Immunity to abomasal parasites in lambs

The parasitic nematodes Teladorsagia (Ostertagia) circumcincta and Haemmonchus contortus are two of the most important pathogens of sheep and goats worldwide. The purpose of the work described in this thesis was to identify the mechanism of resistance to these parasites in young lambs. Lambs infected with T. circumcincta are incapable of controlling their worm burdens. However, it appears that some are capable of controlling the growth and therefore the fecundity of adult female worms. Work described in chapter three shows that the most important mechanism controlling the growth and fecundity of this parasite is the local IgA response. 933 lambs were studied over 5 years. Faecal egg counts were performed on these lambs and 485 of these lambs were slaughtered and the average female worm lengths determined. Analysis showed a highly significant effect of parasite specific IgA on worm length. Those lambs with higher IgA response to fourth-stage larvae had on average shorter worms. This response was heritable. Thus genetic resistance to T. circumcincta acts by reducing worm fecundity and works through a parasite-specific IgA response. In addition, this response is sex related with male lambs having the poorest response and females the best. Not only is the quantity of IgA important in determining host resistance, but also the specificity. Chapter four details work done in investigating the antigen specificity of the IgA response to T. circumcincta

A Simple Cellular Automaton Model for Influenza A Viral Infections

Viral kinetics have been extensively studied in the past through the use of spatially homogeneous ordinary differential equations describing the time evolution of the diseased state. However, spatial characteristics such as localized populations of dead cells might adversely affect the spread of infection, similar to the manner in which a counter-fire can stop a forest fire from spreading. In order to investigate the influence of spatial heterogeneities on viral spread, a simple 2-D cellular automaton (CA) model of a viral infection has been developed. In this initial phase of the investigation, the CA model is validated against clinical immunological data for uncomplicated influenza A infections. Our results will be shown and discussed.Comment: LaTeX, 12 pages, 18 EPS figures, uses document class ReTeX4, and packages amsmath and SIunit

A New Experimental Infection Model in Ferrets Based on Aerosolised Mycobacterium bovis

There is significant interest in developing vaccines to control bovine tuberculosis, especially in wildlife species where this disease continues to persist in reservoir species such as the European Badger (Meles meles). However, gaining access to populations of badgers (protected under UK law) is problematic and not always possible. In this study, a new infection model has been developed in ferrets (Mustela furo), a species which is closely related to the badger. Groups of ferrets were infected using a Madison infection chamber and were examined postmortem for the presence of tuberculous lesions and to provide tissue samples for confirmation of Mycobacterium bovis by culture. An infectious dose was defined, that establishes infection within the lungs and associated lymph nodes with subsequent spread to the mesentery lymph nodes. This model, which emphasises respiratory tract infection, will be used to evaluate vaccines for the control of bovine tuberculosis in wildlife species

A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.</p

Access to Research Veterinary Medicine International Volume

There is significant interest in developing vaccines to control bovine tuberculosis, especially in wildlife species where this disease continues to persist in reservoir species such as the European Badger (Meles meles). However, gaining access to populations of badgers (protected under UK law) is problematic and not always possible. In this study, a new infection model has been developed in ferrets (Mustela furo), a species which is closely related to the badger. Groups of ferrets were infected using a Madison infection chamber and were examined postmortem for the presence of tuberculous lesions and to provide tissue samples for confirmation of Mycobacterium bovis by culture. An infectious dose was defined, that establishes infection within the lungs and associated lymph nodes with subsequent spread to the mesentery lymph nodes. This model, which emphasises respiratory tract infection, will be used to evaluate vaccines for the control of bovine tuberculosis in wildlife species

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome

Relativistic Brownian Motion

Stimulated by experimental progress in high energy physics and astrophysics, the unification of relativistic and stochastic concepts has re-attracted considerable interest during the past decade. Focusing on the framework of special relativity, we review, here, recent progress in the phenomenological description of relativistic diffusion processes. After a brief historical overview, we will summarize basic concepts from the Langevin theory of nonrelativistic Brownian motions and discuss relevant aspects of relativistic equilibrium thermostatistics. The introductory parts are followed by a detailed discussion of relativistic Langevin equations in phase space. We address the choice of time parameters, discretization rules, relativistic fluctuation-dissipation theorems, and Lorentz transformations of stochastic differential equations. The general theory is illustrated through analytical and numerical results for the diffusion of free relativistic Brownian particles. Subsequently, we discuss how Langevin-type equations can be obtained as approximations to microscopic models. The final part of the article is dedicated to relativistic diffusion processes in Minkowski spacetime. Due to the finiteness of velocities in relativity, nontrivial relativistic Markov processes in spacetime do not exist; i.e., relativistic generalizations of the nonrelativistic diffusion equation and its Gaussian solutions must necessarily be non-Markovian. We compare different proposals that were made in the literature and discuss their respective benefits and drawbacks. The review concludes with a summary of open questions, which may serve as a starting point for future investigations and extensions of the theory.Comment: review article, 159 pages, references updated, misprints corrected, App. A.4. correcte

T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world’s countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome