Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection

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Abstract

Fucoidan, a sulfated polysaccharide isolated from an edible brown alga Undaria pinnatifida, was previously shown to be a potent inhibitor of the in vitro replication of herpes simplex virus type 1 (HSV-1). HSV-1 is a member of herpes viruses that cause infections ranging from trivial mucosal ulcers to life-threatening disorders in immunocompromised hosts. In the in vivo conditions, the replication of HSV-1 is controlled under the immunoresponse coordinated by both the innate and adaptive immune systems. In the present study, the effects of the fucoidan were examined on in vivo viral replication and the host's immune defense system. Oral administration of the fucoidan protected mice from infection with HSV-1 as judged from the survival rate and lesion scores. Phagocytic activity of macrophages and B cell blastogenesis in vitro were significantly stimulated by the fucoidan, while no significant change in the release of NO2 by macrophages was observed. In in vivo studies, oral administration of the fucoidan produced the augmentation of NK activity in HSV-1-infected mice immunosuppressed by 5-fluorouracil treatment. CTL activity in HSV-1-infected mice was also enhanced by oral administration of the fucoidan. The production of neutralizing antibodies in the mice inoculated with HSV-1 was significantly promoted during the oral administration of the fucoidan for 3 weeks. These results suggested that oral intake of the fucoidan might take the protective effects through direct inhibition of viral replication and stimulation of both innate and adaptive immune defense functions.

Introduction

Recently, a number of reports have demonstrated the decline of the immune function due to age, stress or medical treatments. Infectious diseases in elderly persons and in patients after surgical operations, radiotherapy or chemotherapy are supposed to have a close relationship with their immunosuppressed status. Serious infectious diseases by non- or low-pathogenic microorganisms often occur when the immune defense mechanism of the host is impaired. Thus, restoration of the decline of the immune function is a beneficial approach for the treatment of infectious diseases in such immunocompromised hosts.

Many kinds of algae have been traditionally used as food especially in East Asia. The biological properties of algae have attracted special interest recently. There are many reports on the immunomodulating and anti-tumor activities of algae [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. The active components contained in algae are known to be polysaccharides including sulfated polysaccharides [7], [8], [9], [10], [11], [13], [14]. Fucoidan is one of the representative sulfated polysaccharides derived from some brown algae [9], [10], [16], [17], [18], [19]. Sulfated polysaccharides have been well known as potent anti-viral agents [20], [21], [22]. We have also isolated several sulfated polysaccharides from algae as anti-viral active components [23], [24], [25], [26].

Teas et al. [27] recently reported, based on epidemiologic data, that regular consumption of dietary algae might help HIV infection and suppress viral load among those infected. In clinical situations, ingestion of the preparation of Tasmanian Undaria pinnatifida showed inhibitory effects on the reactivation of herpes viruses and increased the rate of healing after herpetic outbreaks in patients with herpetic infections [28]. However, so far, there are only limited reports that demonstrate the effects of algae on the immune response of host to viral infection. In the previous paper, we reported that fucoidan, a sulfated polysaccharide isolated from an edible alga (U. pinnatifida), showed anti-viral activity on HSV-1 in vitro[29]. In this paper, we investigated the fucoidan not only for in vivo anti-viral efficacy but also for the effects on innate (non-specific) and adaptive (specific) defense mechanisms that are involved in viral infection.

Section snippets

Animals

All animals were obtained from Japan SLC, Shizuoka, Japan. All experiments were conducted in accordance with the animal experimentation guidelines of the University of Toyama. No side effect due to drug administration was detected throughout the experiments.

Chemicals

Escherichia coli lipopolysaccharide (LPS) (serotype 0111:B4) and acyclovir (ACV) were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Fucoidan was prepared from the dried sporophyll of U. pinnatifida as described previously [29].

In vivo experiments

For

Effect of fucoidan on experimental herpetic infection

The effect of the fucoidan at a dose of 5 mg per day on corneal infection of mice with HSV-1 was evaluated. Three daily oral doses of the fucoidan for 7 or 14 days delayed significantly the appearance of the facial erosions as compared with water-treated control group (Fig. 1). The pretreatment of mice with the fucoidan for 1 week was more effective in suppressing the herpetic lesions as compared with the treatment without the pretreatment, and less effective during the acute phase for 1 week

Discussion

Sulfated polysaccharides have been isolated as active components from different kinds of algae and proved to have broad anti-viral spectrum [22], [23], [24]. Fucoidan is one of the sulfated polysaccharides isolated from several brown algae [10], [18], and also present in U. pinnatifida[29]. In the previous study [29], the fucoidan from U. pinnatifida was shown to exert potent inhibitory action in vitro against replication of HSV-1, HSV-2 and HCMV. These enveloped viruses have a common feature

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