Publications by authors named "Jodi L McGill"

34 Publications

A Recombinant BCG Vaccine Is Safe and Immunogenic in Neonatal Calves and Reduces the Clinical Disease Caused by the Respiratory Syncytial Virus.

Front Immunol 2021 26;12:664212. Epub 2021 Apr 26.

Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, IA, United States.

The human respiratory syncytial virus (hRSV) constitutes a major health burden, causing millions of hospitalizations in children under five years old worldwide due to acute lower respiratory tract infections. Despite decades of research, licensed vaccines to prevent hRSV are not available. Development of vaccines against hRSV targeting young infants requires ruling out potential vaccine-enhanced disease presentations. To achieve this goal, vaccine testing in proper animal models is essential. A recombinant BCG vaccine that expresses the Nucleoprotein of hRSV (rBCG-N-hRSV) protects mice against hRSV infection, eliciting humoral and cellular immune protection. Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. Here, we evaluated the safety, immunogenicity, and protective efficacy of the rBCG-N-hRSV vaccine in a neonatal bovine RSV calf infection model. Newborn, colostrum-replete Holstein calves were either vaccinated with rBCG-N-hRSV, WT-BCG, or left unvaccinated, and then inoculated aerosol challenge with bRSV strain 375. Vaccination with rBCG-N-hRSV was safe and well-tolerated, with no systemic adverse effects. There was no evidence of vaccine-enhanced disease following bRSV challenge of rBCG-N-hRSV vaccinated animals, suggesting that the vaccine is safe for use in neonates. Vaccination increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in PBMCs and lymph nodes at 7dpi. Furthermore, rBCG-N-hRSV vaccinated calves developed reduced clinical disease as compared to unvaccinated control calves, although neither pathology nor viral burden were significantly reduced in the lungs. These results suggest that the rBCG-N-hRSV vaccine is safe in neonatal calves and induces protective humoral and cellular immunity against this respiratory virus. These data from a newborn animal model provide further support to the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.664212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108697PMC
April 2021

Applications of Nanovaccines for Disease Prevention in Cattle.

Front Bioeng Biotechnol 2020 11;8:608050. Epub 2020 Dec 11.

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, United States.

Vaccines are one of the most important tools available to prevent and reduce the incidence of infectious diseases in cattle. Despite their availability and widespread use to combat many important pathogens impacting cattle, several of these products demonstrate variable efficacy and safety in the field, require multiple doses, or are unstable under field conditions. Recently, nanoparticle-based vaccine platforms (nanovaccines) have emerged as promising alternatives to more traditional vaccine platforms. In particular, polymer-based nanovaccines provide sustained release of antigen payloads, stabilize such payloads, and induce enhanced antibod- and cell-mediated immune responses, both systemically and locally. To improve vaccine administrative strategies and efficacy, they can be formulated to contain multiple antigenic payloads and have the ability to protect fragile proteins from degradation. Nanovaccines are also stable at room temperature, minimizing the need for cold chain storage. Nanoparticle platforms can be synthesized for targeted delivery through intranasal, aerosol, or oral administration to induce desired mucosal immunity. In recent years, several nanovaccine platforms have emerged, based on biodegradable and biocompatible polymers, liposomes, and virus-like particles. While most nanovaccine candidates have not yet advanced beyond testing in rodent models, a growing number have shown promise for use against cattle infectious diseases. This review will highlight recent advancements in polymeric nanovaccine development and the mechanisms by which nanovaccines may interact with the bovine immune system. We will also discuss the positive implications of nanovaccines use for combating several important viral and bacterial disease syndromes and consider important future directions for nanovaccine development in beef and dairy cattle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2020.608050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759628PMC
December 2020

Supplementing a Saccharomyces cerevisiae fermentation product modulates innate immune function and ameliorates bovine respiratory syncytial virus infection in neonatal calves.

J Anim Sci 2020 Aug;98(8)

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA.

The objectives of this study were to determine the effects of oral supplementation with Saccharomyces cerevisiae fermentation products (SCFP; SmartCare and NutriTek; Diamond V, Cedar Rapids, IA) on immune function and bovine respiratory syncytial virus (BRSV) infection in preweaned dairy calves. Twenty-four Holstein × Angus, 1- to 2-d-old calves (38.46 ± 0.91 kg initial body weight [BW]) were assigned two treatment groups: control or SCFP treated, milk replacer with 1 g/d SCFP (SmartCare) and calf starter top-dressed with 5 g/d SCFP (NutriTek). The study consisted of one 31-d period. On days 19 to 21 of the supplementation period, calves were challenged via aerosol inoculation with BRSV strain 375. Calves were monitored twice daily for clinical signs, including rectal temperature, cough, nasal and ocular discharge, respiration effort, and lung auscultation. Calves were euthanized on day 10 postinfection (days 29 to 31 of the supplementation period) to evaluate gross lung pathology and pathogen load. Supplementation with SCFP did not affect BW (P = 0.762) or average daily gain (P = 0.750), percentages of circulating white blood cells (P < 0.05), phagocytic (P = 0.427 for neutrophils and P = 0.460 for monocytes) or respiratory burst (P = 0.119 for neutrophils and P = 0.414 for monocytes) activity by circulating leukocytes either before or following BRSV infection, or serum cortisol concentrations (P = 0.321) after BRSV infection. Calves receiving SCFP had reduced clinical disease scores compared with control calves (P = 0.030), reduced airway neutrophil recruitment (P < 0.002), reduced lung pathology (P = 0.031), and a reduced incidence of secondary bacterial infection. Calves receiving SCFP shed reduced virus compared with control calves (P = 0.049) and tended toward lower viral loads in the lungs (P = 0.051). Immune cells from the peripheral blood of SCFP-treated calves produced increased (P < 0.05) quantities of interleukin (IL)-6 and tumor necrosis factor-alpha in response to toll-like receptor stimulation, while cells from the bronchoalveolar lavage (BAL) of SCFP-treated calves secreted less (P < 0.05) proinflammatory cytokines in response to the same stimuli. Treatment with SCFP had no effect on virus-specific T cell responses in the blood but resulted in reduced (P = 0.045) virus-specific IL-17 secretion by T cells in the BAL. Supplementing with SCFP modulates both systemic and mucosal immune responses and may improve the outcome of an acute respiratory viral infection in preweaned dairy calves.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jas/skaa252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457959PMC
August 2020

Innate Immunomodulation in Food Animals: Evidence for Trained Immunity?

