How does Iota-Carrageenan achieve an antiviral effect?

Question

"Cold Defence" nasal sprays are recommended to be taken either preventatively or in the early stages of a cold. The active ingredient in these sprays is Carrageenan. After some research, the active compound is Iota-Carrageenan (ι-Carrageenan).

This study by Eccles et al^[1] shows that this drug is clinically effective. The study was only designed to test efficacy rather than to explain the mechanism, however. A fleeting mention is provided in the discussion section:

The above results suggest that the treatment with Iota-Carrageenan reduces the viral replication. Consequently fewer cells are infected, the immune reaction against the viruses is less pronounced and fewer symptoms occur.

How does ι-Carrageenan produce an anti-viral effect?

1. Eccles R, Meier C, Jawad M, Weinmüllner R, Grassauer A, Prieschl-Grassauer E. 2010. Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold. Respiratory Research, 11:108, doi:10.1186/1465-9921-11-108.

Answer 1

Through two different pathways, one relying on a non-specific (innate) response, and another through a reactive oxygen species, the level of NF-kB^(**) is amplified, as such a response would have happened as a result of the presence of the virus anyway.

In thousands of experiments, carrageenans have been used to induce inflammation, since inflammation is a predictable effect of exposure to carrageenan in animal and cell-based models. For the most part, these experiments were designed to test the effectiveness of anti-inflammatory agents or to study the mediators of inflammation

The innate immune pathway is mediated by toll-like receptor (TLR)-4 and B-cell leukemia lymphoma (BCL)10, leading to increased Interleukin (IL)-8 secretion by both canonical and noncanonical pathways of NF-kB activation. The ROS-mediated pathway of inflammation does not involve TLR4-BCL10, but requires Hsp27 and IkB-kinase (IKK)b, leading to increased phosphorylation of IkBa, and thereby enabling the nuclear translocation of NF-kB.

From the intro to:

Yang B, Bhattacharyya S, Linhardt R, Tobacman J. (2012) Exposure to common food additive carrageenan leads to reduced sulfatase activity and increase in sulfated glycosaminoglycans in human epithelial cells. Biochemie, Mar 5,epub ahead of print, doi

(As an aside, the direct conclusions of this study are that these changes in GAGs may further influence transcription and play a role in determining cell fate, and perhaps may influence cell/cell interactions)

(**)NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens wiki

Answer 2

In the publication by Leibbrandt et al.^[1], it could be shown that the iota-carrageenan directly binds to viruses and thereby prevents the attachment to cells. This is a critical step in the viral life-cycle and therefore replication is reduced. Iota carrageenan rather acts unspecifically and besides influenza also other viruses such as human Rhinoviruses are inhibited^[2]. Similarly, a direct binding to viruses has been shown for iota-carrageenan and papillomaviruses^[3].

In contrast to lambda carrageenan that is widely used as proinflammatory compound in animal experiments, iota carrageenan lacks this activity and therefore a pharmacological / immunological mode of action can be excluded. In addition carrageenans have a high molecular weight which makes it very unlikely that it acts systemically.

1. Leibbrandt A, Meier C, König-Schuster M, Weinmüllner R, Kalthoff D, Pflugfelder B, Graf P, Frank-Gehrke B, Beer M, Fazekas T, Unger H, Prieschl-Grassauer E, Grassauer A. 2010. Iota-Carrageenan Is a Potent Inhibitor of Influenza A Virus Infection. PLoS ONE, 5(12): e14320 doi:10.1371/journal.pone.0014320.
2. Grassauer A, Weinmuellner R, Meier C, Pretsch A, Prieschl-Grassauer E, Unger H. 2008. Iota-Carrageenan is a potent inhibitor of rhinovirus infection. Virology Journal, 5:107, doi:10.1186/1743-422X-5-107.
3. Buck CB, Thompson CD, Roberts JN, Müller M, Lowy DR, Schiller JT. 2006. Carrageenan Is a Potent Inhibitor of Papillomavirus Infection. PLoS Pathogens, 2(7): e69, doi:10.1371/journal.ppat.0020069.