizes the cumulative cases, population size of hospitalization and fatality respectively in a certain future interval. Parameters of Delta and Omicron variants are used respectively in the optimization.ResultsThe estimated contact matrices of cases showed a concentration on middle ages, and has compatible magnitudes compared to estimations from contact surveys in other studies. The VEFIAR model is numerically stable. The optimal controled vaccination strategy requires immediate vaccination on the un-vaccinated high-contact population of age 30-39 to reduce the cumulative cases, and is stable with different basic reproduction numbers ( R 0 ). As for minimizing hospitalization and fatality, the optimized strategy requires vaccination on the un-vaccinated of both aged 30-39 of high contact frequency and the vulnerable older.ConclusionThe objective of reducing transmission requires vaccination in age groups of the highest contact frequency, with more priority for un-vaccinated than un-fully or fully vaccinated. The objective of reducing total hospitalization and fatality requires not only to reduce transmission but also to protect the vulnerable older. The priority changes by vaccination progress. For any region, if the local contact pattern is available, then with the vaccination coverage, efficacy, and disease characteristics of relative risks in heterogeneous populations, the optimal dose-wise vaccinating process will be obtained and gives hints for decision-making.

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Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen.

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Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen.

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