Front Immunol 2020 5;11:1099. Epub 2020 Jun 5.

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, United States.

Antimicrobial resistance (AMR) is a significant problem in health care, animal health, and food safety. To limit AMR, there is a need for alternatives to antibiotics to enhance disease resistance and support judicious antibiotic usage in animals and humans. Immunomodulation is a promising strategy to enhance disease resistance without antibiotics in food animals. One rapidly evolving field of immunomodulation is innate memory in which innate immune cells undergo epigenetic changes of chromatin remodeling and metabolic reprogramming upon a priming event that results in either enhanced or suppressed responsiveness to secondary stimuli (training or tolerance, respectively). Exposure to live agents such as bacille Calmette-Guerin (BCG) or microbe-derived products such as LPS or yeast cell wall ß-glucans can reprogram or "train" the innate immune system. Over the last decade, significant advancements increased our understanding of innate training in humans and rodent models, and strategies are being developed to specifically target or regulate innate memory. In veterinary species, the concept of enhancing the innate immune system is not new; however, there are few available studies which have purposefully investigated innate training as it has been defined in human literature. The development of targeted approaches to engage innate training in food animals, with the practical goal of enhancing the capacity to limit disease without the use of antibiotics, is an area which deserves attention. In this review, we provide an overview of innate immunomodulation and memory, and the mechanisms which regulate this long-term functional reprogramming in other animals (e.g., humans, rodents). We focus on studies describing innate training, or similar phenomenon (often referred to as heterologous or non-specific protection), in cattle, sheep, goats, swine, poultry, and fish species; and discuss the potential benefits and shortcomings of engaging innate training for enhancing disease resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291600PMC
April 2021

The Immunology of Bovine Respiratory Disease: Recent Advancements.

Vet Clin North Am Food Anim Pract 2020 Jul 21;36(2):333-348. Epub 2020 Apr 21.

Ruminant Diseases and Immunology Research Unit, Agricultural Research Services, USDA, PO Box 70, 1920 Dayton Avenue, Ames, IA 50010, USA.

Bovine respiratory disease (BRD) remains a leading cause of morbidity, mortality, and economic loss to the cattle industry. The continued high prevalence of the disease underlines a gap in understanding of the host immune response to respiratory infection. The host immune response is beneficial and detrimental, required for clearing the disease but often leading to tissue damage and long-term defects in lung function. This article highlights advancements made in understanding innate and adaptive immunity in BRD, factors that predispose animals to BRD, and novel intervention strategies that may lead to changes in the approach to treating and controlling BRD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cvfa.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170797PMC
July 2020

Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination.

Sci Rep 2019 11 5;9(1):15996. Epub 2019 Nov 5.

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USA.

The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-52565-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831659PMC
November 2019

Vitamin A deficiency impairs the immune response to intranasal vaccination and RSV infection in neonatal calves.

Sci Rep 2019 10 22;9(1):15157. Epub 2019 Oct 22.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, USDA, Ames, IA, USA.

Respiratory syncytial virus (RSV) infection is a leading cause of severe acute lower respiratory tract infection in infants and children worldwide. Vitamin A deficiency (VAD) is one of the most prevalent nutrition-related health problems in the world and is a significant risk factor in the development of severe respiratory infections in infants and young children. Bovine RSV (BRSV) is a primary cause of lower respiratory tract disease in young cattle. The calf model of BRSV infection is useful to understand the immune response to human RSV infection. We have previously developed an amphiphilic polyanhydride nanoparticle (NP)-based vaccine (i.e., nanovaccine) encapsulating the fusion and attachment proteins from BRSV (BRSV-NP). Calves receiving a single, intranasal dose of the BRSV-NP vaccine are partially protected from BRSV challenge. Here, we evaluated the impact of VAD on the immune response to the BRSV-NP vaccine and subsequent challenge with BRSV. Our results show that VAD calves are unable to respond to the mucosal BRSV-NP vaccine, are afforded no protection from BRSV challenge and have significant abnormalities in the inflammatory response in the infected lung. We further show that acute BRSV infection negatively impacts serum and liver retinol, rendering even well-nourished individuals susceptible to VAD. Our results support the use of the calf model for elucidating the impact of nutritional status on mucosal immunity and respiratory viral infection in infants and underline the importance of VA in regulating immunity in the respiratory mucosa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-51684-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805856PMC
October 2019

Gamma Delta T Cell Function in Ruminants.

Vet Clin North Am Food Anim Pract 2019 Nov;35(3):453-469

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, 1907 Christensen Drive, VMRI Building 5, Ames, IA 50010, USA. Electronic address:

Gamma delta (γδ) T cells constitute a major lymphocyte population in peripheral blood and epithelial surfaces. They play nonredundant roles in host defense against diverse pathogens. Although γδ T cells share functional features with other cells of the immune system, their distinct methods of antigen recognition, rapid response, and tissue tropism make them a unique effector population. This review considers the current state of our knowledge on γδ T cell biology in ruminants and the important roles played by this nonconventional T cell population in protection against several infectious diseases of veterinary and zoonotic importance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cvfa.2019.08.001DOI Listing
November 2019

Characterization of γδ T Cell Effector/Memory Subsets Based on CD27 and CD45R Expression in Response to Infection.

Immunohorizons 2019 06 12;3(6):208-218. Epub 2019 Jun 12.

