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Search Results: 1 - 10 of 229109 matches for " Lars R?berg "
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How to Live with the Enemy: Understanding Tolerance to Parasites
Lars Rberg
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001989
Abstract: How do we defend ourselves against pathogenic microbes and other parasites infecting us? Research on defence against parasites has traditionally focused on resistance—the ability to prevent infection or limit parasite replication. The genetics, physiology, and evolutionary ecology of such traits are now relatively well understood. During the last few years it has been realized that another, conceptually different type of defence also plays an important role in animal host–parasite interactions. This type of defence is called tolerance, and can be defined as the ability to limit the health effects of parasites without preventing infection or controlling parasite replication. Our understanding of the causes and consequences of variation in tolerance is, however, still rudimentary. Three recent studies shed light on these questions. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness. In addition, they illustrate different approaches to untangle tolerance from other factors determining the health effects of infectious disease.
Animal Defenses against Infectious Agents: Is Damage Control More Important Than Pathogen Control
Andrew F. Read,Andrea L. Graham,Lars Rberg
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000004
Abstract:
Maximum Host Survival at Intermediate Parasite Infection Intensities
Martin Stjernman, Lars Rberg, Jan-?ke Nilsson
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002463
Abstract: Background Although parasitism has been acknowledged as an important selective force in the evolution of host life histories, studies of fitness effects of parasites in wild populations have yielded mixed results. One reason for this may be that most studies only test for a linear relationship between infection intensity and host fitness. If resistance to parasites is costly, however, fitness may be reduced both for hosts with low infection intensities (cost of resistance) and high infection intensities (cost of parasitism), such that individuals with intermediate infection intensities have highest fitness. Under this scenario one would expect a non-linear relationship between infection intensity and fitness. Methodology/Principal Findings Using data from blue tits (Cyanistes caeruleus) in southern Sweden, we investigated the relationship between the intensity of infection of its blood parasite (Haemoproteus majoris) and host survival to the following winter. Presence and intensity of parasite infections were determined by microscopy and confirmed using PCR of a 480bp section of the cytochrome-b-gene. While a linear model suggested no relationship between parasite intensity and survival (F = 0.01, p = 0.94), a non-linear model showed a significant negative quadratic effect (quadratic parasite intensity: F = 4.65, p = 0.032; linear parasite intensity F = 4.47, p = 0.035). Visualization using the cubic spline technique showed maximum survival at intermediate parasite intensities. Conclusions/Significance Our results indicate that failing to recognize the potential for a non-linear relationship between parasite infection intensity and host fitness may lead to the potentially erroneous conclusion that the parasite is harmless to its host. Here we show that high parasite intensities indeed reduced survival, but this effect was masked by reduced survival for birds heavily suppressing their parasite intensities. Reduced survival among hosts with low parasite intensities suggests costs of controlling parasite infections; however, the nature of such costs remains to be elucidated.
Animal Defenses against Infectious Agents: Is Damage Control More Important Than Pathogen Control
Andrew F Read ,Andrea L Graham,Lars Rberg
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.1000004
Abstract:
Quantitative Analysis of Immune Response and Erythropoiesis during Rodent Malarial Infection
Martin R. Miller,Lars Rberg,Andrew F. Read,Nicholas J. Savill
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000946
Abstract: Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2–3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems.
