scholarly journals Oral administration of an anti-CfaE secretory IgA antibody protects against Enterotoxigenic Escherichia coli diarrheal disease in a non-human primate model

2019 ◽  
Author(s):  
Matteo Stoppato ◽  
Carlos Gaspar ◽  
James Regeimbal ◽  
Gladys Nunez ◽  
Serena Giuntini ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Oral Administration ◽  
Attack Rate ◽  
Protective Efficacy ◽  
Enterotoxigenic Escherichia Coli ◽  
Secretory Iga ◽  
Primate Model ◽  
Group 3 ◽  
Group 2 ◽  
Human Primate

ABSTACTEnterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea-associated illness in developing countries. There is currently no vaccine licensed to prevent ETEC and the development of an efficacious prophylaxis would provide an intervention with significant impact. Recent studies suggested that effective protection could be achieved by inducing immunity to block colonization of ETEC. Here, we evaluated the efficacy of secretory (s) IgA2 and dimeric (d) IgA2 of an anti-colonization factor antigen antibody, 68-61, in the Aotus nancymaae non-human primate (NHP) ETEC challenge model via oral and parental delivery. Thirty-nine animals were distributed across 3 groups of 13, and challenged with 5.0×1011 cfu of H10407 on Day 0. Group 1 received a dIgA2 68-61 subcutaneously on day 0. Group 2 received a SIgA2 68-61 orally on days −1, 0, and +1, and Group 3 received an irrelevant SIgA2 antibody orally on days −1, 0, and +1. All animals were observed for symptoms of diarrhea, and stools were collected for ETEC colony counts. SIgA2 treatment significantly lowered the attack rate, resulting in a protective efficacy of 71.4% (p=0.025) in Group 2 as compared to Group 3. Anti-CfaE dIgA2 treatment group reduced the diarrheal attack rate, although the reduction did not reach significance (57.1%; P=0.072) as compared to the irrelevant SIgA2 Group 3. Our results demonstrated the feasibility of oral administration of SIgA as a potential immunoprophylaxis against enteric infections. To our knowledge, this is the first study to demonstrate the efficacy of administrated SIgA in a non-human primate model.

scholarly journals Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis Against Enterotoxigenic Escherichia coli Infection

2018 ◽  
Author(s):  
Serena Giuntini ◽  
Matteo Stoppato ◽  
Maja Sedic ◽  
Monir Ejemel ◽  
Jessica R. Pondish ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Monoclonal Antibodies ◽  
Oral Administration ◽  
Enterotoxigenic Escherichia Coli ◽  
Secretory Iga ◽  
Watery Diarrhea ◽  
Human Monoclonal Antibodies ◽  
Receptor Binding Site ◽  
Colonization Factor

AbstractBackgroundEnterotoxigenicEscherichia coli(ETEC) cause diarrheal illness in infants in the developing world and travelers to endemic countries including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea.MethodsMice transgenic for human immunoglobulin genes were immunized with CfaE to generate a panel of human monoclonal IgG1 antibodies (HuMAbs). The most potent IgG1 identified in thein vitrofunctional assays were selected and isotype switched to secretory IgA (sIgA) and tested in animal colonization assays via oral administration.ResultsOver 300 unique anti-CfaE IgG1 HuMabs were identified. The lead IgG1 anti-CfaE HuMAbs completely inhibited hemagglutination and blocked adhesion of ETEC to Caco-2 cells. Epitope mapping studies revealed that HuMAbs recognized epitopes in the N-terminal domain of CfaE near the putative receptor binding site. Oral administration of anti-CfaE antibodies in either IgG or secretory IgA isotypes inhibited intestinal colonization in mice challenged with ETEC. A two to four log decrease of colony forming units was observed as compared to irrelevant isotype controls.ConclusionsWe identified fully human monoclonal antibodies against CfaE adhesion domain that can be potentially employed as an immunoprophylaxis to prevent ETEC-related diarrhea.

scholarly journals Immunogenicity and protective efficacy of enterotoxigenic Escherichia coli (ETEC) total RNA against ETEC challenge in a mouse model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mandi Liu ◽  
Yue Zhang ◽  
Di Zhang ◽  
Yun Bai ◽  
Guomei Liu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mouse Model ◽  
Immune Responses ◽  
Protective Efficacy ◽  
Enterotoxigenic Escherichia Coli ◽  
Economic Losses ◽  
Th2 Response ◽  
Total Rna ◽  
Etec Infection

