scholarly journals A Bovine Enteric Mycobacterium Infection Model to Analyze Parenteral Vaccine-Induced Mucosal Immunity and Accelerate Vaccine Discovery

2020 ◽  
Vol 11 ◽  
Author(s):  
Antonio Facciuolo ◽  
Amy H. Lee ◽  
Michael J. Trimble ◽  
Neil Rawlyk ◽  
Hugh G. G. Townsend ◽  
...  
Keyword(s):  
Small Intestine ◽  
Immune Responses ◽  
Vaccine Development ◽  
Natural Host ◽  
Lymphoid Cells ◽  
Intestinal Lumen ◽  
Infection Model ◽  
Enteric Infection ◽  
Intestinal Segments ◽  
Mucosal Immune Responses

Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. Mycobacteriumavium ssp. paratuberculosis (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum® – a commercial MAP bacterin – we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer’s patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335+ innate lymphoid cells, and increased expression of IL21 and IL27. Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.

scholarly journals Dietary Selenium in Immune Mechanisms During an Enteric Bacterial Infection (OR12-08-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shaneice Nettleford ◽  
Luming Zhao ◽  
James Fraser ◽  
Adwitia Dey ◽  
Dhimant Desai ◽  
...  
Keyword(s):  
Immune Responses ◽  
Trace Element ◽  
Lymphoid Cells ◽  
Nutritional Deficiencies ◽  
Enteric Infection ◽  
Bacterial Burden ◽  
Citrobacter Rodentium ◽  
T Helper 17 ◽  
Western Blots ◽  
Deficient Mice

Abstract Objectives Enteropathogenic Escherichia coli (EPEC) poses a great threat to developing countries, as EPEC can result in diarrhea and colitis in children. Interestingly, the effect of trace element nutritional deficiencies as well as their supplementation on disease pathogenesis is increasingly being recognized. We have previously reported that supplementation of mice with selenium (Se), a trace element that is incorporated into selenoproteins as the 21st amino acid, resulted in the amelioration of chemically induced colitis through the downregulation of pro-inflammatory mediators of the arachidonic acid pathway, including prostaglandin E2 (PGE2). Here we examined the effects of Se supplementation on immune responses during an enteric infection with Citrobacter rodentium, a natural murine enteropathogen. Methods C57BL/6 mice placed on Se-deficient (0.01 ppm Se), Se-adequate (0.08 ppm Se), or Se-supplemented (0.4 ppm Se) diets for 8 weeks were infected with Citrobacter rodentium, the murine equivalent of EPEC with a shared core set of virulence factors. Mice were euthanized, and colons were collected for further analysis including western blots and flow cytometry. Results Se-deficient mice experienced increased bacterial burden, mortality, and decreased colon length following infection, compared to Se-adequate and Se-supplemented mice. Studies revealed that there was an increase type 3 innate-lymphoid cells (ILC3s) and IL-22 producing T helper 17 (Th17) cells, but a decrease in regulatory T- cells (Tregs) and 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that preferentially oxidizes PGE2, in the colon of Se-deficient mice compared to Se-adequate and Se-supplemented mice. Treatment of Se-adequate mice with CAY10397, an inhibitor of 15-PGDH, increased the bacterial burden following infection. Infection of mice that lack expression of selenoproteins in macrophages (Trspfl/fl LysMCre) showed increased mortality despite being fed diets replete with Se. Conclusions Adequate to supplemental levels of dietary Se is required to maximize the expression of selenoproteins to effectively mediate resolution of enteric infections. Selenoproteins act through diverse mechanisms, including modulation of immune responses and inflammation through the oxidative metabolism of PGE2. Funding Sources National Institute of Health.

scholarly journals Parenteral Vaccination Can Be an Effective Means of Inducing Protective Mucosal Responses

2016 ◽  
Vol 23 (6) ◽  
pp. 438-441 ◽  
Author(s):  
John D. Clements ◽  
Lucy C. Freytag
Keyword(s):  
Experimental Data ◽  
Immune Responses ◽  
Vaccine Development ◽  
Effective Means ◽  
Rare Occurrence ◽  
Mucosal Tissues ◽  
Mucosal Immune Responses ◽  
Paradigm Shifting ◽  
Current Paradigm ◽  
The Way

