Publications by authors named "Jayne C Hope"

51 Publications

Diagnostic accuracy of the interferon-gamma release assay (IGRA) for cases of feline mycobacteriosis.

Prev Vet Med 2021 Aug 8;193:105409. Epub 2021 Jun 8.

The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom.

The aim of this study was to evaluate the sensitivity and specificity of the interferon-gamma release assay (IGRA) for diagnosing infections with members of the Mycobacterium (M.) tuberculosis-complex (MTBC) and non-tuberculous mycobacteria (NTM) in domestic cats, and to generate defined feline-specific cut-off values using receiver operating characteristic (ROC) curve analysis to improve test performance. Records of 594 cats that had been tested by IGRA were explored to identify individuals that had a culture and/or polymerase chain reaction (PCR)-confirmed case of mycobacterial disease, and those that had a final diagnosis of non-mycobacterial disease. A total of 117 cats - 80 with mycobacterial disease and 37 diagnosed with a condition other than mycobacteriosis - were identified for further detailed analysis. This population was used to estimate test sensitivity and specificity, as well as likelihood ratios for the IGRA to correctly identify a cat with or without mycobacterial disease. Agreement between IGRA results and culture/PCR using current and proposed new cut-off values was also determined. ROC analysis of defined confirmed infected and non-mycobacterial disease control cats allowed an adjustment of current test cut-offs that increased the overall test sensitivity for MTBC infections from 83.1 % (95 % confidence interval [CI]: 71.5-90.5 %) to 90.2 % (95 % CI: 80.2-95.4%), and M. bovis infection from 43 % (95 % CI: 28.2-60.7%) to 68 % (95 % CI: 51.4-82.1%) while maintaining high test specificity (100 % in both cases). Overall agreement between IGRA results and culture/PCR, while recognising that neither culture nor PCR tests have perfect sensitivity, improved from weak (κ = 0.57) to moderate (κ = 0.71) using new proposed IGRA test cut-off values. Application of these results, based upon the statistical analysis of accumulated test data, can improve the diagnostic performance of the feline IGRA, particularly for identifying infections with M. bovis, without compromising specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prevetmed.2021.105409DOI Listing
August 2021

Serial Interferon-Gamma Release Assay (IGRA) Testing to Monitor Treatment Responses in Cases of Feline Mycobacteriosis.

Pathogens 2021 May 26;10(6). Epub 2021 May 26.

The Royal (Dick) School of Veterinary Studies and The Roslin Institute, Easter Bush Campus, University of Edinburgh, Midlothian EH25 9RG, UK.

The interferon-gamma release assay (IGRA) is used to diagnose cases of feline mycobacteriosis, but the use of serial testing to monitor treatment responses has not been evaluated in this species. From a population of cats that underwent IGRA testing for diagnostic investigation, individuals were identified with a pre- and end-of-treatment IGRA that passed control thresholds. The number of cats which reverted to negative at the end-of-treatment IGRA, changes in paired antigen-specific optical density (OD) values and differences in the pre-treatment antigen-specific OD values for those which underwent reversion were compared. Factors to explain reversion or recurrence of disease post-treatment were explored. Four of 18 cats (22%) reverted to negativity at the point of clinical resolution ( = 0.33), there was no difference in paired antigen-specific OD values ( ≥ 0.12), and cats that reverted did not have a lower baseline OD value ( = 0.63). No statistically significant factors were identified to predict reversion ( ≥ 0.08). Remaining positive at the end of treatment IGRA was not associated with recurrence of disease post-treatment ( = 0.34). Overall, these data suggest there is limited value in the use of the IGRA to monitor treatment responses in cats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pathogens10060657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226617PMC
May 2021

Ocular Tuberculosis: More than 'Of Mice and Men'.

Ocul Immunol Inflamm 2020 Sep 18:1-5. Epub 2020 Sep 18.

Royal (Dick) School of Veterinary Studies and the Roslin Institute, The University of Edinburgh, Midlothian, UK.

Tuberculosis (TB), caused by infection with members of the -complex, is one of the oldest known infectious disease entities, resulting in the death of millions of humans each year. It also results in a substantial degree of morbidity and mortality in animal species. Extrapulmonary TB is well recognized in humans, and the eye is one site that can be affected. Studies seeking to understand ocular TB have often relied on animal models; however, these have their limitations and may not truly reflect what happens in humans. We wish to raise awareness among ophthalmologists and vision scientists of naturally occurring cases of ocular TB in animals, namely cattle and domestic cats, and the possibilities of gaining further understanding of this presentation of TB by adopting a collaborative approach. This will hopefully improve outcomes for both human and animal patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09273948.2020.1797116DOI Listing
September 2020

The Veterinary Immunological Toolbox: Past, Present, and Future.

Front Immunol 2020 28;11:1651. Epub 2020 Jul 28.

The Pirbright Institute, Woking, United Kingdom.

It is well-recognized that research capability in veterinary species is restricted by a lack of immunological reagents relative to the extensive toolboxes for small rodent biomedical model species and humans. This creates a barrier to the strategic development of disease control solutions for livestock, companion animals and wildlife that not only affects animal health but can affect human health by increasing the risk of transmission of zoonotic pathogens. There have been a number of projects aimed at reducing the capability gaps in the veterinary immunological toolbox, the majority of these focusing on livestock species. Various approaches have been taken to veterinary immunological reagent development across the globe and technological advances in molecular biology and protein biochemistry have accelerated toolbox development. While short-term funding initiatives can address specific gaps in capability, they do not account for long-term sustainability of reagents and databases that requires a different funding model. We review the past, present and future of the veterinary immunological toolbox with specific reference to recent developments discussed at the International Union of Immunological Societies (IUIS) Veterinary Immunology Committee (VIC) Immune Toolkit Workshop at the 12th International Veterinary Immunology Symposium (IVIS) in Seattle, USA, 16-19 August 2019. The future availability of these reagents is critical to research for improving animal health, responses to infectious pathogens and vaccine design as well as for important analyses of zoonotic pathogens and the animal /human interface for One Health initiatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399100PMC
April 2021

Anatomical distribution of respiratory tract leukocyte cell subsets in neonatal calves.

