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PLoS pathogens2018; 14(7); e1007160; doi: 10.1371/journal.ppat.1007160

Antibody to Poly-N-acetyl glucosamine provides protection against intracellular pathogens: Mechanism of action and validation in horse foals challenged with Rhodococcus equi.

Abstract: Immune correlates of protection against intracellular bacterial pathogens are largely thought to be cell-mediated, although a reasonable amount of data supports a role for antibody-mediated protection. To define a role for antibody-mediated immunity against an intracellular pathogen, Rhodococcus equi, that causes granulomatous pneumonia in horse foals, we devised and tested an experimental system relying solely on antibody-mediated protection against this host-specific etiologic agent. Immunity was induced by vaccinating pregnant mares 6 and 3 weeks prior to predicted parturition with a conjugate vaccine targeting the highly conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG). We ascertained antibody was transferred to foals via colostrum, the only means for foals to acquire maternal antibody. Horses lack transplacental antibody transfer. Next, a randomized, controlled, blinded challenge was conducted by inoculating at ~4 weeks of age ~10(6) cfu of R. equi via intrabronchial challenge. Eleven of 12 (91%) foals born to immune mares did not develop clinical R. equi pneumonia, whereas 6 of 7 (86%) foals born to unvaccinated controls developed pneumonia (P = 0.0017). In a confirmatory passive immunization study, infusion of PNAG-hyperimmune plasma protected 100% of 5 foals against R. equi pneumonia whereas all 4 recipients of normal horse plasma developed clinical disease (P = 0.0079). Antibodies to PNAG mediated killing of extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms depended on antibody recognition of surface expression of PNAG on infected cells, along with complement deposition and PMN-assisted lysis of infected macrophages. Peripheral blood mononuclear cells from immune and protected foals released higher levels of interferon-γ in response to PNAG compared to controls, indicating vaccination also induced an antibody-dependent cellular release of this critical immune cytokine. Overall, antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against diseases caused by intracellular bacterial pathogens.
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Publication Date: 2018-07-19 PubMed ID: 30024986PubMed Central: PMC6053243DOI: 10.1371/journal.ppat.1007160Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Validation Study

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article investigates how antibodies can protect against internal bacterial infections, challenging the conventional belief that only cell-mediated immunity can do so. It uses horse foals infected with Rhodococcus equi, a type of bacteria causing pneumonia, to validate this defence mechanism enabled by a vaccine targeting the microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG).

Research Methodology

  • This study was designed to focus on an immunity system based solely on antibodies against Rhodococcus equi, a bacteria that specifically causes pneumonia in horse foals.
  • The research team vaccinated pregnant horses 6 and 3 weeks before their estimated childbirth timings. The vaccine being used targeted PNAG, a polysaccharide present on the bacterial surface which is considerably consistent.
  • The team ensured the antibody was passed on to the foals through colostrum, an initial form of milk produced by mammals during pregnancies. This is significant as foals only get maternal antibodies via colostrum, not through the placenta.
  • In a randomized, controlled, and blinded challenge, the foals were subjected to an intrabronchial challenge, inducing R. equi infection, when they were about four weeks old.
  • In a second experiment, a direct infusion of PNAG-hyperimmune plasma was given to the foals.

Research Findings

  • The findings revealed that 91% of foals born to vaccinated mothers did not develop clinical R. equi pneumonia. However, 86% of foals born to unvaccinated horses did develop this disease.
  • The second experiment showed that 100% of foals receiving PNAG-hyperimmune plasma were protected from R. equi pneumonia, whilst all those receiving normal horse plasma developed the disease.
  • The study identifies that antibodies against PNAG can kill both extracellular and intracellular R. equi and other intracellular pathogens. This killing relies on the antibody’s recognition of the surface expression of PNAG on infected cells, together with depositing complements and white blood cell aided lysis of infected macrophages.
  • The immunity also triggers higher levels of interferon-γ in response to PNAG, a critical immune cytokine that appears to have an important role in the vaccine’s function.

Research Implication

  • The research emphasizes that antibody-mediated opsonic killing, along with the release of interferon-γ in response to PNAG, potentially provides a protective mechanism against diseases caused by intracellular bacterial pathogens, broadening the understanding of the immunity system.
  • This research could help modify the treatment methodologies against intracellular bacterial infections, introducing a new perspective in addressing bacterial diseases.

Cite This Article

APA
Cywes-Bentley C, Rocha JN, Bordin AI, Vinacur M, Rehman S, Zaidi TS, Meyer M, Anthony S, Lambert M, Vlock DR, Giguère S, Cohen ND, Pier GB. (2018). Antibody to Poly-N-acetyl glucosamine provides protection against intracellular pathogens: Mechanism of action and validation in horse foals challenged with Rhodococcus equi. PLoS Pathog, 14(7), e1007160. https://doi.org/10.1371/journal.ppat.1007160

Publication

PLoS pathogens
ISSN: 1553-7374
NlmUniqueID: 101238921
Country: United States
Language: English
Volume: 14
Issue: 7
Pages: e1007160
PII: e1007160

Researcher Affiliations

Cywes-Bentley, Colette
  • Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States of America.
Rocha, Joana N
  • College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States of America.
Bordin, Angela I
  • College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States of America.
Vinacur, Mariana
  • Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States of America.
Rehman, Safia
  • Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States of America.
Zaidi, Tanweer S
  • Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States of America.
Meyer, Mark
  • Mg Biologics, Ames, IA, United States of America.
Anthony, Sarah
  • Mg Biologics, Ames, IA, United States of America.
Lambert, McKenzie
  • Mg Biologics, Ames, IA, United States of America.
Vlock, Daniel R
  • ALOPEXX Vaccine LLC, Concord, MA, United States of America.
Giguère, Steeve
  • College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America.
Cohen, Noah D
  • College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States of America.
Pier, Gerald B
  • Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States of America.

MeSH Terms

  • Acetylglucosamine / immunology
  • Actinomycetales Infections / immunology
  • Animals
  • Animals, Newborn
  • Antibodies, Bacterial / immunology
  • Antigens, Bacterial / immunology
  • Bacterial Vaccines / immunology
  • Horses
  • Rhodococcus equi

Conflict of Interest Statement

Gerald B. Pier is an inventor of intellectual properties [human monoclonal antibody to PNAG and PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Vaccine, LLC, and Alopexx Pharmaceuticals, LLC, entities in which GBP also holds equity. As an inventor of intellectual properties, GBP also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC, and Alopexx Vaccine, LLC. GBP’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies. Colette Cywes-Bentley is an inventor of intellectual properties [use of human monoclonal antibody to PNAG and use of PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Pharmaceuticals, LLC. As an inventor of intellectual properties, CC-B also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC. Noah D. Cohen has received an unrestricted gift to the EIDL from Alopexx Vaccines, LLC. Daniel Vlock, holds an equity share and potential royalty income from Alopexx Vaccines, LLC for vaccines to PNAG and monoclonal antibody to PNAG from Alopexx Pharmaceuticals, LLC. Mark Meyer holds minority equity shares of Mg Biologics, Inc. Sarah Anthony and McKenzie Lambert are employees of Mg Biologics, Inc.

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Citations

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