Anthrax-Protective Effects of Yeast Beta1,3 Glucans

Bill Kournikakis, PhD; Rosemonde Mandeville, MD, PhD; Pauline Brousseau, PhD; Gary Ostroff, PhD

Disclosures
In This Article

Abstract and Introduction

Abstract

Context: The recent events increasing the threat of bioterrorism have prompted a widespread search for defenses against this peril.
Objective: To evaluate the anthrax-protective effect of beta1,3-glucan immune modulators (PGG-glucan and WGP beta glucan) in an experimental animal model.
Design: Beta1,3-glucan immune modulators were administered by subcutaneous injection to Balb/c mice 2 days prior to anthrax challenge. WGP beta glucan was administered by daily oral gavage for 7 days prior to challenge, or in drinking water for 10 days postchallenge with a lethal dose of Bacillus anthracis spores. Survival, survival time, and microbial bioburden relative to an infected, untreated control group were assessed.
Results: A single injected dose of PGG-glucan or WGP beta glucan immune modulators given 2 days before challenge significantly: (a) increased the survival rate of infected mice (2.5-fold), (b) diminished the bacterial load in the lungs of infected mice (4-8-fold), and (c) increased the proportion of bacteria-free animals 10 days after challenge (2-fold). In mice prophylactically administered oral WGP beta glucan for 1 week prior to infection, survival increased from 50% to 100%; therapeutic administration of oral WGP beta glucan for 10 days postinfection increased survival from 30% up to 90% in treatment groups.
Conclusions: These results demonstrate the potential for beta1,3-glucan immune modulators to provide a significant degree of protection against anthrax, a potential biological warfare (BW) agent in a mouse model of anthrax infection. Further studies are needed to optimize protection, evaluate activity in combination with other treatment options, demonstrate activity in a validated primate model of infection, and determine if protection is effective against other potential BW agents.

Introduction

A recent national survey found that more Americans -- nearly two thirds -- are concerned about the possibility of a bioterrorism attack than they were in the weeks following September 11, 2001.[1] One potential bioterrorism agent is B anthracis, which has been weaponized by several nations and killed 5 Americans in 2001. B anthracis is a very large aerobic Gram-positive rod-shaped micro-organism that commonly infects herbivorous animals, causing a serious and often fatal disease.

Anthrax spores are produced at temperatures below 30ºC in soil and on inanimate objects. In humans, anthrax is very rare. The most common form of the disease in humans is cutaneous anthrax, which is usually acquired via injured skin or mucous membrane when in contact with spores or infected tissues. The spores germinate, vegetative cells multiply, and a characteristic gelatinous edema develops at the site. Death following treatment is very rare, but the untreated mortality rate is near 20%. Ingestion of undercooked meat may result in gastrointestinal anthrax. Nausea, vomiting, and gastrointestinal bleeding ensue within 12 to 18 hours, and infection spreads to the bloodstream and can be fatal. Inhalation of anthrax spores causes an influenza-like illness within 2 to 43 days of exposure.[2] The inhalation form of anthrax is nearly always fatal because of the rapid progression of the disease and the gradual onset of flu-like symptoms.[3]

The recent dissemination of anthrax spores through the mail has raised our awareness that we have relatively few prevention and treatment options to protect the US public. Conventional antimicrobial therapies, such as antibiotics, are useful to treat some bioterrorist threats, but their widespread prophylactic use is not recommended to protect the public due to the fear of antibiotic resistance.[4] Prophylactic administration of vaccines provides an opportunity to protect the public from infection; however, a single vaccine does not provide broad protection against the many possible pathogenic bioterrorist threats. In the case of anthrax, the licensed human vaccine that consists of a series of 6 doses with yearly boosters is limited to military use and those at high risk of exposure (eg, laboratory workers, veterinarians).[5] Further, there remain the issues of the timeframe for the development of safe and effective vaccines, or treatments, and the cost-effective delivery of these treatments to a large military or civilian population.

The use of immune modulators, either as a prophylaxis and/or as part of a treatment regimen following exposure, may represent a broad-spectrum approach to protect the public when exposed to a pathogenic challenge.[6] Immune modulators can increase the nonspecific components of the immune system, such as the macrophage/neutrophil innate immune response, and stimulate the maturation of myeloid progenitor cells. Macrophage/neutrophil activation is largely considered the first line of defense against bacterial, fungal, and some viral infections. These cells are also necessary for the efficient presentation of antigens, and their level of activation determines the efficacy of the acquired immune system, the second line of defense leading to effective humoral (antibody) and cellular (T-cell) immune responses.[7] Thus, immune modulators have the potential to enhance the effectiveness of other medical countermeasures, such as vaccines, monoclonal antibodies, and antibiotics.

One class of extensively studied immune modulators is known as the beta1,3-glucans. Beta1,3-glucans are carbohydrate polymers purified from yeast, mushroom, bacteria, algae, or cereals.[8] The chemical structure of beta1,3-glucan is dependent on the source; different physicochemical parameters, such as solubility, primary structure, molecular weight, and branching, play a role in biological activities of beta1,3-glucans.[9] Beta1,3-glucan works, in part, by stimulating the innate antifungal immune mechanisms to fight against a range of pathogenic challenges, including bacterial, fungal, parasitic, and viral infections.

Yeast beta-glucans are produced in 2 forms, an insoluble particle (whole glucan particle (WGP) beta glucan) and a solution (PGG-glucan). WGP beta glucan is purified from baker's yeast cell walls following extraction of cellular proteins, nucleic acids, lipids, and most nonglucose-based oligosaccharides (eg, chitins, mannans) by a morphologically nondestructive proprietary process.[10] What remains is a highly purified, 3-5 micron, spherical beta1,3-glucan particle. PGG-glucan (poly-1-6-beta-D-glucopyranosyl-1-3- beta-D-glucopyranose) is a highly purified soluble glucose polymer prepared by acid hydrolysis of WGP beta glucan.[11] Both forms of beta1,3-glucan have been studied in preclinical and clinical studies.[12] The mechanism of action of systemically administered beta1,3-glucan has been established in a series of published studies. Beta1,3-glucan binds to beta-glucan receptors present in the membranes of phagocytic cells and initiates a cascade of events leading to the expression of an overall heightened cellular immune response.[13,14] This response also includes the proliferation of white blood cells in the bone marrow, leading to higher levels of these cells in the body, and an increased immune functionality of these cells.[15] It is believed that this enhancement of macrophage and neutrophil function by beta1,3-glucan leads to the observed enhancement in microbial clearance and reduction in mortality of lethally infected animals.[16,17] The oral protective effect of beta1,3-glucan appears to be mediated through receptor-mediated interactions with M cells found in Peyer's patches in the intestinal mucosa leading to the stimulation of cytokine production (interleukin-2, interferon-beta, tumor necrosis factor-alpha), enhanced resistance to infection, and an enhanced antitumor immune response.[18,19,20,21]

This report evaluates the potential of the immune modulators PGG-glucan and WGP beta glucan to enhance resistance against a lethal systemic B anthracis spore infection in a mouse model system.

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