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50010; and

Tuberculosis (TB) remains a leading cause of death from infectious diseases worldwide. is the causative agent of bovine TB and zoonotic TB infection. γδ T cells are known to participate in the immune control of mycobacterial infections. Data in human and nonhuman primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of γδ T cells. To date, the impact of infection on bovine γδ T cells and their effector and memory differentiation remains unknown. In this study, we show that circulating γδ T cells from -infected cattle can be differentiated based on the expression of CD27, which is indicative of their capacity to respond to virulent infection: CD27 γδ T cells proliferated in response to Ag and, thus, may comprise the adaptive γδ T cell compartment in cattle. We further show that bovine -specific γδ T cells express surface markers characteristic of central memory T cells (CD45RCD27CD62L) and that -specific CD4 and γδ T cells both upregulate the expression of the tissue-homing receptors CXCR3 and CCR5 during infection. Our studies contribute significantly to our understanding of γδ T cell differentiation during TB infection and provide important insights into the link between phenotypic and functional subsets in the bovine. Accurate characterization of γδ T cell effector and memory-like responses induced during mycobacterial infection will contribute to improved strategies for harnessing the γδ T cell response in protection against TB for humans and animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/immunohorizons.1900032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875775PMC
June 2019

Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus.

Front Microbiol 2019 3;10:873. Epub 2019 May 3.

Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.

The human respiratory syncytial virus (hRSV) is the main etiologic agent of severe lower respiratory tract infections that affect young children throughout the world, associated with significant morbidity and mortality, becoming a serious public health problem globally. Up to date, no licensed vaccines are available to prevent severe hRSV-induced disease, and the generation of safe-effective vaccines has been a challenging task, requiring constant biomedical research aimed to overcome this ailment. Among the difficulties presented by the study of this pathogen, it arises the fact that there is no single animal model that resembles all aspects of the human pathology, which is due to the specificity that this pathogen has for the human host. Thus, for the study of hRSV, different animal models might be employed, depending on the goal of the study. Of all the existing models, the murine model has been the most frequent model of choice for biomedical studies worldwide and has been of great importance at contributing to the development and understanding of vaccines and therapies against hRSV. The most notable use of the murine model is that it is very useful as a first approach in the development of vaccines or therapies such as monoclonal antibodies, suggesting in this way the direction that research could have in other preclinical models that have higher maintenance costs and more complex requirements in its management. However, several additional different models for studying hRSV, such as other rodents, mustelids, ruminants, and non-human primates, have been explored, offering advantages over the murine model. In this review, we discuss the various applications of animal models to the study of hRSV-induced disease and the advantages and disadvantages of each model, highlighting the potential of each model to elucidate different features of the pathology caused by the hRSV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2019.00873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510261PMC
May 2019

Prophylactic digoxin treatment reduces IL-17 production in vivo in the neonatal calf and moderates RSV-associated disease.

PLoS One 2019 25;14(3):e0214407. Epub 2019 Mar 25.

Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, Kansas, United States of America.

Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in human infants. Bovine RSV infection of neonatal calves is pathologically and immunologically similar to RSV infection in infants, and is therefore a useful preclinical model for testing novel therapeutics. Treatment of severe RSV bronchiolitis relies on supportive care and may include use of bronchodilators and inhaled or systemic corticosteroids. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. It is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection. Digoxin was recently identified to selectively inhibit IL-17 production by antagonizing its transcription factor, retinoid-related orphan receptor γ t (RORγt). Digoxin inhibits RORγt binding to IL-17 and Th17 associated genes, and suppresses IL-17 production in vitro in human and murine leukocytes and in vivo in rodent models of autoimmune disease. We demonstrate here that in vitro and in vivo digoxin treatment also inhibits IL-17 production by bovine leukocytes. To determine the role of IL-17 in primary RSV infection, calves were treated prophylactically with digoxin and infected with BRSV. Digoxin treated calves demonstrated reduced signs of clinical illness after BRSV infection, and reduced lung pathology compared to untreated control calves. Digoxin treatment did not adversely affect virus shedding or lung viral burden, but had a significant impact on pulmonary inflammatory cytokine expression on day 10 post infection. Together, our results suggest that exacerbated expression of IL-17 has a negative impact on RSV disease, and that development of specific therapies targeting Th17 immunity may be a promising strategy to improve disease outcome during severe RSV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433258PMC
December 2019

Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves.

PLoS One 2019 22;14(2):e0212751. Epub 2019 Feb 22.

Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, Iowa, United States of America.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine for use against tuberculosis (TB); however, it is known to reduce childhood mortality from infections other than TB. The unspecific protection induced by BCG vaccination has been associated with the induction of memory-like traits of the innate immune system identified as 'trained' immunity. In humans and mouse models, in vitro and in vivo BCG training leads to enhanced production of monocyte-derived proinflammatory cytokines in response to secondary unrelated bacterial and fungal pathogens. While BCG has been studied extensively for its ability to induce innate training in humans and mouse models, BCG's nonspecific protective effects have not been defined in agricultural species. Here, we show that in vitro BCG training induces a functional change in bovine monocytes, characterized by increased transcription of proinflammatory cytokines upon restimulation with the toll-like receptor agonists. Importantly, in vivo, aerosol BCG vaccination in young calves also induced a 'trained' phenotype in circulating peripheral blood mononuclear cells (PBMCs), that lead to a significantly enhanced TLR-induced proinflammatory cytokine response and changes in cellular metabolism compared to PBMCs from unvaccinated control calves. Similar to the long-term training effects of BCG reported in humans, our results suggest that in young calves, the effects of BCG induced innate training can last for at least 3 months in circulating immune populations. Interestingly, however, aerosol BCG vaccination did not 'train' the innate immune response at the mucosal level, as alveolar macrophages from aerosol BCG vaccinated calves did not mount an enhanced inflammatory response to secondary stimulation, compared to cells isolated from control calves. Together, our results suggest that, like mice and humans, the innate immune system of calves can be 'trained'; and that BCG vaccination could be used as an immunomodulatory strategy to reduce disease burden in juvenile food animals before the adaptive immune system has fully matured.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212751PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386280PMC
November 2019

Utility of the Neonatal Calf Model for Testing Vaccines and Intervention Strategies for Use against Human RSV Infection.