ABSTRACTThe current paradigm in vaccine development is that nonreplicating vaccines delivered parenterally fail to induce immune responses in mucosal tissues. However, both clinical and experimental data have challenged this concept, and numerous studies have shown that induction of mucosal immune responses after parenteral vaccination is not a rare occurrence and might, in fact, significantly contribute to the protection against mucosal infections afforded by parenteral vaccines. While the mechanisms underlying this phenomenon are not well understood, the realization that parenteral vaccination can be an effective means of inducing protective mucosal responses is paradigm-shifting and has potential to transform the way vaccines are designed and delivered.

scholarly journals Trehalose Ingestion Modifies Mucosal Immune Responses of the Small Intestine in Mice

2002 ◽  
Vol 48 (3) ◽  
pp. 282-287 ◽  
Author(s):  
Norie Arai ◽  
Chiyo Yoshizane ◽  
Chikako Arai ◽  
Toshiharu Hanaya ◽  
Shigeyuki Arai ◽  
...  
Keyword(s):  
Small Intestine ◽  
Immune Responses ◽  
Mucosal Immune Responses

scholarly journals Role of antigen specific T and B cells in systemic and mucosal immune responses in ETEC and Shigella infections, and their potential to serve as correlates of protection in vaccine development

Vaccine ◽  
2019 ◽  
Vol 37 (34) ◽  
pp. 4787-4793 ◽  
Author(s):  
Sachin Mani ◽  
Franklin R. Toapanta ◽  
Monica A. McArthur ◽  
Firdausi Qadri ◽  
Ann-Mari Svennerholm ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Vaccine Development ◽  
T And B Cells ◽  
Correlates Of Protection ◽  
Mucosal Immune Responses

scholarly journals Enhanced Mucosal Immune Responses to HIV Virus-Like Particles Containing a Membrane-Anchored Adjuvant

mBio ◽  
2011 ◽  
Vol 2 (1) ◽  
Author(s):  
Elena V. Vassilieva ◽  
Bao-Zhong Wang ◽  
Andrei N. Vzorov ◽  
Li Wang ◽  
Ying-Chun Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mucosal Immunity ◽  
Vaccine Development ◽  
Transmitted Disease ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Significant Drop ◽  
Virus Like Particles ◽  
Hiv Virus ◽  
Mucosal Immune Responses

ABSTRACTPreviously, a modified HIV Env protein with a heterologous membrane anchor was found to be incorporated into HIV virus-like particles (VLPs) at 10-fold-higher levels than those of unmodified Env. To further improve the immunogenicity of such VLPs, membrane-anchored forms of bacterial flagellin (FliC) or a flagellin with a truncated variable region (tFliC) were constructed to be incorporated into the VLPs as adjuvants. HIV-specific immune responses induced by the resulting VLPs were determined in a guinea pig model. The VLPs induce enhanced systemic antibody responses by either systemic or mucosal vaccination and enhanced mucosal immunity by a mucosal immunization route, as demonstrated by high levels of HIV-specific serum IgG and mucosal IgG and IgA. The quality of the antibody responses was also improved, as shown by enhanced neutralization capacity. VLPs incorporating FliC were more effective in inducing systemic responses, while VLPs containing tFliC were more effective in inducing mucosal IgA responses. The IgG titers in sera were found to last for at least 5 months without a significant drop. These results indicate that HIV VLPs incorporating high levels of Env and a molecular adjuvant have excellent potential for further development as a prophylactic HIV vaccine.IMPORTANCEA prophylactic vaccine is urgently needed to control the spread of HIV/AIDS. Antigens inducing strong systemic and mucosal immune responses are promising as vaccines for this mucosally transmitted disease. We found that novel HIV virus-like particles (VLPs) presenting a high level of Env in its native membrane-bound form and coincorporating an innate immune-signaling adjuvant in the same particles were effective in inducing enhanced systemic and mucosal immunity. As new HIV vaccine candidates, these VLPs bridge the gaps of the innate and adaptive, as well as systemic and mucosal, immune responses, providing a new approach for HIV vaccine development.

scholarly journals Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407

2015 ◽  
Vol 23 (1) ◽  
pp. 55-64 ◽  
Author(s):  
Subhra Chakraborty ◽  
Clayton Harro ◽  
Barbara DeNearing ◽  
Malathi Ram ◽  
Andrea Feller ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Immune Responses ◽  
Vaccine Development ◽  
Lavage Fluid ◽  
Antibody Responses ◽  
Enterotoxigenic Escherichia Coli ◽  
Effective Vaccine ◽  
Content Type ◽  
Mucosal Immune Responses