AbstractEnterotoxigenic Escherichia coli (ETEC), an essential cause of post-weaning diarrhea (PWD) in piglets, leads to significant economic losses to the pig industry. The present study aims to identify the role of ETEC total RNA in eliciting immune responses to protect animals against ETEC infection. The results showed that the total RNA isolated from pig-derived ETEC K88ac strain effectively stimulated the IL-1β secretion of porcine intestinal epithelial cells (IPEC-J2). The mouse model immunized with ETEC total RNA via intramuscular injection (IM) or oral route (OR) was used to evaluate the protective efficiency of the ETEC total RNA. The results suggested that 70 μg ETEC total RNA administered by either route significantly promoted the production of the serum IL-1β and K88ac specific immunoglobulins (IgG, IgM, and IgA). Besides, the ETEC RNA administration augmented strong mucosal immunity by elevating K88ac specific IgA level in the intestinal fluid. Intramuscularly administered RNA induced a Th1/Th2 shift toward a Th2 response, while the orally administered RNA did not. The ETEC total RNA efficiently protected the animals against the ETEC challenge either by itself or as an adjuvant. The histology characterization of the small intestines also suggested the ETEC RNA administration protected the small intestinal structure against the ETEC infection. Particularly of note was that the immunity level and protective efficacy caused by ETEC RNA were dose-dependent. These findings will help understand the role of bacterial RNA in eliciting immune responses, and benefit the development of RNA-based vaccines or adjuvants.

scholarly journals Erectogenic Effect of Thyme (Thymus vulgaris) Extract in Normal and 5-Fluorouracil induced Oxidative Stressed Adult Male Wistar Rats

2021 ◽  
pp. 22-34
Author(s):  
O. Abimbola Akintemi ◽  
R. O. Babalola ◽  
S. O. Babatunde
Keyword(s):  
Vitamin C ◽  
Oral Administration ◽  
Thymus Vulgaris ◽  
Male Wistar Rats ◽  
Group 3 ◽  
Group 5 ◽  
Group 2 ◽  
Phosphodiesterase 5 ◽  
Thiol Level ◽  
Group 1

This study determined the effect of oral administration of aqueous extract from Thyme (Thymus vulgaris) extract (TVE) on the antioxidant status and activity of some penile function enzymes (acetylcholinesterase (AChE), phosphodiesterase-5 (PDE-5), adenosine diaminase (ADA), and arginase) activity in normal and 5- Fluorouracil- induced oxidative stressed rats. Sixty adult Wister rats (210-225)g were divided into ten (10) groups (n=6): Group 1: received oral administration  of normal saline (NC), Group 2: received 100 mg/kg of thyme extract orally (TE 100 mg/kg), Group 3: received 200 mg/kg of thyme extract orally (TE 200 mg/kg), rats in group four were treated with 400 mg/kg of thyme extract orally (TE 400 mg/kg), Those in group 5: received 25 mg/kg of Vitamin C orally, while group 6 to 10 were induced with 150 mg/kg of 5-Fluorouracil solution (5-FLU, i.p), but group 7-10 were treated 100 mg/kg, 200 mg/kg, 400 mg/kg and Vitamin C (25mg/kg), respectively. After fourteen (14) days of treatment, the rats were sacrificed and the penile tissue was carefully isolated and prepared into homogenate, which was used for antioxidant and enzymes biochemical analysis. The result revealed that i.p induction of 5-FLU caused a significant increase in malondialdehyde level, as well as AChE, ADA, PDE-5 and arginase activities wth concomitant decrease in thiol level when compared to control rats. However, the administration of TVE was found to reverse the effect of 5-FLU. The TVE was also found the reduced MDA level and all the enzyme activities, but boosted the thiol level in the normal rats when compared to control rats. Interestingly the effect of the TVE was found dose-dependently, and 400 mg/kg TVE was found to be more potent among all the doses used in both normal and 5-FLU-induced oxidative stress rats.