Vaccines (Basel) 2019 Jan 8;7(1). Epub 2019 Jan 8.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA 50010, USA.

Respiratory syncytial virus (RSV) is a significant cause of pediatric respiratory tract infections. It is estimated that two-thirds of infants are infected with RSV during the first year of life and it is one of the leading causes of death in this age group worldwide. Similarly, bovine RSV is a primary viral pathogen in cases of pneumonia in young calves and plays a significant role in bovine respiratory disease complex. Importantly, naturally occurring infection of calves with bovine RSV shares many features in common with human RSV infection. Herein, we update our current understanding of RSV infection in cattle, with particular focus on similarities between the calf and human infection, and the recent reports in which the neonatal calf has been employed for the development and testing of vaccines and therapeutics which may be applied to hRSV infection in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines7010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466205PMC
January 2019

A Single-Step Gold Nanoparticle-Blood Serum Interaction Assay Reveals Humoral Immunity Development and Immune Status of Animals from Neonates to Adults.

ACS Infect Dis 2019 02 19;5(2):228-238. Epub 2018 Dec 19.

Department of Chemistry and NanoScience Technology Center , University of Central Florida , 12424 Research Parkway Suite 400 , Orlando , Florida 32826 , United States.

A well-developed, functional immune system is paramount to combat harmful attacks from pathogenic organisms and prevent infectious diseases. Newborn animals and humans have only limited immunity upon birth, but their immune functions are expected to develop within weeks to months and eventually to reach a maturity that will provide full protection. Despite the importance of immune activity in animal and human health management, there is no convenient test available that allows for rapid assessment of the state of immune function in nonlaboratory settings. Here we report an extremely simple and rapid blood test that may be used in point-of-care clinics or field settings to evaluate the humoral immune status of animals. The test detects a cooperative interaction between a gold nanoparticle and arguably the three most important proteins involved in the immune system: immunoglobulin M (IgM), immunoglobulin G (IgG), and at least one complement protein, C3, in the blood serum. Such interactions cause the gold nanoparticles to form clusters and aggregates. The average particle size of the gold nanoparticle-serum mixture, measured by dynamic light scattering, corresponds positively to the immune status and activity of the subject. Our study demonstrates that the test may be used not only for monitoring the immune function development from neonates to adults, but also for detecting active immune responses during infection. Although data reported here are largely based on murine and bovine models, it is likely that this test will be applicable to humans as well.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsinfecdis.8b00213DOI Listing
February 2019

Antigen-Specific CD4CD8 Double-Positive T Cells Are Increased in the Blood and Spleen During Infection in the Canine Host.

Front Immunol 2018 11;9:1585. Epub 2018 Jul 11.

Center of Excellence for Vector-Borne Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States.

is an obligate intracellular bacterium belonging to the order, Rickettsiales and is a frequent cause of severe and fatal tick-borne infection in people in North America. The reservoir host for is the white-tailed deer, while humans and dogs are regarded as common incidental hosts. In dogs, we and others have shown that establishes a chronic infection that persists for several weeks to months, while promoting the development of Th1 and Th17 cellular responses and pathogen-specific humoral immunity. We demonstrate here that vaccination with a live, attenuated clone of bearing a targeted mutation in the Ech_0230 gene neither promotes the development of long-lived cellular or humoral immunity, nor confers protection against secondary wild-type challenge. In dogs, a population of mature CD4CD8 double-positive (DP) T cells exists in the periphery that shares similarities with the DP T cell populations that have been described in humans and swine. Little is known about the function of these cells, particularly in the context of infectious diseases. Here, we demonstrate that canine DP T cells expand significantly in response to infection. Using antigen recall assays, we further demonstrate that canine DP T cells undergo clonal expansion, produce IFNγ and IL-17, and upregulate expression of granzyme B and granulysin. Together, our results demonstrate that DP T cells accumulate in the host during infection, and suggest that alternative lymphocyte populations may participate in the immune response to tick-borne infections in the incidental host.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050357PMC
July 2018

Efficacy of mucosal polyanhydride nanovaccine against respiratory syncytial virus infection in the neonatal calf.

Sci Rep 2018 02 14;8(1):3021. Epub 2018 Feb 14.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, USDA, Ames, IA, USA.

Human respiratory syncytial virus (HRSV) is a leading cause of severe acute lower respiratory tract infection in infants and children worldwide. Bovine RSV (BRSV) is closely related to HRSV and a significant cause of morbidity in young cattle. BRSV infection in calves displays many similarities to RSV infection in humans, including similar age dependency and disease pathogenesis. Polyanhydride nanoparticle-based vaccines (i.e., nanovaccines) have shown promise as adjuvants and vaccine delivery vehicles due to their ability to promote enhanced immunogenicity through the route of administration, provide sustained antigen exposure, and induce both antibody- and cell-mediated immunity. Here, we developed a novel, mucosal nanovaccine that encapsulates the post-fusion F and G glycoproteins from BRSV into polyanhydride nanoparticles and determined the efficacy of the vaccine against RSV infection using a neonatal calf model. Calves receiving the BRSV-F/G nanovaccine exhibited reduced pathology in the lungs, reduced viral burden, and decreased virus shedding compared to unvaccinated control calves, which correlated with BRSV-specific immune responses in the respiratory tract and peripheral blood. Our results indicate that the BRSV-F/G nanovaccine is highly immunogenic and, with optimization, has the potential to significantly reduce the disease burden associated with RSV infection in both humans and animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-21292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813012PMC
February 2018

Measuring bovine γδ T cell function at the site of Mycobacterium bovis infection.