Vet Immunol Immunopathol 2020 Sep 2;227:110090. Epub 2020 Jul 2.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush, Midlothian, Scotland, EH259RG, United Kingdom. Electronic address:

Neonatal calves are highly susceptible to a number of diseases including those that infect via the mucosal surfaces of the respiratory and gastrointestinal tracts. In order to determine appropriate vaccine design and delivery systems, or to identify suitable immunostimulatory methods to combat these infections, a detailed understanding of the immune cell populations present at clinically relevant sites is key. Few studies have assessed the immune cell composition of the neonatal calf lung and comparisons with circulating immune cells in the blood are lacking. We describe immune cell populations present in the peripheral blood, bronchoalveolar lavage (BAL) fluid and lung tissue of young disease-free calves. Flow cytometric analysis revealed significant differences in cell subset distribution between the peripheral blood and respiratory tract, and between compartments within the respiratory tract. Notably, whereas WC1 γδ TCR + T lymphocytes dominate the peripheral blood, both the BAL fluid and lung tissue contained a high proportion of myeloid cells which expressed CD14 and CD172a (SIRPα). Very low numbers of tissue myeloid cells expressed MHC Class II in comparison to circulating myeloid cells in the blood. Respiratory tract tissues had low frequencies of CD4+ and CD8 + T lymphocytes, which were significantly lower than in the blood. Differences in the proportion of NKp46+ natural killer cells were also observed between tissue compartments. In order to target vaccines or immunostimulatory therapeutics appropriately, these differences in immune cell populations in tissue compartments should be taken into consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2020.110090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331561PMC
September 2020

The UK Veterinary Immunological Toolbox Website: promoting vaccine research by facilitating communication and removing reagent barriers.

Immunology 2020 09 29;161(1):25-27. Epub 2020 Jul 29.

The Pirbright Institute, Woking, UK.

Using the best animal models to study immune responses against specific pathogens or vaccines can dramatically accelerate our understanding. Veterinary species are well studied, particularly livestock, to reduce their disease burden. They have also proven to be powerful models, especially for zoonotic pathogens and novel vaccination strategies. A prerequisite for any model selection is having the right quality and range of species-specific immunological reagents. To help promote the widest possible use of veterinary species, an open access website (https://www.immunologicaltoolbox.co.uk) has been created as a central community annotated hub for veterinary immunological reagents. The website is also the portal into services offered by the UK Immunological Toolbox project that includes antibody generation, sequencing and recombinant expression. The funding for this effort is linked into sustainable sources, but ultimate success relies on community engagement to continually increase the quality and quantity of information. It is hoped that as more users and reagent owners engage, it will become an essential resource for researchers, veterinarians and clinicians alike by removing barriers that prevent the use of the most informative animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450168PMC
September 2020

Nature and consequences of interactions between Salmonella enterica serovar Dublin and host cells in cattle.

Vet Res 2019 Nov 27;50(1):99. Epub 2019 Nov 27.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, EH25 9RG, UK.

Salmonella enterica is a veterinary and zoonotic pathogen of global importance. While murine and cell-based models of infection have provided considerable knowledge about the molecular basis of virulence of Salmonella, relatively little is known about salmonellosis in naturally-affected large animal hosts such as cattle, which are a reservoir of human salmonellosis. As in humans, Salmonella causes bovine disease ranging from self-limiting enteritis to systemic typhoid-like disease and exerts significant economic and welfare costs. Understanding the nature and consequences of Salmonella interactions with bovine cells will inform the design of effective vaccines and interventions to control animal and zoonotic infections. In calves challenged orally with S. Dublin expressing green fluorescent protein (GFP) we observed that the bacteria were predominantly extracellular in the distal ileal mucosa and within gut-associated lymph nodes 48 h post-infection. Intracellular bacteria, identified by flow cytometry using the GFP signal, were predominantly within MHCII macrophage-like cells. In contrast to observations from murine models, these S. Dublin-infected cells had elevated levels of MHCII and CD40 compared to both uninfected cells from the same tissue and cells from the cognate tissue of uninfected animals. Moreover, no gross changes of the architecture of infected lymph nodes were observed as was described previously in a mouse model. In order to further investigate Salmonella-macrophage interactions, net replication of S. enterica serovars that differ in virulence in cattle was measured in bovine blood-derived macrophages by enumeration of gentamicin-protected bacteria and fluorescence dilution, but did not correlate with host-specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13567-019-0720-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880441PMC
November 2019

Quantifying Mycobacterium avium subspecies paratuberculosis infection of bovine monocyte derived macrophages by confocal microscopy.

J Microbiol Methods 2020 01 19;168:105779. Epub 2019 Nov 19.

The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, Edinburgh EH25 9RG, UK.