Association of Enterohemorrhagic Escherichia coliHemolysin with Serotypes of Shiga-Like-Toxin-ProducingEscherichia coli of Human and Bovine Origins

1998 ◽  
Vol 64 (11) ◽  
pp. 4134-4141 ◽  
Author(s):  
Carlton Gyles ◽  
Roger Johnson ◽  
Anli Gao ◽  
Kim Ziebell ◽  
Denis Pierard ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Severe Disease ◽  
Sheep Erythrocyte ◽  
Pcr Amplification ◽  
E Coli ◽  
Hemolysin Gene ◽  
Group 3 ◽  
Group 2 ◽  
Bovine Feces ◽  
Group 1

ABSTRACT In this study we investigated whether the enterohemorrhagicEscherichia coli (EHEC) hemolysin gene ehxAcould be used as an indicator of pathogenicity in Shiga-like-toxin-producing Escherichia coli (SLTEC) isolates. The isolates in a collection of 770 SLTEC strains of human and bovine origins were assigned to group 1 (230 human and 138 bovine SLTEC isolates belonging to serotypes frequently implicated in human disease), group 2 (85 human and 183 bovine isolates belonging to serotypes less frequently implicated in disease), and group 3 (134 bovine isolates belonging to serotypes not implicated in disease). PCR amplification was used to examine all of the SLTEC isolates for the presence of ehxA and the virulence-associated geneseae, slt-I, and slt-II. The percentages of human isolates in groups 1 and 2 that were positive forehxA were 89 and 46%, respectively, and the percentages of bovine isolates in groups 1 to 3 that were positive forehxA were 89, 51, and 52%, respectively. The percentages of human isolates in groups 1 and 2 that were positive foreae were 92 and 27%, respectively, and the percentages of bovine isolates in groups 1 to 3 that were positive for eaewere 78, 15, and 19%, respectively. The frequencies of bothehxA and eae were significantly higher for group 1 isolates than for group 2 isolates. The presence of the ehxA gene was associated with serotype, as was the presence of the eae gene. Some serotypes, such as O117:H4, lacked both eae and ehxA and have been associated with severe disease, but only infrequently. Theslt-I genes were more frequent in group 1 isolates than in group 2 isolates, and the slt-II genes were more frequent in group 2 isolates than in group 1 isolates. In a second experiment we determined the occurrence of the ehxA andslt genes in E. coli isolated from bovine feces. Fecal samples from 175 animals were streaked onto washed sheep erythrocyte agar plates. Eight E. coli-like colonies representing all of the morphological types were transferred to MacConkey agar. A total of 1,080 E. coli isolates were examined, and the ehxA gene was detected in 12 independent strains, only 3 of which were positive for slt. We concluded that the ehxA gene was less correlated with virulence than the eae gene was and that EHEC hemolysin alone has limited value for screening bovine feces for pathogenic SLTEC because of presence of the ehxA gene in bovine isolates that are not SLTEC.

scholarly journals EXTH-57. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE PROCASPASE-ACTIVATING COMPOUND, PAC-1, FOLLOWING ORAL ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi97-vi97
Author(s):  
Cynthia Lester McCully ◽  
Rafael Cruz ◽  
Alexander V Lyubimov ◽  
Alexander D Zakharov ◽  
James H Fischer ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Oral Administration ◽  
Primate Model ◽  
Human Primate

scholarly journals Transcutaneous Immunization Using Colonization Factor and Heat-Labile Enterotoxin Induces Correlates of Protective Immunity for Enterotoxigenic Escherichia coli

2002 ◽  
Vol 70 (3) ◽  
pp. 1056-1068 ◽  
Author(s):  
Jianmei Yu ◽  
Frederick Cassels ◽  
Tanya Scharton-Kersten ◽  
Scott A. Hammond ◽  
Antoinette Hartman ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protective Immunity ◽  
Diarrheal Disease ◽  
Surface Protein ◽  
Enterotoxigenic Escherichia Coli ◽  
Vaccine Antigen ◽  
Secretory Iga ◽  
Colonization Factor ◽  
Heat Labile ◽  
Transcutaneous Immunization

