Monday, July 6, 2020

Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection

Staff Writer, DL Mullan 
COVID-19 / Corona Virus / Vitamin C

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Abstract

L-ascorbic acid (vitamin C) is one of the well-known anti-viral agents, especially to influenza virus. Since the in vivo anti-viral effect is still controversial, we investigated whether vitamin C could regulate influenza virus infection in vivo by using Gulo (-/-) mice, which cannot synthesize vitamin C like humans. First, we found that vitamin C-insufficient Gulo (-/-) mice expired within 1 week after intranasal inoculation of influenza virus (H3N2/Hongkong). Viral titers in the lung of vitamin C-insufficient Gulo (-/-) mice were definitely increased but production of anti-viral cytokine, interferon (IFN)-α/β, was decreased. On the contrary, the infiltration of inflammatory cells into the lung and production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-α/β, were increased in the lung. Taken together, vitamin C shows in vivo anti-viral immune responses at the early time of infection, especially against influenza virus, through increased production of IFN-α/β.

INTRODUCTION

Vitamin C is known as an essential anti-oxidant (1,2) and enzymatic co-factor for physiological reactions such as hormone production, collagen synthesis (3) and immune potentiation (4-6). Naturally, an insufficiency of vitamin C leads to severe injuries to multiple organs, especially to the heart and brain, since they are both highly aerobic organs that produce more oxygen radicals. In fact, studies of in vivo effect on vitamin C are difficult since most animals, except human and some primate, are capable of synthesizing vitamin C endogenously (7). However, Gulo (-/-) mice were recently developed by the L-gulono-γ-lactone oxidase (Gulo) gene deletion like human, thus they should be supplied with dietary vitamin C (8). It already has been reported that vitamin C concentration was decreased by 10~15% in plasma of the Gulo (-/-) mice without supplementation of vitamin C for 2 weeks (8). We also reported that vitamin C level was remarkably decreased in the most organs in the Gulo (-/-) mice without supplementation of vitamin C for 3 weeks (9).

In addition, we found that numbers of T cell was decreased in the spleen of vitamin C-insufficient Gulo (-/-) mice (10). Even though it is thought that vitamin C shows its anti-viral or anti-tumor effects through the up-regulation of the activity of natural killer (NK) cells and tumor specific cytolytic T lymphocytes (CTLs), its related evidences in vivo are still unclear. The reason why it is impossible to investigate in vivo effect of vitamin C is that all of animals could synthesize vitamin C from glucose thorough the action of L-glunolactone-γ-oxidase (Gulo), as described above (7). However, we confirmed that vitamin C up-regulates NK cell activity through the regulation of activating/inhibitory receptors on the surface of NK cell (our unpublished data). Since it is commonly known that vitamin C and NK cells are closely related to the prevention of common cold and the flu (11-13), we evaluated in vivo anti-viral effect of vitamin C and its related mechanism in Gulo (-/-) mice against influenza virus (H3N2/Honkong/1/68). First, wild type, vitamin C-sufficient Gulo (-/-) mice and vitamin C-insufficient Gulo (-/-) mice were subjected to intranasal inoculation of 20 hemagglutination units (HAU) of influenza virus, and then their survival was monitored. Interestingly, we observed that vitamin C-insufficient Gulo (-/-) mice expired within 1 week, but all of wild type and vitamin C-sufficient Gulo (-/-) mice survived (Fig. 1B). However, the supplementation of vitamin C on a day after virus inoculation could not prevent the death of vitamin C-insufficient Gulo (-/-) mice (Fig. 1B). It suggests that a sufficient amount of vitamin C is needed to prevent in vivo pathogenesis of influenza virus. Also, considering that H3N2 influenza virus shows a good circulation in humans and pigs as well as a slow antigenic drift in swine (14), we believe that the antigenic divergence between human and swine influenza virus might be increased. Therefore, our results shown in Fig. 1 suggest that vitamin C may effectively prevent severe or fatal damages in humans by the infection of influenza virus as well. To clarify the underlying mechanisms on the survival by the presence of the sufficient amounts vitamin C in the mice, we examined the viral titers in the lung of each experimental group. As shown in Fig. 2, viral titer in the lung from vitamin C-insufficient Gulo (-/-) mice was 10 to 15-fold increased, when it was compared with viral titer in wild type and vitamin C-sufficient Gulo (-/-) mice. However, when Gulo (-/-) mice were supplemented with vitamin C after virus inoculation, we could not observe a definite suppression of viral replication. This provides the importance of the vitamin C concentration at the initial stage of influenza virus infection. That is to say, damages through the replication of influenza viruses can be effectively prevented, when vitamin C concentration is sufficiently high at the initial stage of viral infection. If it is insufficient, however, the pathogenesis of influenza virus could not be prevented.

Read the entire report on the NIH's website.

Source: NIH

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