Vet Immunol Immunopathol 2017 Dec 27;193-194:38-49. Epub 2017 Oct 27.

Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS, USA. Electronic address:

Bovine γδ T cells are amongst the first cells to accumulate at the site of Mycobacterium bovis infection; however, their role in the developing lesion remains unclear. We utilized transcriptomics analysis, in situ hybridization, and a macrophage/γδ T cell co-culture system to elucidate the role of γδ T cells in local immunity to M. bovis infection. Transcriptomics analysis revealed that γδ T cells upregulated expression of several novel, immune-associated genes in response to stimulation with M. bovis antigen. BCG-infected macrophage/γδ T cell co-cultures confirmed the results of our RNAseq analysis, and revealed that γδ T cells from M. bovis-infected animals had a significant impact on bacterial viability. Analysis of γδ T cells within late-stage M. bovis granulomas revealed significant expression of IFN-γ and CCL2, but not IL-10, IL-22, or IL-17. Our results suggest γδ T cells influence local immunity to M. bovis through cytokine secretion and direct effects on bacterial burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2017.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703227PMC
December 2017

Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination.

Front Immunol 2016 17;7:421. Epub 2016 Oct 17.

Infectious Bacterial Diseases of Livestock Research Unit, National Animal Disease Center , Ames, IA , USA.

Central memory T cell (Tcm) and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector/memory populations from bacille Calmette-Guerin (BCG) vaccinated and non-vaccinated calves by flow cytometry prior to and after aerosol challenge with virulent . Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and -infected calves, only differing in magnitude (i.e., infected > vaccinated). BCG vaccination, however, did alter the kinetics of the ensuing response to virulent infection. Early after challenge (3 weeks post-infection), non-vaccinates had greater antigen-specific interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α) and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains) were detected in memory subsets, as well as in effector cells, as early as 3 weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden, while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2016.00421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066095PMC
October 2016

Bovine Gamma Delta T Cells Contribute to Exacerbated IL-17 Production in Response to Co-Infection with Bovine RSV and Mannheimia haemolytica.

PLoS One 2016 4;11(3):e0151083. Epub 2016 Mar 4.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, Ames, Iowa, United States of America.

Human respiratory syncytial virus (HRSV) is a leading cause of severe lower respiratory tract infection in children under five years of age. IL-17 and Th17 responses are increased in children infected with HRSV and have been implicated in both protective and pathogenic roles during infection. Bovine RSV (BRSV) is genetically closely related to HRSV and is a leading cause of severe respiratory infections in young cattle. While BRSV infection in the calf parallels many aspects of human infection with HRSV, IL-17 and Th17 responses have not been studied in the bovine. Here we demonstrate that calves infected with BRSV express significant levels of IL-17, IL-21 and IL-22; and both CD4 T cells and γδ T cells contribute to this response. In addition to causing significant morbidity from uncomplicated infections, BRSV infection also contributes to the development of bovine respiratory disease complex (BRDC), a leading cause of morbidity in both beef and dairy cattle. BRDC is caused by a primary viral infection, followed by secondary bacterial pneumonia by pathogens such as Mannheimia haemolytica. Here, we demonstrate that in vivo infection with M. haemolytica results in increased expression of IL-17, IL-21 and IL-22. We have also developed an in vitro model of BRDC and show that co-infection of PBMC with BRSV followed by M. haemolytica leads to significantly exacerbated IL-17 production, which is primarily mediated by IL-17-producing γδ T cells. Together, our results demonstrate that calves, like humans, mount a robust IL-17 response during RSV infection; and suggest a previously unrecognized role for IL-17 and γδ T cells in the pathogenesis of BRDC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778910PMC
July 2016

γδ T cells and the immune response to respiratory syncytial virus infection.

Vet Immunol Immunopathol 2016 Nov 21;181:24-29. Epub 2016 Feb 21.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, 1920 Dayton Ave., Ames, IA 50010, USA.

γδ T cells are a subset of nonconventional T cells that play a critical role in bridging the innate and adaptive arms of the immune system. γδ T cells are particularly abundant in ruminant species and may constitute up to 60% of the circulating lymphocyte pool in young cattle. The frequency of circulating γδ T cells is highest in neonatal calves and declines as the animal ages, suggesting these cells may be particularly important in the immune system of the very young. Bovine respiratory syncytial virus (BRSV) is a significant cause of respiratory infection in calves, and is most severe in animals under one year of age. BRSV is also a significant factor in the development of bovine respiratory disease complex (BRDC), the leading cause of morbidity and mortality in feedlot cattle. Human respiratory syncytial virus (RSV) is closely related to BRSV and a leading cause of lower respiratory tract infection in infants and children worldwide. BRSV infection in calves shares striking similarities with RSV infection in human infants. To date, there have been few studies defining the role of γδ T cells in the immune response to BRSV or RSV infection in animals or humans, respectively. However, emerging evidence suggests that γδ T cells may play a critical role in the early recognition of infection and in shaping the development of the adaptive immune response through inflammatory chemokine and cytokine production. Further, while it is clear that γδ T cells accumulate in the lungs during BRSV and RSV infection, their role in protection vs. immunopathology remains unclear. This review will summarize what is currently known about the role of γδ T cells in the immune response to BRSV and BRDC in cattle, and where appropriate, draw parallels to the role of γδ T cells in the human response to RSV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2016.02.012DOI Listing
November 2016

Vaccination with an Attenuated Mutant of Ehrlichia chaffeensis Induces Pathogen-Specific CD4+ T Cell Immunity and Protection from Tick-Transmitted Wild-Type Challenge in the Canine Host.

PLoS One 2016 3;11(2):e0148229. Epub 2016 Feb 3.

Center of Excellence for Vector-Borne Diseases, Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America.