Quantification of Mycobacterium avium subspecies paratuberculosis (MAP) during in vitro infection experiments is challenging due to limitations of currently utilised methods, such as colony counting. Here we describe quantifying MAP infection of bovine macrophages (Mφ) using confocal microscopy. Bovine monocyte derived macrophages were infected with MAP at a high or low dose and the number of intracellular bacteria calculated at 2 h post infection using confocal microscopy. Bacteria within simultaneously infected Mφ were quantified by colony counting in order to compare confocal microscopy results with results obtained by an established method. Confocal microscopy provided a robust alternative quantification method that allowed for assessment of the infection at the individual Mφ level. This demonstrated that MAP infection was not homogeneous, and that there were higher numbers of both infected Mφ and intracellular bacteria and bacterial aggregates at the high dose compared to the low dose, potentially impacting the Mφ response to infection. Confocal microscopy can therefore provide a level of detail regarding the infection unobtainable by other quantification methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mimet.2019.105779DOI Listing
January 2020

Retrospective application of transposon-directed insertion-site sequencing to investigate niche-specific virulence of Salmonella Typhimurium in cattle.

BMC Genomics 2019 Jan 8;20(1):20. Epub 2019 Jan 8.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, EH25 9RG, UK.

Background: Salmonella enterica subspecies enterica is an animal and zoonotic pathogen of global importance. Cattle are a significant reservoir of human non-typhoidal salmonellosis and can suffer enteric and systemic disease owing to the ability of Salmonella to survive within the bovine lymphatic system and intestines. Contamination of food can occur due to the incorporation of contaminated peripheral lymph nodes or by direct contamination of carcasses with gut contents. It is essential to understand the mechanisms used by Salmonella to enter and persist within the bovine lymphatic system and how they differ from those required for intestinal colonization to minimize zoonotic infections.

Results: Transposon-directed insertion site sequencing (TraDIS) was applied to pools of mutants recovered from mesenteric lymph nodes (MLNs) draining the distal ileum of calves after oral inoculation with a library of 8550 random S. Typhimurium mini-Tn5Km2 mutants in pools of 475 mutants per calf. A total of 8315 mutants representing 2852 different genes were detected in MLNs and their in vivo fitness was calculated. Using the same improved algorithm for analysis of transposon-flanking sequences, the identity and phenotype of mutants recovered from the distal ileal mucosa of the same calves was also defined, enabling comparison with previously published data and of mutant phenotypes across the tissues. Phenotypes observed for the majority of mutants were highly significantly correlated in the two tissues. However, 32 genes were identified in which transposon insertions consistently resulted in differential fitness in the ileal wall and MLNs, suggesting niche-specific roles for these genes in pathogenesis. Defined null mutations affecting ptsN and spvC were confirmed to result in tissue-specific phenotypes in calves, thus validating the TraDIS dataset.

Conclusions: This validation of the role of thousands of Salmonella genes and identification of genes with niche-specific roles in a key target species will inform the design of control strategies for bovine salmonellosis and zoonotic infections, for which efficacious and cross-protective vaccines are currently lacking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-018-5319-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325888PMC
January 2019

ADGRE1 (EMR1, F4/80) Is a Rapidly-Evolving Gene Expressed in Mammalian Monocyte-Macrophages.

Front Immunol 2018 1;9:2246. Epub 2018 Oct 1.

Mater Research-University of Queensland, Woolloongabba, QLD, Australia.

The F4/80 antigen, encoded by the locus, has been widely-used as a monocyte-macrophage marker in mice, but its value as a macrophage marker in other species is unclear, and has even been questioned. ADGRE1 is a seven transmembrane G protein-coupled receptor with an extracellular domain containing repeated Epidermal Growth Factor (EGF)-like calcium binding domains. Using a new monoclonal antibody, we demonstrated that ADGRE1 is a myeloid differentiation marker in pigs, absent from progenitors in bone marrow, highly-expressed in mature granulocytes, monocytes, and tissue macrophages and induced by macrophage colony-stimulating factor (CSF1) treatment . Based upon these observations, we utilized RNA-Seq to assess the expression of mRNA in bone marrow or monocyte-derived macrophages (MDM) and alveolar macrophages from 8 mammalian species including pig, human, rat, sheep, goat, cow, water buffalo, and horse. mRNA was expressed by macrophages in each species, with inter-species variation both in expression level and response to lipopolysaccharide (LPS) stimulation. Analysis of the RNA-Seq data also revealed additional exons in several species compared to current Ensembl annotations. The ruminant species and horses appear to encode a complete duplication of the 7 EGF-like domains. In every species, Sashimi plots revealed evidence of exon skipping of the EGF-like domains, which are highly-variable between species and polymorphic in humans. Consistent with these expression patterns, key elements of the promoter and a putative enhancer are also conserved across all species. The rapid evolution of this molecule and related ADGRE family members suggests immune selection and a role in pathogen recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174849PMC
October 2019

An outbreak of tuberculosis due to Mycobacterium bovis infection in a pack of English Foxhounds (2016-2017).

Transbound Emerg Dis 2018 Dec 30;65(6):1872-1884. Epub 2018 Jul 30.

Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK.

Mycobacterium bovis can cause tuberculosis (TB) in social mammals including lions, cattle and man, but canine infections are considered rare. In 2016/17 we investigated a M. bovis TB outbreak in a pack of approximately 180 Foxhounds within the bovine TB Edge Area of England. We employed a combination of immunological tests including an interferon gamma release assay (IGRA) and a serological assay (DPP VetTB, Chembio). Test-positive hounds were euthanased and subjected to post-mortem examination (PME). Overall 164 hounds were tested; 97 (59%) responded positively to at least one test. Eighty-five (52%) dogs responded to M. bovis antigens by IGRA while only 21 (12.9%) had detectable serological responses. At PME three hounds (3.1%) had visible lesions (VL) due to M. bovis infection, later confirmed by culture. Samples from 24 non-VL hounds were cultured and M. bovis infection was confirmed in a further three hounds (11%). This study is the first investigation and report of an outbreak of M. bovis TB in a canine species. We establish that, in principle, diagnostic tests used for identifying infected individuals of other species can effectively be used in the dog. Further work is urgently needed to establish the sensitivity and specificity of the testing approach used in this study for future clinical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tbed.12969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282731PMC
December 2018

Direct Manipulation of T Lymphocytes by Proteins of Gastrointestinal Bacterial Pathogens.

