Interleukin 18 (IL-18) – 22 (IL-22) inhibit rotavirus infection

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A combination of two substances secreted by the immune system can cure and prevent rotavirus infection, as well as potentially treat other viral infections that target epithelial cells, which cover body surfaces such as skin, blood vessels, organs and the urinary tract, according to researchers in the Institute for Biomedical Sciences at Georgia State University.

Rotavirus, which causes severe, life-threatening diarrhea in young children and moderate gastrointestinal distress in adults, leads to thousands of deaths in children annually, particularly in developing countries where rotavirus vaccines are only moderately effective.

Rotavirus is an RNA virus that primarily infects intestinal epithelial cells.

The substances identified in the study, officially known as cytokines, are interleukin 18 (IL-18) and interleukin 22 (IL-22).

IL-18 and IL-22 are produced when the body detects a protein in the whip-like appendage of bacteria.

The study, which investigated how these cytokines inhibit rotavirus infection, found when mice were treated with both IL-18 and IL-22, the cytokines promoted each other’s expression, but also impeded rotavirus by independent, distinct mechanisms that involved activating receptors in intestinal epithelial cells.

These actions resulted in rapid and complete expulsion of rotavirus, even in hosts with severely compromised immune systems. The therapy was also found to be effective for norovirus, a contagious virus that causes vomiting and diarrhea.

The findings are published in the journal Science Immunology.

“Our study reports a novel means of eradicating a viral infection, particularly viruses that infect epithelial cells,” said Dr. Andrew Gewirtz, senior author of the study and a professor in the Institute for Biomedical Sciences at Georgia State.

“The results suggest that a cocktail that combines IL-18 and IL-22 could be a means of treating viral infections that target short-lived epithelial cells with high turnover rates.”

Biomedical sciences researchers find new way to prevent and cure rotavirus, other viral infections
Biomedical sciences researchers find new way to prevent and cure rotavirus, other viral infections
Biomedical sciences researchers find new way to prevent and cure rotavirus, other viral infections
Treatment of rotavirus-infected mice with another cytokine called EGF (right) induced migration of rotavirus-infected cells up the crypt villus axis, albeit not quite as robustly as IL-22. Credit: Zhang et al., Sci. Immunol. 5, eabd2876 (2020)

Rotavirus is a genus of viruses in the Reoviridae family, which are the leading cause of acute diarrhea among children aged < 5 years1.

It is estimated that rotavirus gastroenteritis kills nearly 200,000 children each year, mainly in developing countries2. Rotavirus infection can cause vomiting, nausea, fever, abdominal cramps, and abdominal watery diarrhea, resulting in symptoms of dehydration3.

There is no effective specific treatment for rotavirus gastroenteritis. Oral rehydration has been the most commonly employed treatment to mitigate the effects of infection4. However, mucosal and systemic immunomodulatory medications, such as active antiviral agents, are often inadequate for treating rotavirus gastroenteritis5.

Currently, two licensed rotavirus vaccines, a monovalent human vaccine, Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium), and a pentavalent human-bovine reassortant vaccine, RotaTeq (Merck and Co. Inc., West Point, PA, USA), are used in more than 100 countries6.

The widespread use of these two vaccines has had a significant impact on reducing morbidity, mortality, and hospitalization associated with rotavirus diarrhea globally7. However, in terms of the capacity of rotavirus vaccination to prevent severe gastroenteritis, clinical trials have reported efficacy rates of 45–79% in developing countries and less than 87% in developed countries8,9,10,11,12.

Moreover, unusual rotaviruses (e.g., G9, G11, G12, and P[4] genotypes) have recently been isolated from vaccinated infants, and these strains were generated from human and animal rotavirus reassortment13,14,15.

Therefore, there is a need to find new strategies to control diarrhea and gastroenteritis caused by rotaviruses. There are several natural and synthetic compounds that reduce rotavirus activity. The synthetic compounds 1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin), 3-deazaguanine (3-DG), and inosine pranobex have shown inhibitory effects against the simian rotavirus SA11 strain in MA104 cells16,17.

Natural products from plants, such as black tea (theaflavin compound)18, Stevia rebaudiana (anionic polysaccharide compound)19, Brazilian medicinal plants20,21, Quillaja saponaria22, and dietary plants23, have inhibited the absorption or replication of human and animal rotaviruses. However, medicinal plants and natural molecules for preventing and treating rotavirus infections are currently limited.

Genipin, an aglycone derived from geniposide, is a chemical compound found in the natural fruit of Gardenia jasminoides. Genipin is also known as a cross-linker for proteins, gelatin, and chitosan, and it has been reported to be an excellent traditional Oriental medicine with various pharmacologic functions, such as anti-inflammatory, anti-apoptotic, anti-microbial, and anti-tumour effects24,25,26.

Recent studies have reported that genipin has antiviral activity against human immunodeficiency virus, swine influenza virus H1N1, Epstein–Barr virus, and Kaposi’s sarcoma-associated herpesvirus24,27,28,29. However, the potential antiviral effects of genipin against rotavirus have not been determined.

In this study, the anti-rotavirus and anti-inflammatory activities of genipin, as a potential preventive and therapeutic agent against rotavirus infection, were evaluated using human and murine rotavirus strains in in vitro and in vivo models.

References

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More information: Z. Zhang el al., “IL-22 induced cell extrusion and IL-18-induced cell death prevent and cure rotavirus infection,” Science Immunology (2020). immunology.sciencemag.org/look … 6/sciimmunol.abd2876

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