Ehrlichia chaffeensis is a tick-borne rickettsial pathogen and the causative agent of human monocytic ehrlichiosis. Transmitted by the Amblyomma americanum tick, E. chaffeensis also causes disease in several other vertebrate species including white-tailed deer and dogs. We have recently described the generation of an attenuated mutant strain of E. chaffeensis, with a mutation in the Ech_0660 gene, which is able to confer protection from secondary, intravenous-administered, wild-type E. chaffeensis infection in dogs. Here, we extend our previous results, demonstrating that vaccination with the Ech_0660 mutant protects dogs from physiologic, tick-transmitted, secondary challenge with wild-type E. chaffeensis; and describing, for the first time, the cellular and humoral immune responses induced by Ech_0660 mutant vaccination and wild-type E. chaffeensis infection in the canine host. Both vaccination and infection induced a rise in E. chaffeensis-specific antibody titers and a significant Th1 response in peripheral blood as measured by E. chaffeensis antigen-dependent CD4+ T cell proliferation and IFNγ production. Further, we describe for the first time significant IL-17 production by peripheral blood leukocytes from both Ech_0660 mutant vaccinated animals and control animals infected with wild-type E. chaffeensis, suggesting a previously unrecognized role for IL-17 and Th17 cells in the immune response to rickettsial pathogens. Our results are a critical first step towards defining the role of the immune system in vaccine-induced protection from E. chaffeensis infection in an incidental host; and confirm the potential of the attenuated mutant clone, Ech_0660, to be used as a vaccine candidate for protection against tick-transmitted E. chaffeensis infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148229PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739596PMC
July 2016

Parainfluenza Virus 3 Blocks Antiviral Mediators Downstream of the Interferon Lambda Receptor by Modulating Stat1 Phosphorylation.

J Virol 2015 Dec 30;90(6):2948-58. Epub 2015 Dec 30.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, Iowa, USA Molecular, Cellular and Developmental Biology Graduate Program, Iowa State University, Ames, Iowa, USA Immunobiology Graduate Program, Iowa State University, Ames, Iowa, USA

Unlabelled: Parainfluenza viruses are known to inhibit type I interferon (IFN) production; however, there is a lack of information regarding the type III IFN response during infection. Type III IFNs signal through a unique heterodimeric receptor, IFN-λR1/interleukin-10R2 (IL-10R2), which is primarily expressed by epithelial cells. Parainfluenza virus 3 (PIV-3) infection is highly restricted to the airway epithelium. We therefore sought to examine type III IFN signaling pathways during PIV-3 infection of epithelial cells. We used three strains of PIV-3: human PIV-3 (HPIV-3), bovine PIV-3 (BPIV-3), and dolphin PIV-1 (Tursiops truncatus PIV-1, or TtPIV-1). Here, we show that message levels of IL-29 are significantly increased during PIV-3 infection, yet downstream antiviral signaling molecules are not upregulated to levels similar to those of the positive control. Furthermore, in Vero cells infected with PIV-3, stimulation with recombinant IL-29/-28A/-28B does not cause upregulation of downstream antiviral molecules, suggesting that PIV-3 interferes with the JAK/STAT pathway downstream of the IFN-λR1/IL-10R2 receptor. We used Western blotting to examine the phosphorylation of Stat1 and Stat2 in Vero cells and the bronchial epithelial cell line BEAS-2B. In Vero cells, we observed reduced phosphorylation of the serine 727 (S727) site on Stat1, while in BEAS-2B cells Stat1 phosphorylation was decreased at the tyrosine 701 (Y701) site during PIV-3 infection. PIV-3 therefore interferes with the phosphorylation of Stat1 downstream of the type III IFN receptor. These data provide new evidence regarding strategies employed by parainfluenza viruses to effectively circumvent respiratory epithelial cell-specific antiviral immunity.

Importance: Parainfluenza virus (PIV) in humans is associated with bronchiolitis and pneumonia and can be especially problematic in infants and the elderly. Also seen in cattle, bovine PIV-3 causes respiratory infections in young calves. In addition, PIV-3 is one of a number of pathogens that contribute to the bovine respiratory disease complex (BRDC). As their name suggests, interferons (IFNs) are produced by cells to interfere with viral replication. Paramyxoviruses have previously been shown to block production and downstream signaling of type I IFNs. For the first time, it is shown here that PIV-3 can induce protective type III IFNs in epithelial cells, the primary site of PIV-3 infection. However, we found that PIV-3 modulates signaling pathways downstream of the type III IFN receptor to block production of several specific molecules that aid in a productive antiviral response. Importantly, this work expands our understanding of how PIV-3 effectively evades host innate immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.02502-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810625PMC
December 2015

Interleukin-17A as a Biomarker for Bovine Tuberculosis.

Clin Vaccine Immunol 2016 02 16;23(2):168-80. Epub 2015 Dec 16.

Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, New York, USA.

T helper 17 (Th17)-associated cytokines are integral to the immune responses to tuberculosis, initiating both protective and harmful inflammatory responses. The aim of the present study was to evaluate applied aspects of interleukin-17 (IL-17) biology in the context of Mycobacterium bovis infection of cattle. Using transcriptome sequencing (RNA-Seq), numerous Th17-associated cytokine genes (including IL-17A, IL-17F, IL-22, IL-19, and IL-27) were upregulated >9-fold in response to purified protein derivative stimulation of peripheral blood mononuclear cells from experimentally M. bovis-infected cattle. Protective vaccines elicited IL-17A, IL-17F, IL-22, and IL-27 responses. Reduced IL-17A responses by vaccine recipients, compared to nonvaccinated animals, at 2.5 weeks after M. bovis challenge correlated with reduced disease burdens. Additionally, IL-17A and interferon gamma (IFN-γ) responses were highly correlated and exhibited similar diagnostic capacities. The present findings support the use of Th17-associated cytokines as biomarkers of infection and protection in the immune responses to bovine tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CVI.00637-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744917PMC
February 2016

Novel Atlantic bottlenose dolphin parainfluenza virus TtPIV-1 clusters with bovine PIV-3 genotype B strains.