Infect Immun 2018 05 23;86(5). Epub 2018 Apr 23.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom.

Gastrointestinal bacterial infection represents a significant threat to human health, as well as a burden on food animal production and welfare. Although there is advanced knowledge about the molecular mechanisms underlying pathogenesis, including the development of immune responses to these pathogens, gaps in knowledge persist. It is well established that gastrointestinal bacterial pathogens produce a myriad of proteins that affect the development and effectiveness of innate immune responses. However, relatively few proteins that directly affect lymphocytes responsible for humoral or cell-mediated immunity and memory have been identified. Here, we review factors produced by gastrointestinal bacterial pathogens that have direct T cell interactions and what is known about their functions and mechanisms of action. T cell-interacting bacterial proteins that have been identified to date mainly target three major T cell responses: activation and expansion, chemotaxis, or apoptosis. Further, the requirement for more focused studies to identify and understand additional mechanisms used by bacteria to directly affect the T cell immune response and how these may contribute to pathogenesis is highlighted. Increased knowledge in this area will help to drive development of better interventions in prevention and treatment of gastrointestinal bacterial infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00683-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913853PMC
May 2018

Quantifying the Survival of Multiple Salmonella enterica Serovars via Massively Parallel Whole-Genome Sequencing To Predict Zoonotic Risk.

Appl Environ Microbiol 2018 02 31;84(4). Epub 2018 Jan 31.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom

is an animal and zoonotic pathogen of worldwide importance. serovars that differ in their host and tissue tropisms exist. Cattle are an important reservoir of human nontyphoidal salmonellosis, and contaminated bovine peripheral lymph nodes enter the food chain via ground beef. The relative abilities of different serovars to survive within the bovine lymphatic system are poorly understood and constrain the development of control strategies. This problem was addressed by developing a massively parallel whole-genome sequencing method to study mixed-serovar infections serovars differ genetically by naturally occurring single nucleotide polymorphisms (SNPs) in certain genes. It was hypothesized that these SNPs could be used as markers to simultaneously identify serovars in mixed populations and quantify the abundance of each member in a population. The performance of the method was validated using simulated pools containing up to 11 serovars in various proportions. It was then applied to study serovar survival in cattle challenged orally with the same 11 serovars. All the serovars successfully colonized the bovine lymphatic system, including the peripheral lymph nodes, and thus pose similar risks of zoonosis. This method enables the fates of multiple genetically unmodified strains to be evaluated simultaneously in a single animal. It could be useful in reducing the number of animals required to study mixed-strain infections and in testing the cross-protective efficacy of vaccines and treatments. It also has the potential to be applied to diverse bacterial species which possess shared but polymorphic alleles. While some serovars are more frequently isolated from lymph nodes rather than the feces and environment of cattle, the relative abilities of serovars to survive within the lymphatic system of cattle remain ill defined. A sequencing-based method which used available information from sequenced genomes to study the dynamics of mixed-serovar infections was developed. The main advantages of the method include the simultaneous identification and quantification of multiple strains without any genetic modification and minimal animal use. This approach could be used in vaccination trials or in epidemiological surveys where an understanding of the dynamics of closely related strains of a pathogen in mixed populations could inform the prediction of zoonotic risk and the development of intervention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AEM.02262-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795071PMC
February 2018

Bovine cryptosporidiosis: impact, host-parasite interaction and control strategies.

Vet Res 2017 08 11;48(1):42. Epub 2017 Aug 11.

Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh, EH26 0PZ, Scotland, UK.

Gastrointestinal disease caused by the apicomplexan parasite Cryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. At present, effective therapeutic and preventative measures are not available and a better understanding of the host-pathogen interactions is required. Cryptosporidium parvum is also an important zoonotic pathogen causing severe disease in people, with young children being particularly vulnerable. Our knowledge of the immune responses induced by Cryptosporidium parasites in clinically relevant hosts is very limited. This review discusses the impact of bovine cryptosporidiosis and describes how a thorough understanding of the host-pathogen interactions may help to identify novel prevention and control strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13567-017-0447-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553596PMC
August 2017

Subset-Specific Expression of Toll-Like Receptors by Bovine Afferent Lymph Dendritic Cells.

Front Vet Sci 2017 3;4:44. Epub 2017 Apr 3.

Institute for Animal Health, Newbury, Berkshire, UK.

Within the ruminant system, several possibilities exist to generate dendritic cells migrating out from the tissue into the regional draining lymph nodes as afferent lymph dendritic cells (ALDCs). Here, we analyzed toll-like receptor (TLR) 1-10 mRNA expression by using quantitative real-time PCR in highly purified subsets of bovine ALDC. As TLR expression may be influenced by pathogens or vaccines and their adjuvant, it is necessary to understand what TLRs are expressed in a steady-state system to elucidate specific differences and to potentially optimize targeted vaccines. In this study, we have assessed the TLR expression profiles of the four main bovine ALDC subsets [cDC1 and cDC2 (subsets 2-4)]. We demonstrate differences in TLR expression between the four subsets that may reflect the ability of these cells to respond to different pathogens or to respond to adjuvants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fvets.2017.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376590PMC
April 2017

Enhancing the toolbox to study IL-17A in cattle and sheep.