ABSTRACTEnterotoxigenicEscherichia coli(ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective vaccine for ETEC, no licensed vaccines are currently available. A significant challenge to successful vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC vaccines and immunization regimens in the future.

scholarly journals Yersinia enterocolitica Infection of Mice Reveals Clonal Invasion and Abscess Formation

2007 ◽  
Vol 75 (8) ◽  
pp. 3802-3811 ◽  
Author(s):  
Mark F. Oellerich ◽  
Christoph A. Jacobi ◽  
Sandra Freund ◽  
Katy Niedung ◽  
Alexandra Bach ◽  
...  
Keyword(s):  
Small Intestine ◽  
Yersinia Enterocolitica ◽  
Fluorescent Protein ◽  
Gastrointestinal Disease ◽  
Abscess Formation ◽  
Peyer's Patches ◽  
Intestinal Lumen ◽  
Infection Model ◽  
Peyer’S Patches

ABSTRACT Yersinia enterocolitica is a common cause of food-borne gastrointestinal disease leading to self-limiting diarrhea and mesenteric lymphadenitis. Occasionally, focal abscess formation in the livers and spleens of certain predisposed patients (those with iron overload states such as hemochromatosis) is observed. In the mouse oral infection model, yersiniae produce a similar disease involving the replication of yersiniae in the small intestine, the invasion of Peyer's patches, and dissemination to the liver and spleen. In these tissues and organs, yersiniae are known to replicate predominately extracellularly and to form microcolonies. By infecting mice orally with a mixture of equal amounts of green- and red-fluorescing yersiniae (yersiniae expressing green or red fluorescent protein), we were able to show for the first time that yersiniae produce exclusively monoclonal microcolonies in Peyer's patches, the liver, and the spleen, indicating that a single bacterium is sufficient to induce microcolony and microabscess formation in vivo. Furthermore, we present evidence for the clonal invasion of Peyer's patches from the small intestine. The finding that only very few yersiniae are required to establish microcolonies in Peyer's patches is due to both Yersinia-specific and host-specific factors. We demonstrate that yersiniae growing in the small intestinal lumen show strongly reduced levels of invasin, the most important factor for the early invasion of Peyer's patches. Furthermore, we show that the host severely restricts sequential microcolony formation in previously infected Peyer's patches.

scholarly journals Production and Clinical Evaluation of Norwalk GI.1 Virus Lot 001-09NV in Norovirus Vaccine Development

2019 ◽  
Vol 221 (6) ◽  
pp. 919-926 ◽  
Author(s):  
Roberto Mateo ◽  
Lisa C Lindesmith ◽  
Shaily J Garg ◽  
Keith Gottlieb ◽  
Karen Lin ◽  
...  
Keyword(s):  
Immune Responses ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Geometric Mean ◽  
Infection Model ◽  
Norwalk Virus ◽  
Igg Antibody ◽  
Peripheral Blood Mononuclear ◽  
Immune Correlates

Abstract Background Human noroviruses (HuNoV) are the leading cause of gastroenteritis. No vaccine is currently available to prevent norovirus illness or infection. Safe, infectious challenge strains are needed to assess vaccine efficacy in the controlled human infection model (CHIM). Methods A stock of HuNoV strain Norwalk virus ([NV] GI.1) was prepared. Healthy, genetically susceptible adults were inoculated with NV Lot 001-09NV and monitored for infection, gastroenteritis symptoms, and immune responses. Results Lot 001-09NV induced gastroenteritis in 9 (56%) and infection in 11 (69%) of 16 genetically susceptible subjects. All infected subjects developed strong immune responses to GI.1 with a 30-fold (geometric mean titer) increase in blocking titers (BT50) and a 161-fold increase in GI.1-specific immunoglobulin (Ig)G titers when compared with baseline. GI.1-specific cellular responses in peripheral blood were observed 9 days postchallenge with an average of 3253 IgA and 1227 IgG antibody-secreting cells per million peripheral blood mononuclear cells. Conclusions GI.1 Lot 001-09NV appears to be similar in virulence to previous passages of NV strain 8fIIa. The safety profile, attack rate, and duration of illness make GI.1 Lot 001-09NV a useful challenge strain for future vaccine studies aimed at establishing immune correlates.

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