Virus Genes 2015 Oct 15;51(2):198-208. Epub 2015 Jul 15.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA, USA.

Parainfluenza virus 3 (PIV-3) is a common viral infection not only in humans, but also in many other species. Serological evidence suggests that nearly 100 % of children in the United States have been infected with PIV-3 by 5 years of age. Similarly, in cattle, PIV-3 is commonly associated with bovine respiratory disease complex. A novel dolphin PIV-3 (TtPIV-1) was described by Nollens et al. in 2008 from a dolphin that was diagnosed with an unknown respiratory illness. At that time, TtPIV-1 was found to be most similar to, but distinct from, bovine PIV-3 (BPIV-3). In the present study, similar viral growth kinetics and pro-inflammatory cytokine (IL-1β, IL-6, and CXCL8) production were seen between BPIV-3 and TtPIV-1 in BEAS-2B, MDBK, and Vero cell lines. Initial nomenclature of TtPIV-1 was based on partial sequence of the fusion and RNA polymerase genes. Based on the similarities we saw with the in vitro work, it was important to examine the TtPIV-1 genome in more detail. Full genome sequencing and subsequent phylogenetic analysis revealed that all six viral genes of TtPIV-1 clustered within the recently described BPIV-3 genotype B strains, and it is proposed that TtPIV-1 be re-classified with BPIV-3 genotype B strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11262-015-1224-7DOI Listing
October 2015

Bovine viral diarrhea virus type 2 in vivo infection modulates TLR4 responsiveness in differentiated myeloid cells which is associated with decreased MyD88 expression.

Virus Res 2015 Oct 1;208:44-55. Epub 2015 Jun 1.

Immunobiology Interdepartmental Graduate Program, Iowa State University, 2018 Molecular Biology Building, Ames, IA 50011, USA; Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Avenue, Ames, IA 50010, USA. Electronic address:

Symptoms of bovine viral diarrhea virus (BVDV) infection range from subclinical to severe, depending on strain virulence. Several in vitro studies showed BVDV infection impaired leukocyte function. Fewer studies have examined the effects of in vivo BVDV infection on monocyte/macrophage function, especially with strains of differing virulence. We characterized cytokine production by bovine myeloid cells isolated early or late in high (HV) or low virulence (LV) BVDV2 infection. Given BVDV infection may enhance susceptibility to secondary bacterial infection, LPS responses were examined as well. Monocytes from HV and LV infected calves produced higher levels of cytokines compared to cells from controls. In contrast, monocyte-derived macrophage cytokine levels were generally reduced. Modulated cytokine expression in HV BVDV2 macrophages was associated with decreased MyD88 expression, likely due to its interaction with viral NS5A. These data and those of others, suggest that certain Flaviviridae may have evolved strategies for subverting receptor signaling pathways involving MyD88.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virusres.2015.05.017DOI Listing
October 2015

Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza a virus infection.

Alcohol Clin Exp Res 2014 Sep 26;38(9):2403-13. Epub 2014 Aug 26.

Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa.

Background: It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza A virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce interferon γ (IFNγ). However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown.

Methods: Utilizing the Meadows-Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV, and the activation and effector functions of IAV-specific CD8 T cells were determined in both the lung-draining lymph nodes (dLN) and lungs.

Results: Our results confirm the defect in IFNγ production; however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the dLN of IAV-infected, EtOH-consuming mice.

Conclusions: These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acer.12522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461571PMC
September 2014

The role of gamma delta T cells in immunity to Mycobacterium bovis infection in cattle.

Vet Immunol Immunopathol 2014 Jun 24;159(3-4):133-43. Epub 2014 Feb 24.

Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA, United States.

Accumulating evidence suggests that γδ T cells play a critical role in the early response to Mycobacterium bovis and may be key in bridging innate and adaptive immunity following infection. In vitro, γδ T cells proliferate and produce robust amounts of IFNγ in response to complex, protein and non-protein mycobacterial antigens including M. bovis purified protein derivative (PPD), heat shock proteins and cell wall components such as mycolylarabinogalactan peptidoglycan (mAGP). Vaccination with Bacille Calumette-Guerin (BCG), as well as infection with virulent M. bovis, induces an increase in the frequency and activation of WC1(+) γδ T cells circulating in the blood. Gamma delta T cells are rapidly recruited to the lungs and draining lymph nodes following BCG vaccination, and accumulate in developing lesions early following M. bovis infection. In Severe Combined Immuno-deficient (SCID)-bo mice, depletion of γδ T cells prior to M. bovis infection results in impaired granuloma formation, suggesting a role for γδ T cells in immune cell recruitment and lesion development. In vivo depletion of WC1(+) γδ T cells from calves prior to M. bovis infection results in significantly reduced levels of M. bovis specific IgG2 and IFNγ, and increased IL-4 production compared to non-depleted control animals, suggesting that γδ T cells may also play a role in shaping the character of the adaptive M. bovis specific immune response. Whereas it is clear that γδ T cells are responding during M. bovis infection, much remains to be understood about their function in vivo and their ability to shape the innate and adaptive immune responses. This review focuses on recent advances in our understanding of γδ T cell biology with a particular emphasis on the immune response of γδ T cells in cattle during M. bovis infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2014.02.010DOI Listing
June 2014

Relevance of bovine tuberculosis research to the understanding of human disease: historical perspectives, approaches, and immunologic mechanisms.

Vet Immunol Immunopathol 2014 Jun 22;159(3-4):113-32. Epub 2014 Feb 22.

Infectious Bacterial Diseases of Livestock Research Unit, National Animal Disease Center, Ames, IA, United States.