ABSTRACT Enterotoxigenic Escherichia coli (ETEC) diarrheal disease is a worldwide problem that may be addressed by transcutaneous delivery of a vaccine. In several human settings, protective immunity has been associated with immune responses to E. coli colonization factors and to the heat-labile toxin that induces the diarrhea. In this set of animal studies, transcutaneous immunization (TCI) using recombinant colonization factor CS6 and cholera toxin (CT) or heat-labile enterotoxin (LT) as the adjuvant induced immunoglobulin G (IgG) and IgA anti-CS6 responses in sera and stools and antibody responses that recognized CS6 antigen in its native configuration. The antitoxin immunity induced by TCI was also shown to protect against enteric toxin challenge. Although immunization with LT via the skin induced mucosal secretory IgA responses to LT, protection could also be achieved by intravenous injection of the immune sera. Finally, a malaria vaccine antigen, merzoite surface protein 142 administered with CT as the adjuvant, induced both merzoite surface protein antibodies and T-cell responses while conferring protective antitoxin immunity, suggesting that both antiparasitic activity and antidiarrheal activity can be obtained with a single vaccine formulation. Overall, our results demonstrate that relevant colonization factor and antitoxin immunity can be induced by TCI and suggest that an ETEC traveler's diarrhea vaccine could be delivered by using a patch.

scholarly journals Human Mucosal IgA Immune Responses against Enterotoxigenic Escherichia coli

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 714
Author(s):  
Saman Riaz ◽  
Hans Steinsland ◽  
Kurt Hanevik
Keyword(s):  
Escherichia Coli ◽  
Vaccine Development ◽  
Enterotoxigenic Escherichia Coli ◽  
Secretory Iga ◽  
Small Intestinal Mucosa ◽  
Middle Income ◽  
Middle Income Countries ◽  
Human Volunteers ◽  
Iga Response ◽  
Small Intestinal

Infection with enterotoxigenic Escherichia coli (ETEC) is a major contributor to diarrheal illness in children in low- and middle-income countries and travelers to these areas. There is an ongoing effort to develop vaccines against ETEC, and the most reliable immune correlate of protection against ETEC is considered to be the small intestinal secretory IgA response that targets ETEC-specific virulence factors. Since isolating IgA from small intestinal mucosa is technically and ethically challenging, requiring the use of invasive medical procedures, several other indirect methods are used as a proxy for gauging the small intestinal IgA responses. In this review, we summarize the literature reporting on anti-ETEC human IgA responses observed in blood, activated lymphocyte assayss, intestinal lavage/duodenal aspirates, and saliva from human volunteers being experimentally infected with ETEC. We describe the IgA response kinetics and responder ratios against classical and noncanonical ETEC antigens in the different sample types and discuss the implications that the results may have on vaccine development and testing.

scholarly journals Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

2016 ◽  
Vol 23 (7) ◽  
pp. 628-637 ◽  
Author(s):  
Qingwei Luo ◽  
Tim J. Vickers ◽  
James M. Fleckenstein
Keyword(s):  
Escherichia Coli ◽  
Vaccine Development ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Enterotoxigenic Escherichia Coli ◽  
Oral Vaccination ◽  
Content Type ◽  
Degree Of Protection ◽  
Alternative Routes

EnterotoxigenicEscherichia coli(ETEC) strains are a common cause of diarrhea. Extraordinary antigenic diversity has prompted a search for conserved antigens to complement canonical approaches to ETEC vaccine development. EtpA, an immunogenic extracellular ETEC adhesin relatively conserved in the ETEC pathovar, has previously been shown to be a protective antigen following intranasal immunization. These studies were undertaken to explore alternative routes of EtpA vaccination that would permit use of a double mutant (R192G L211A) heat-labile toxin (dmLT) adjuvant. Here, oral vaccination with EtpA adjuvanted with dmLT afforded significant protection against small intestinal colonization, and the degree of protection correlated with fecal IgG, IgA, or total fecal antibody responses to EtpA. Sublingual vaccination yielded compartmentalized mucosal immune responses with significant increases in anti-EtpA fecal IgG and IgA, and mice vaccinated via this route were also protected against colonization. In contrast, while intradermal (i.d.) vaccination achieved high levels of both serum and fecal antibodies against both EtpA and dmLT, mice vaccinated via the i.d. route were not protected against subsequent colonization and the avidity of serum IgG and IgA EtpA-specific antibodies was significantly lower after i.d. immunization compared to other routes. Finally, we demonstrate that antiserum from vaccinated mice significantly impairs binding of LT to cognate GM1 receptors and shows near complete neutralization of toxin delivery by ETECin vitro. Collectively, these data provide further evidence that EtpA could complement future vaccine strategies but also suggest that additional effort will be required to optimize its use as a protective immunogen.

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