Significance of cross-reactive antibody responses and isotype bias in malaria- helminth co-infection

The socio-economic and geographical distribution of malaria overlaps with that of many parasitic helminths and in these areas co-infections are common. Co-infection with helminths can influence disease outcome causing either exacerbation or amelioration of malaria. Understanding the complex host-parasite interactions that lead to these different disease outcomes is important for the success of control programmes aimed at these parasites. The immune system has evolved diverse types of response (e.g. T-helper 1 (Th1) and T-helper 2 (Th2)) to efficiently combat infection with ‘microparasites’ and helminths respectively. When faced with co-infection however, the need for the host to multitask means it must manage these counter-regulatory responses. In this study a murine model of malaria-hookworm (Plasmodium chabaudi- Nippostrongylus brasiliensis) co-infection was utilised to investigate how changes in T-helper bias affect malaria disease outcome. Antibody isotypes were used as indicators of Th1/Th2 bias and revealed that helminth co-infection reduced the malaria-specific Th1 response. Counter-intuitively this resulted in ‘protection’ from malaria with co-infected mice having reduced peak P. chabaudi parasitaemia and suffering less severe anaemia. In addition to providing a measure of Th1/Th2 bias, analysis of antibody responses revealed the occurrence of cross-reactive antibodies. The potential for these crossreactive antibodies to influence disease outcome was investigated but in this murine model resource-mediated mechanisms of parasite regulation appear to be responsible for the ‘protection’ that co-infection affords. The question of why cross-reactive antibodies are produced has important immunological and ecological implications. Cross-reactive responses may arise through some physiological constraint on the immune mechanisms that usually result in antibody-specificity. However experiments designed to investigate if the specificity of antibodies is constrained by availability of antigen suggest that this is not the case in the model system used here. There is also the possibility that production of cross-reactive antibodies represents an evolutionary optimal strategy for a host faced with unpredictable exposure to a variety of parasites. However a major finding of this study indicates these two taxonomically distinct parasite species share antigens, which in itself is crucial to understanding host-parasite interactions in a co-infection setting. The main findings of this thesis are relevant to co-infection studies in general and the implications for both evolutionary and applied biology are discussed

Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer’s disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination

Plasmodium chabaudi limits early Nippostrongylus brasiliensis-induced pulmonary immune activation and Th2 polarization in co-infected mice

<p>Abstract</p> <p>Background</p> <p>Larvae of several common species of parasitic nematodes obligately migrate through, and often damage, host lungs. The larvae induce strong pulmonary Type 2 immune responses, including T-helper (Th)2 cells as well as alternatively activated macrophages (AAMφ) and associated chitinase and Fizz/resistin family members (ChaFFs), which are thought to promote tissue repair processes. Given the prevalence of systemic or lung-resident Type 1-inducing pathogens in geographical areas in which nematodes are endemic, we wished to investigate the impact of concurrent Type 1 responses on the development of these Type 2 responses to nematode larval migration. We therefore infected BALB/c mice with the nematode <it>Nippostrongylus brasiliensis</it>, in the presence or absence of <it>Plasmodium chabaudi chabaudi </it>malaria parasites. Co-infected animals received both infections on the same day, and disease was assessed daily before immunological measurements were taken at 3, 5, 7 or 20 days post-infection.</p> <p>Results</p> <p>We observed that the nematodes themselves caused transient loss of body mass and red blood cell density, but co-infection then slightly ameliorated the severity of malarial anaemia. We also tracked the development of immune responses in the lung and thoracic lymph node. By the time of onset of the adaptive immune response around 7 days post-infection, malaria co-infection had reduced pulmonary expression of ChaFFs. Assessment of the T cell response demonstrated that the Th2 response to the nematode was also significantly impaired by malaria co-infection.</p> <p>Conclusion</p> <p><it>P. c. chabaudi </it>co-infection altered both local and lymph node Type 2 immune activation due to migration of <it>N. brasiliensis </it>larvae. Given recent work from other laboratories showing that <it>N. brasiliensis</it>-induced ChaFFs correlate to the extent of long-term lung damage, our results raise the possibility that co-infection with malaria might alter pulmonary repair processes following nematode migration. Further experimentation in the co-infection model developed here will reveal the longer-term consequences of the presence of both malaria and helminths in the lung.</p

Quantifying variation in the potential for antibody-mediated apparent competition among nine genotypes of the rodent malaria parasite Plasmodium chabaudi

Within-host competition among parasite genotypes affects epidemiology as well as the evolution of virulence. In the rodent malaria Plasmodium chabaudi, competition among genotypes, as well as clone-specific and clone-transcending immunity are well documented. However, variation among genotypes in the induction of antibodies is not well understood, despite the important role of antibodies in the clearance of malaria infection. Here, we quantify the potential for antibodies induced by one clone to bind another (i.e., to cause antibody-mediated apparent competition) for nine genetically distinct P. chabaudi clones. We hypothesised that clones would vary in the strength of antibody induction, and that the propensity for clone-transcending immunity between a pair of clones would increase with increasing genetic relatedness at key antigenic loci. Using serum collected from mice 35 days post-infection, we measured titres of antibody to an unrelated antigen, Keyhole Limpet Haemocyanin (KLH), and two malaria antigens: recombinant Apical Membrane Antigen-1 (AMA-1) and Merozoite Surface Protein-119 (MSP-119). Amino acid sequence homology within each antigenic locus was used as a measure of relatedness. We found significant parasite genetic variation for the strength of antibody induction. We also found that relatedness at MSP-119 but not AMA-1 predicted clone-transcending binding. Our results help explain the outcome of chronic-phase mixed infections and generate testable predictions about the pairwise competitive ability of P. chabaudi clones