Pioneer studies on infectious disease and immunology by Jenner, Pasteur, Koch, Von Behring, Nocard, Roux, and Ehrlich forged a path for the dual-purpose with dual benefit approach, demonstrating a profound relevance of veterinary studies for biomedical applications. Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is an exemplary model for the demonstration of this concept. Early studies with cattle were instrumental in the development of the use of Koch's tuberculin as an in vivo measure of cell-mediated immunity for diagnostic purposes. Calmette and Guerin demonstrated the efficacy of an attenuated M. bovis strain (BCG) in cattle prior to use of this vaccine in humans. The interferon-γ release assay, now widely used for TB diagnosis in humans, was developed circa 1990 for use in the Australian bovine TB eradication program. More recently, M. bovis infection and vaccine efficacy studies with cattle have demonstrated a correlation of vaccine-elicited T cell central memory (TCM) responses to vaccine efficacy, correlation of specific antibody to mycobacterial burden and lesion severity, and detection of antigen-specific IL-17 responses to vaccination and infection. Additionally, positive prognostic indicators of bovine TB vaccine efficacy (i.e., responses measured after infection) include: reduced antigen-specific IFN-γ, iNOS, IL-4, and MIP1-α responses; reduced antigen-specific expansion of CD4(+) T cells; and a diminished activation profile on T cells within antigen stimulated cultures. Delayed type hypersensitivity and IFN-γ responses correlate with infection but do not necessarily correlate with lesion severity whereas antibody responses generally correlate with lesion severity. Recently, serologic tests have emerged for the detection of tuberculous animals, particularly elephants, captive cervids, and camelids. B cell aggregates are consistently detected within tuberculous lesions of humans, cattle, mice and various other species, suggesting a role for B cells in the immunopathogenesis of TB. Comparative immunology studies including partnerships of researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in both man and animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetimm.2014.02.009DOI Listing
June 2014

Specific recognition of mycobacterial protein and peptide antigens by γδ T cell subsets following infection with virulent Mycobacterium bovis.

J Immunol 2014 Mar 14;192(6):2756-69. Epub 2014 Feb 14.

Ruminant Diseases and Immunology Research Unit, National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA 50010;

Promoting effective immunity to Mycobacterium bovis infection is a challenge that is of interest to the fields of human and animal medicine alike. We report that γδ T cells from virulent M. bovis-infected cattle respond specifically and directly to complex, protein, and nonprotein mycobacterial Ags. Importantly, to our knowledge, we demonstrate for the first time that bovine γδ T cells specifically recognize peptide Ags derived from the mycobacterial protein complex ESAT6:CFP10 and that this recognition requires direct contact with APCs and signaling through the T cell Ag receptor but is independent of MHC class I or II. Furthermore, we show that M. bovis infection in cattle induces robust IL-17A protein responses. Interestingly, in contrast to results from mice, bovine CD4 T cells, and not γδ T cells, are the predominant source of this critical proinflammatory mediator. Bovine γδ T cells are divided into subsets based upon their expression of Workshop Cluster 1 (WC1), and we demonstrate that the M. bovis-specific γδ T cell response is composed of a heterogeneous mix of WC1-expressing populations, with the serologically defined WC1.1(+) and WC1.2(+) subsets responding in vitro to mycobacterial Ags and accumulating in the lesions of M. bovis-infected animals. The results described in this article enhance our understanding of γδ T cell biology and, because virulent M. bovis infection of cattle represents an excellent model of tuberculosis in humans, contribute to our overall understanding of the role of γδ T cells in the mycobacterial-specific immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1302567DOI Listing
March 2014

Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus.

Virus Res 2014 Apr 12;183:95-106. Epub 2014 Feb 12.

Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1683 Campus Delivery, Fort Collins, CO 80523-1683, USA. Electronic address:

Development of transplacental infection depends on the ability of the virus to cross the placenta and replicate within the fetus while counteracting maternal and fetal immune responses. Unfortunately, little is known about this complex process. Non-cytopathic (ncp) strains of bovine viral diarrhea virus (BVDV), a pestivirus in the Flaviviridae family, cause persistent infection in early gestational fetuses (<150 days; persistently infected, PI), but are cleared by immunocompetent animals and late gestational fetuses (>150 days; transiently infected, TI). Evasion of innate immune response and development of immunotolerance to ncp BVDV have been suggested as possible mechanisms for the establishment of the persistent infection. Previously we have observed a robust temporal induction of interferon (IFN) type I (innate immune response) and upregulation of IFN stimulated genes (ISGs) in BVDV TI fetuses. Modest chronic upregulation of ISGs in PI fetuses and calves reflects a stimulated innate immune response during persistent BVDV infection. We hypothesized that establishing persistent fetal BVDV infection is also accompanied by the induction of IFN-gamma (IFN-γ). The aims of the present study were to determine IFN-γ concentration in blood and amniotic fluid from control, TI and PI fetuses during BVDV infection and analyze induction of the IFN-γ downstream pathways in fetal lymphoid tissues. Two experiments with in vivo BVDV infections were completed. In Experiment 1, pregnant heifers were infected with ncp BVDV type 2 on day 75 or 175 of gestation or kept naïve to generate PI, TI and control fetuses, respectively. Fetuses were collected by Cesarean section on day 190. In Experiment 2, fetuses were collected on days 82, 89, 97, 192 and 245 following infection of pregnant heifers on day 75 of gestation. The results were consistent with the hypothesis that ncp BVDV infection induces IFN-γ secretion during acute infection in both TI and PI fetuses and that lymphoid tissues such as spleen, liver and thymus, serve both as possible sources of IFN-γ and target organs for its effects. Notably, induction of IFN-γ coincides with a decrease in BVDV RNA concentrations in PI fetal blood and tissues. This is the first report indicating the possible presence of an adaptive immune response in persistent BVDV infections, which may be contributing to the observed reduction of viremia in PI fetuses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virusres.2014.02.002DOI Listing
April 2014