IFN-γ production in response to in vitro stimulation with collagen type II in rheumatoid arthritis is associated with HLA-DRB1*0401 and HLA-DQ8
Louise Berg, Johan R?nnelid, Carani B Sanjeevi, Jon Lampa, Lars Klareskog
Arthritis Research & Therapy , 1999, DOI: 10.1186/ar71
Abstract: Despite much work over past decades, whether antigen-specific immune reactions occur in rheumatoid arthritis (RA) and to what extent such reactions are directed towards joint-specific autoantigens is still questionable. One strong indicator for antigenic involvement in RA is the fact that certain major histocompatibility complex (MHC) class II genotypes [human leucocyte antigen (HLA)-DR4 and HLA-DR1] predispose for the development of the disease [1]. In the present report, collagen type II (CII) was studied as a putative autoantigen on the basis of both clinical and experimental data that show an increased frequency of antibodies to CII in RA patients [2,3,4] and that show that CII can induce experimental arthritis [5].It is evident from the literature that RA peripheral blood mononuclear cells (PBMCs) respond poorly to antigenic stimulation [6,7,8], and in particular evidence for a partial tolerization to CII has been presented [9]. The strategy of the present work has accordingly been to reinvestigate T-cell reactivity to CII in RA patients, to relate it to the response to commonly used recall antigens and to analyze IFN-γ responses as an alternative to proliferative responses.To study cellular immune reactivity to CII in patients with RA and in healthy control individuals and to correlate this reactivity to HLA class II genotypes and to the presence of antibodies to CII in serum.Forty-five patients who met the 1987 American College of Rheumatology classification criteria for RA [10] and 25 healthy control individuals of similar age and sex were included. Twenty-six of these patients who had low levels of anti-CII in serum were randomly chosen, whereas 19 patients with high anti-CII levels were identified by enzyme-linked immunosorbent assay (ELISA)-screening of 400 RA sera.Heparinized blood was density gradient separated and PBMCs were cultured at 1 × 106/ml in RPMI-10% fetal calf serum with or without antigenic stimulation: native or denatured CII (100 μ g/ml),
Streptococcus pneumoniae stabilizes tumor necrosis factor α mRNA through a pathway dependent on p38 MAPK but independent of Toll-like receptors
Trine H Mogensen, Randi S Berg, Lars ?stergaard, S?ren R Paludan
BMC Immunology , 2008, DOI: 10.1186/1471-2172-9-52
Abstract: In this study, we have examined how S. pneumoniae affects expression of the inflammatory cytokine tumor necrosis factor (TNF) α, and the molecular mechanisms involved. Secretion of TNF-α was strongly induced by S. pneumoniae, which was able to stabilize TNF-α mRNA through a mechanism dependent on the viability of the bacteria as well as the adenylate uridylate-rich elements in the 3'untranslated region of TNF-α mRNA. The ability of S. pneumoniae to stabilize TNF-α mRNA was dependent on the mitogen-activated protein kinase (MAPK) p38 whereas inhibition of Toll-like receptor signaling via MyD88 did not affect S. pneumoniae-induced mRNA stabilization. P38 was activated through a pathway involving the upstream kinase transforming growth factor-activated kinase 1 and MAPK kinase 3.Thus, S. pneumoniae stabilizes TNF-α mRNA through a pathway dependent on p38 but independent of Toll-like receptors. Production of TNF-α may contribute significantly to the inflammatory response raised during pneumococcal infection.Streptococcus pneumoniae is an important cause of severe invasive infections, including pneumonia, bacteremia, and meningitis [1,2]. Nasopharyngeal carriage of S. pneumoniae is common among children, but in most cases bacterial invasion into the lungs or bloodstream is prevented by local host defenses in the upper airways [3]. However, in a minority of individuals, pneumocooci gain access to deeper structures of the body and thereby cause invasive disease [3], which are almost uniformly fatal if not treated with antibiotics. Even in the presence of appropriate treatment, invasive pneumococcal disease bears a relatively poor prognosis [4]. Pneumococci are known to elicit a very potent inflammatory response [1,5], a key component of which is the production of cytokines and chemokines, which participate in the elimination of bacteria but may also result in undesirable excessive immunological responses, which may be harmful to the host [1].The cytokine tumor necrosis fac
MHC-I Affects Infection Intensity but Not Infection Status with a Frequent Avian Malaria Parasite in Blue Tits
Helena Westerdahl, Martin Stjernman, Lars Rberg, Mimi Lannefors, Jan-?ke Nilsson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072647
Abstract: Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC) molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load) and infection status (infected or not). It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.
Immune-Mediated Competition in Rodent Malaria Is Most Likely Caused by Induced Changes in Innate Immune Clearance of Merozoites
Jayanthi Santhanam ,Lars Rberg,Andrew F. Read,Nicholas Jon Savill
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003416
Abstract: Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter , the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery.
On the Best Quadratic Minimum Bias Non-Negative Estimator of a Two-Variance Component Model
Lars E. Sj berg
Journal of Geodetic Science , 2011, DOI: 10.2478/v10156-011-0006-y
Abstract: Variance components (VCs) in linear adjustment models are usually successfully computed by unbiased estimators. However, for many unbiased VC techniques estimated variance components might be negative, a result that cannot be tolerated by the user. This is, for example, the case with the simple additive VC model aσ2/1 + bσ2/2 with known coefficients a and b, where either of the unbiasedly estimated variance components σ2/1 + σ2/2 may frequently come out negative. This fact calls for so-called non-negative VC estimators. Here the Best Quadratic Minimum Bias Non-negative Estimator (BQMBNE) of a two-variance component model is derived. A special case with independent observations is explicitly presented.
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