Vet Res 2017 04 8;48(1):20. Epub 2017 Apr 8.

Moredun Research Institute, International Research Centre, Pentlands Science Park, Bush Loan, Penicuik, Scotland, EH26 0PZ, UK.

The development of methods to detect cytokine expression by T cell subsets in ruminants is fundamental to strategic development of new livestock vaccines for prevention of infectious diseases. It has been possible to detect T cell expression of IFN-γ, IL-4 and IL-10 in ruminants for many years but methods to detect expression of IL-17A are relatively limited. To address this gap in capability we have cloned bovine and ovine IL-17A cDNAs and expressed biologically-active recombinant proteins in Chinese Hamster Ovary (CHO) cells. We used the transfected CHO cells to screen commercially-available antibodies for their ability to detect IL-17A expression intracellularly and in culture supernates. We demonstrate that an ELISA for bovine IL-17A detects native ovine IL-17A. Moreover, the constituent polyclonal antibodies (pabs) in the ELISA were used to enumerate peripheral blood mononuclear cells (PBMC) expressing IL-17A from cattle and sheep by ELISpot. We identified two monoclonal antibodies (mabs) that detect recombinant intracellular IL-17A in CHO cells by flow cytometry. One of these mabs was used to detect native intracellular IL-17A expression in PBMC in conjunction with cell surface phenotyping mabs [CD4+ve, CD8+ve and Workshop Cluster 1 (WC-1)+ve gamma-delta (γδ)] we show that distinct T cell subsets in cattle (defined as CD4+ve, CD8+ve or WC-1+ve) and sheep (defined as CD4+ve or WC-1+ve) can express IL-17A following activation. These novel techniques provide a solid basis to investigate IL-17A expression and define specific CD4+ve T cell subset activation in ruminants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13567-017-0426-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385008PMC
April 2017

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood.

Immunology 2017 05 7;151(1):89-97. Epub 2017 Feb 7.

The Roslin Institute, University of Edinburgh, Midlothian, UK.

Natural killer (NK) cells are widely distributed in lymphoid and non-lymphoid tissues, but little is known about the recirculation of NK cells between blood and tissues. This is relevant to understanding recirculation in the steady-state and also for determining the roles for NK cells in vaccine-induced immunity and responses to infection. Therefore, the percentage of NK cells and their phenotype across peripheral blood, afferent lymph and lymph nodes in steady-state conditions was investigated in cattle using the pseudo-afferent lymphatic cannulation model. CD2 CD25 NK cells were the predominant subset of NK cells within the blood. In contrast, CD2 CD25 NK cells were the main subset present within the skin-draining afferent lymphatic vessels and lymph nodes, indicating that CD2 NK cells are the principal NK cell subset trafficking to lymph nodes via the afferent lymphatic vessel. Furthermore, a low percentage of NK cells were present in efferent lymph, which were predominantly of the CD2 subset, indicating that NK cells can egress from lymph nodes and return to circulation in steady-state conditions. These compartmentalization data indicate that NK cells represent a population of recirculating lymphocytes in steady-state conditions and therefore may be important during immune responses to vaccination or infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.12708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382329PMC
May 2017

Inhibition of Antigen-Specific and Nonspecific Stimulation of Bovine T and B Cells by Lymphostatin from Attaching and Effacing Escherichia coli.

Infect Immun 2017 02 26;85(2). Epub 2017 Jan 26.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom.

Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are enteric bacterial pathogens of worldwide importance. Most EPEC and non-O157 EHEC strains express lymphostatin (also known as LifA), a chromosomally encoded 365-kDa protein. We previously demonstrated that lymphostatin is a putative glycosyltransferase that is important in intestinal colonization of cattle by EHEC serogroup O5, O111, and O26 strains. However, the nature and consequences of the interaction between lymphostatin and immune cells from the bovine host are ill defined. Using purified recombinant protein, we demonstrated that lymphostatin inhibits mitogen-activated proliferation of bovine T cells and, to a lesser extent, proliferation of cytokine-stimulated B cells, but not NK cells. It broadly affected the T cell compartment, inhibiting all cell subsets (CD4, CD8, WC-1, and γδ T cell receptor [γδ-TCR]) and cytokines examined (interleukin 2 [IL-2], IL-4, IL-10, IL-17A, and gamma interferon [IFN-γ]) and rendered T cells refractory to mitogen for a least 18 h after transient exposure. Lymphostatin was also able to inhibit proliferation of T cells stimulated by IL-2 and by antigen presentation using a Theileria-transformed cell line and autologous T cells from Theileria-infected cattle. We conclude that lymphostatin is likely to act early in T cell activation, as stimulation of T cells with concanavalin A, but not phorbol 12-myristate 13-acetate combined with ionomycin, was inhibited. Finally, a homologue of lymphostatin from E. coli O157:H7 (ToxB; L7095) was also found to possess comparable inhibitory activity against T cells, indicating a potentially conserved strategy for interference in adaptive responses by attaching and effacing E. coli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00845-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278176PMC
February 2017

Interactions between natural killer cells and dendritic cells favour T helper1-type responses to BCG in calves.

Vet Res 2016 08 17;47(1):85. Epub 2016 Aug 17.

The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK.

Vaccination of neonatal calves with BCG induces a significant level of protection from infection with Mycobacterium bovis, the causative agent of bovine tuberculosis. Since neonatal vaccination of humans with BCG induces activation of NK cells, and young calves have high circulating numbers of these cells, we hypothesised that NK cells are important in the protective response to BCG. Furthermore, since NK cells play a role in shaping adaptive immune responses through interactions with DCs, we investigated the interactions between NK cells and DCs in the context of BCG. DCs infected with BCG expressed significantly higher levels of MHC class II and the co-stimulatory molecules CD40 and CD80, alongside augmented production of the Th1 polarising cytokine IL-12, when compared with uninfected DCs. Following in vitro co-culture with BCG-infected DCs, NK cells increased their expression of the activatory molecule CD25, with preferential activation of the CD2- NK cell subset. NK cell effector function, as measured by production of IFN-γ, was also significantly enhanced following co-culture with BCG-infected DCs. This study provides novel evidence to demonstrate that NK cells phenotypically and functionally mature after interactions with DCs in the context of BCG. Furthermore, through the production of IFN-γ and IL-12 by NK cells and DCs respectively, this interaction may drive protective Th1-type immune responses to Mycobacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13567-016-0367-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988014PMC
August 2016

Animal African Trypanosomiasis: Time to Increase Focus on Clinically Relevant Parasite and Host Species.

Trends Parasitol 2016 08 8;32(8):599-607. Epub 2016 May 8.

Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.

Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and Trypanosoma vivax, remains one of the most important livestock diseases in sub-Saharan Africa, particularly affecting cattle. Despite this, our detailed knowledge largely stems from the human pathogen Trypanosoma brucei and mouse experimental models. In the postgenomic era, the genotypic and phenotypic differences between the AAT-relevant species of parasite or host and their model organism counterparts are increasingly apparent. Here, we outline the timeliness and advantages of increasing the research focus on both the clinically relevant parasite and host species, given that improved tools and resources for both have been developed in recent years. We propose that this shift of emphasis will improve our ability to efficiently develop tools to combat AAT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pt.2016.04.012DOI Listing
August 2016

Immunity, safety and protection of an Adenovirus 5 prime--Modified Vaccinia virus Ankara boost subunit vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves.

Vet Res 2014 Oct 29;45:112. Epub 2014 Oct 29.

Institute of Infection and Immunity, St, George's University of London, Cranmer Terrace, London SW17 0RE, UK.

Vaccination is the most cost effective control measure for Johne's disease caused by Mycobacterium avium subspecies paratuberculosis (MAP) but currently available whole cell killed formulations have limited efficacy and are incompatible with the diagnosis of bovine tuberculosis by tuberculin skin test. We have evaluated the utility of a viral delivery regimen of non-replicative human Adenovirus 5 and Modified Vaccinia virus Ankara recombinant for early entry MAP specific antigens (HAV) to show protection against challenge in a calf model and extensively screened for differential immunological markers associated with protection. We have shown that HAV vaccination was well tolerated, could be detected using a differentiation of infected and vaccinated animals (DIVA) test, showed no cross-reactivity with tuberculin and provided a degree of protection against challenge evidenced by a lack of faecal shedding in vaccinated animals that persisted throughout the 7 month infection period. Calves given HAV vaccination had significant priming and boosting of MAP derived antigen (PPD-J) specific CD4+, CD8+ IFN-γ producing T-cell populations and, upon challenge, developed early specific Th17 related immune responses, enhanced IFN-γ responses and retained a high MAP killing capacity in blood. During later phases post MAP challenge, PPD-J antigen specific IFN-γ and Th17 responses in HAV vaccinated animals corresponded with improvements in peripheral bacteraemia. By contrast a lack of IFN-γ, induction of FoxP3+ T cells and increased IL-1β and IL-10 secretion were indicative of progressive infection in Sham vaccinated animals. We conclude that HAV vaccination shows excellent promise as a new tool for improving control of MAP infection in cattle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13567-014-0112-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258034PMC
October 2014

Natural Killer Cells in Afferent Lymph Express an Activated Phenotype and Readily Produce IFN-γ.

Front Immunol 2013 22;4:395. Epub 2013 Nov 22.

Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science , Oslo , Norway.

Natural killer (NK) cells are motile cells that migrate between peripheral blood (PB), lymph nodes (LNs), and various organs. Domestic animals have frequently been used to study cellular migration, and offer unique opportunities for such studies. The aim of this study was to characterize the phenotype and cytokine producing capacity of NK cells in bovine skin-draining lymph. NKp46/NCR1(+) CD3(-) cells constituted 2-11% of mononuclear cells in afferent lymph (AL), a majority of cells were CD16(+), CD8α(+), and CD2(-/low), and elevated CD25 and CD44 expression indicated an activated phenotype. Interestingly, significantly fewer AL NK cells expressed the early activation marker CD69 compared to PB NK cells. A large proportion of lymph and blood NK cells produced interferon (IFN)-γ following stimulation with IL-2 and IL-12. Notably, in AL, but not blood, a similar amount of IFN-γ(+) NK cells was observed when cells were stimulated with IL-12 alone. Overall, AL NK cells were more similar to LN-residing NK cells than those circulating in PB. We conclude that AL appears to be an important migration route for tissue-activated NK cells, and may represent an alternative route for NK cell traffic to LNs. These findings may have important implications in the development of adjuvant strategies that aim to target NK cells in a vaccine response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2013.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837235PMC
December 2013

Breadth of the CD4+ T cell response to Anaplasma marginale VirB9-1, VirB9-2 and VirB10 and MHC class II DR and DQ restriction elements.

Immunogenetics 2012 Jul 24;64(7):507-23. Epub 2012 Feb 24.

Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA.

MHC class II molecules influence antigen-specific CD4+ T lymphocyte responses primed by immunization and infection. CD4+ T cell responses are important for controlling infection by many bacterial pathogens including Anaplasma marginale and are observed in cattle immunized with the protective A. marginale outer membrane (OM) vaccine. Immunogenic proteins that comprise the protective OM vaccine include type IV secretion system (T4SS) proteins VirB9-1, VirB9-2 and VirB10, candidates for inclusion in a multiepitope vaccine. Our goal was to determine the breadth of the VirB9-1, VirB9-2 and VirB10 T cell response and MHC class II restriction elements in six cattle with different MHC class II haplotypes defined by DRB3, DQA and DQB allele combinations for each animal. Overlapping peptides spanning each T4SS protein were tested in T cell proliferation assays with autologous antigen-presenting cells (APC) and artificial APC expressing combinations of bovine DR and DQ molecules. Twenty immunostimulatory peptides were identified; three representing two or more epitopes in VirB9-1, ten representing eight or more epitopes in VirB9-2 and seven representing seven or more epitopes in VirB10. Of the eight DRA/DRB3 molecules, four presented 15 peptides, which was biased as DRA/DRB3*1201 presented ten and DRA/DRB3*1101 presented four peptides. Four DQA/DQB molecules composed of two intrahaplotype and two interhaplotype pairs presented seven peptides, of which five were uniquely presented by DQ molecules. In addition, three functional mixed isotype (DQA/DRB3) restriction elements were identified. The immunogenicity and broad MHC class II presentation of multiple VirB9-1, VirB9-2 and VirB10 peptide epitopes justify their testing as a multiepitope vaccine against A. marginale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00251-012-0606-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372765PMC
July 2012

CD205 antigen targeting combined with dendritic cell recruitment factors and antigen-linked CD40L activation primes and expands significant antigen-specific antibody and CD4(+) T cell responses following DNA vaccination of outbred animals.

Vaccine 2012 Feb 10;30(9):1624-35. Epub 2012 Jan 10.

Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA.

Dendritic cell antigen targeting primes robust immune responses in mouse models. Optimizing this immunization strategy in the actual hosts that require protection will advance development of efficacious contemporary vaccines. In a proof-of-concept study, we tested the immunogenicity of a single, low dose of a novel multi-component DNA construct expressing a CD205-targeted antigen fused to a CD40L minimal functional domain for linked DC activation. The DNA construct was formulated with DNA-encoded Flt3L and GM-CSF for DC recruitment and the formulation was evaluated in MHC class II-matched calves. Immunization of the calves with the CD205 antigen-targeting construct mixed with the cytokine constructs induced significant IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and antibody responses detectable within one week post-immunization. CD205 antigen-targeting significantly expanded IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and IgG antibody responses three weeks post-immunization. Nineteen weeks post-priming, the IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and the IgG titers were waning, but they remained significant. Following boosting at nineteen weeks post-immunization, the immune responses primed by the CD205-targeted antigen underwent rapid recall and the mean response tripled within one week post-boost. Comparative analysis of the immune responses observed one week post-priming versus the responses detected one week post-boost revealed that the average number of the IFN-γ-secreting CD4(+) T-cells observed in the calves immunized with the CD205 antigen targeting construct increased five-fold, the mean CD4(+) T-cell proliferation increased three-fold, whereas the mean IgG antibody titer increased two hundred-fold. These promising outcomes support testing the protective efficacy of CD205-targeted antigens in the calf model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2011.12.110DOI Listing
February 2012

Tuberculosis immunity: opportunities from studies with cattle.

Clin Dev Immunol 2011 6;2011:768542. Epub 2010 Dec 6.

National Animal Disease Center, Agricultural Research Service, US Department of Agriculture, Ames, IA 50010, USA.

Mycobacterium tuberculosis and M. bovis share >99% genetic identity and induce similar host responses and disease profiles upon infection. There is a rich history of codiscovery in the development of control measures applicable to both human and bovine tuberculosis (TB) including skin-testing procedures, M. bovis BCG vaccination, and interferon-γ release assays. The calf TB infection model offers several opportunities to further our understanding of TB immunopathogenesis. Recent observations include correlation of central memory immune responses with TB vaccine efficacy, association of SIRPα(+) cells in ESAT-6:CFP10-elicited multinucleate giant cell formation, early γδ T cell responses to TB, antimycobacterial activity of memory CD4(+) T cells via granulysin production, association of specific antibody with antigen burden, and suppression of innate immune gene expression in infected animals. Partnerships teaming researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in man and animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2011/768542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004413PMC
June 2011

Characterisation of antibodies to bovine Toll-like receptor (TLR)-2 and cross-reactivity with ovine TLR2.

Vet Immunol Immunopathol 2011 Feb 13;139(2-4):313-8. Epub 2010 Oct 13.

Institute for Animal Health, High Street, Compton, Newbury, Berkshire RG207NN, United Kingdom.

Host recognition of conserved pathogen-associated molecular patterns (PAMPs) and their interactions with pattern-recognition receptors, including the Toll-like receptors (TLR) is essential for innate immune response induction. The TLR1 family (TLR1, 2, 6 and 10) is involved in the recognition of gram-positive and gram-negative bacteria and heterodimers of TLR1 or TLR6 with TLR2 are crucial for the identification of several PAMPs. Studies on cell surface expression of TLR in ruminants are hampered by the lack of specific antibodies and no convincingly cross-reactive anti-human antibodies have been described so far. We describe herein four antibodies which recognise bovine TLR2. Differences in TLR2 expression were evident on bovine antigen presenting cells with high level expression on peripheral blood monocytes and monocyte-derived macrophages. Lower levels of expression were evident on dendritic cell populations derived in vitro and ex vivo, and on alveolar macrophages. One of the antibodies recognised TLR2 expression on ovine peripheral blood monocytes. The identification of antibodies specific for bovine and ovine TLR2 will facilitate studies of the role of this important PRR in the initiation of immune responses to important pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2010.10.014DOI Listing
February 2011

Cytotoxicity and cytokine production by bovine alveolar macrophages challenged with wild type and leukotoxin-deficient Mannheimia haemolytica.

Vet J 2011 May 12;188(2):221-7. Epub 2010 Jun 12.

Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA.

Leukotoxin (LKT) is a virulence factor for Mannheimia haemolytica. In this study, bovine alveolar macrophages (BAMs) were challenged with wild type (wt) and LKT deficient (lkt(-)) M. haemolytica at a concentration of 1 bacterium/BAM and the cytokine response was quantified by ELISA and real-time reverse transcriptase-PCR. Significant increases in protein concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-10 were observed in supernatants obtained from BAMs challenged with the lkt(-) strain of M. haemolytica compared with wt challenged BAMs. There were no significant differences in mRNA expression of TNFα, IL-1ß, IL-6, IL-8 or IL-10 between BAMs challenged with the lkt(-) strain of M. haemolytica compared with wt challenged BAMs. BAMs challenged with the wt strain exhibited, on average, 43% more cytotoxicity than lkt(-) challenged BAMs (P<0.01).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tvjl.2010.05.015DOI Listing
May 2011

Natural killer cell number and phenotype in bovine peripheral blood is influenced by age.

Vet Immunol Immunopathol 2009 Dec 18;132(2-4):101-8. Epub 2009 May 18.

Institute for Animal Health, Compton, Newbury, Berkshire, RG20 7NN, United Kingdom.

Natural killer (NK) cells are critical to the innate defence against intracellular infection. High NK cell frequencies have been detected in human neonates, which may compensate for the relative immaturity of the specific immune response. Additionally, phenotypic subsets of NK cells have been identified in humans with different functional properties. In this study, we examined the age distribution and phenotype of NK populations in bovine peripheral blood, including neonatal animals. We found that the NK cell populations defined by the phenotypes CD3(-)CD2(+) and NKp46(+) largely overlapped, so that the majority of NK cells in bovine peripheral blood were CD3(-)CD2(+)NKp46(+). The remainder of the NK-like cells comprised two minor populations, CD3(-)CD2(+)NKp46(-) and CD3(-)CD2(-)NKp46(+); the relative proportions of these varied with age. The lowest frequency of NK cells was recorded in 1-day-old calves, with the highest frequency in day 0 calves. The phenotypic characteristics of CD3(-)CD2(+) and NKp46(+) NK populations were similar; both populations expressed CD45RO, CD45RB, CD11b, CC84, CD8alphaalpha and CD8alphabeta and did not express CD21, WC1, CD14 or gammadelta TCR. Age-related phenotypic differences were apparent. The phenotypic characteristics of three NK subpopulations were described; a significantly greater proportion of the CD3(-)CD2(-)NKp46(+) population expressed CD8alpha compared to CD3(-)CD2(+)NKp46(+) cells. Furthermore, a significantly greater proportion of the CD3(-)CD2(+)NKp46(-) population expressed CD8 compared to total CD3(-)CD2(+) cells. Adult cattle had a significantly higher proportion of perforin(+) cells compared to calves aged
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2009.05.002DOI Listing
December 2009

Th1-Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages.

Vet Immunol Immunopathol 2009 Mar 17;128(1-3):37-43. Epub 2008 Oct 17.

Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, Dublin 8, Ireland.

Autophagy is a major intracellular pathway for the lysosomal degradation of long-lived cytoplasmic macromolecules and damaged or surplus organelles. More recently, autophagy has also been linked with innate and adaptive immune responses against intracellular pathogens, including Mycobacterium tuberculosis, which can survive within macrophages by blocking fusion of the phagosome with lysosomes. Induction of autophagy by the Th1 cytokine IFN-gamma enables infected macrophages to overcome this phagosome maturation block and inhibit the intracellular survival of mycobacteria. Conversely, the Th2 cytokines IL-4 and IL-13 inhibit autophagy in murine and human macrophages. We discuss how differential modulation of autophagy by Th1 and Th2 cytokines may represent an important feature of the host response to mycobacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2008.10.293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789833PMC
March 2009

Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosis.

J Infect Dis 2008 Dec;198(12):1842-50

St. James's Hospital and Trinity College Dublin, Dublin, Ireland.

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that mediates inflammation in response to various pathogens, including Mycobacterium tuberculosis, but is also a key factor in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Three TNF-alpha-suppressing drugs have been approved to treat selected autoimmune diseases; 2 are monoclonal antibodies against TNF-alpha (adalimumab and infliximab), and the other is a soluble TNF receptor/Fc fusion protein (etanercept). TNF blockers have been shown to increase the risk of reactivation of latent tuberculosis, and this risk is higher in patients treated with the monoclonal antibodies. We studied the effects of TNF-alpha blockers on the maturation of mycobacteria-containing phagosomes in human macrophages. All 3 drugs had an inhibitory effect on IFN-gamma-induced phagosome maturation in phorbolmyristate acetate-differentiated human THP-1 cells. Adalimumab and infliximab, but not etanercept, suppressed phagosome maturation in primary human peripheral blood monocyte-derived macrophages in the presence or absence of IFN-gamma. Treatment of macrophages with TNF-alpha led to increased maturation of phagosomes containing Mycobacterium bovis bacillus Calmette-Guérin or M. tuberculosis H37Rv. These results suggest a role for TNF-alpha in activating phagosome maturation and highlight a mechanism through which TNF-alpha blockade can affect the host response to mycobacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/593174DOI Listing
December 2008