Expression and Function of IL-33/ST2 Axis in the Central Nervous System Under Normal and Diseased Conditions

Interleukin-33 (IL-33) is a well-recognized immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. The abundant expression of IL-33 in brain and spinal cord prompted many scientists to explore its unique role in the central nervous system (CNS) under physiological and pathological conditions. Indeed emerging evidence from over a decade's research suggests that IL-33 acts as one of the key molecular signaling cues coordinating the network between the immune and CNS systems, particularly during the development of neurological diseases. Here, we highlight the recent advances in our knowledge regarding the distribution and cellular localization of IL-33 and its receptor ST2 in specific CNS regions, and more importantly the key roles IL-33/ST2 signaling pathway play in CNS function under normal and diseased conditions

Identification of the amino acids in the major histocompatibility complex class II region of scottish blackface sheep that are associated with resistance to nematode infection

Lambs with the Major Histocompatibility Complex DRB1*1101 allele have been shown to produce fewer nematode eggs following natural and deliberate infection. These sheep also possess fewer adult Teladorsagia circumcincta than sheep with alternative alleles at the DRB1 locus. However, it is unclear if this allele is responsible for the reduced egg counts or merely acts as a marker for a linked gene. This study defined the MHC haplotypes in a population of naturally infected Scottish Blackface sheep by PCR amplification and sequencing, and examined the associations between MHC haplotypes and faecal egg counts by generalised linear mixed modelling. The DRB1*1101 allele occurred predominately on one haplotype and a comparison of haplotypes indicated that the causal mutation or mutations occurred in or around this locus. Additional comparisons with another resistant haplotype indicated that mutations in or around the DQB2*GU191460 allele were also responsible for resistance to nematode infections. Further analyses identified six amino acid substitutions in the antigen binding site of DRB1*1101 that were significantly associated with reductions in the numbers of adult T. circumcincta

Vaccination against the brown stomach worm, Teladorsagia circumcincta, followed by parasite challenge, induces inconsistent modifications in gut microbiota composition of lambs

Funder: Isaac Newton Trust (GB)Abstract: Background: Growing evidence points towards a role of gastrointestinal (GI) helminth parasites of ruminants in modifying the composition of the host gut flora, with likely repercussions on the pathophysiology of worm infection and disease, and on animal growth and productivity. However, a thorough understanding of the mechanisms governing helminth-microbiota interactions and of their impact on host health and welfare relies on reproducibility and replicability of findings. To this aim, in this study, we analysed quantitative and qualitative fluctuations in the faecal microbiota composition of lambs vaccinated against, and experimentally infected with, the parasitic GI nematode Teladorsagia circumcincta over the course of two separate trials performed over two consecutive years. Methods: Two trials were conducted under similar experimental conditions in 2017 and 2018, respectively. In each trial, lambs were randomly assigned to one of the following experimental groups: (i) vaccinated/infected, (ii) unvaccinated/infected and (iii) unvaccinated/uninfected. Faecal samples collected from individual animals were subjected to DNA extraction followed by high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene and bioinformatics and biostatistical analyses of sequence data. Results: Substantial differences in the populations of bacteria affected by immunisation against and infection by T. circumcincta were detected when comparing data from the two trials. Nevertheless, the abundance of Prevotella spp. was significantly linked to helminth infection in both trials. Conclusions: Despite the largely conflicting findings between the two trials, our data revealed that selected gut microbial populations are consistently affected by T. circumcincta infection and/or vaccination. Nevertheless, our study calls for caution when interpreting data generated from in vivo helminth-microbiome interaction studies that may be influenced by several intrinsic and extrinsic host-, parasite- and environment-related factors. Graphical Abstract

Vaccination against the brown stomach worm, Teladorsagia circumcincta, followed by parasite challenge, induces inconsistent modifications in gut microbiota composition of lambs

Funder: Isaac Newton Trust (GB)Abstract: Background: Growing evidence points towards a role of gastrointestinal (GI) helminth parasites of ruminants in modifying the composition of the host gut flora, with likely repercussions on the pathophysiology of worm infection and disease, and on animal growth and productivity. However, a thorough understanding of the mechanisms governing helminth-microbiota interactions and of their impact on host health and welfare relies on reproducibility and replicability of findings. To this aim, in this study, we analysed quantitative and qualitative fluctuations in the faecal microbiota composition of lambs vaccinated against, and experimentally infected with, the parasitic GI nematode Teladorsagia circumcincta over the course of two separate trials performed over two consecutive years. Methods: Two trials were conducted under similar experimental conditions in 2017 and 2018, respectively. In each trial, lambs were randomly assigned to one of the following experimental groups: (i) vaccinated/infected, (ii) unvaccinated/infected and (iii) unvaccinated/uninfected. Faecal samples collected from individual animals were subjected to DNA extraction followed by high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene and bioinformatics and biostatistical analyses of sequence data. Results: Substantial differences in the populations of bacteria affected by immunisation against and infection by T. circumcincta were detected when comparing data from the two trials. Nevertheless, the abundance of Prevotella spp. was significantly linked to helminth infection in both trials. Conclusions: Despite the largely conflicting findings between the two trials, our data revealed that selected gut microbial populations are consistently affected by T. circumcincta infection and/or vaccination. Nevertheless, our study calls for caution when interpreting data generated from in vivo helminth-microbiome interaction studies that may be influenced by several intrinsic and extrinsic host-, parasite- and environment-related factors