Anti-Zika virus and anti-Usutu virus activity of human milk and its components

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Abstract
The benefits of human milk are mediated by multiple nutritional, trophic, and immunological components, able to promote infant’s growth, maturation of its immature gut, and to confer protection against infections. Despite these widely recognized properties, breast-feeding represents an important mother-to-child transmission route of some viral infections. Different studies show that some flaviviruses can occasionally be detected in breast milk, but their transmission to the newborn is still controversial. The aim of this study is to investigate the antiviral activity of human milk (HM) in its different stages of maturation against two emerging flaviviruses, namely zika virus (ZIKV) and Usutu virus (USUV) and to verify whether HM-derived extracellular vesicles (EVs) and glycosaminoglycans (GAGs) contribute to the milk protective effect. Colostrum, transitional and mature milk samples were collected from 39 healthy donors. The aqueous fractions were tested in vitro with specific antiviral assays and EVs and GAGs were derived and characterized. HM showed antiviral activity against ZIKV and USUV at all the stages of lactation with no significant differences in the activity of colostrum, transitional or mature milk. Mechanism of action studies demonstrated that colostrum does not inactivate viral particles, but it hampers the binding of both flaviviruses to cells. We also demonstrated that HM-EVs and HM-GAGs contribute, at least in part, to the anti-ZIKV and anti-USUV action of HM. This study discloses the intrinsic antiviral activity of HM against ZIKV and USUV and demonstrates the contribution of two bioactive components in mediating its protective effect. Since the potential infectivity of HM during ZIKV and USUV infection is still unclear, these data support the World Health Organization recommendations about breast-feeding during ZIKV infection and could contribute to producing new guidelines for a possible USUV epidemic. ZIKV and USUV are emerging flaviviruses that cause conditions ranging from mild febrile diseases to more sever outcomes. ZIKV is associated with microcephaly in newborns and USUV neurotropism represents a growing concern for human health. We studied these viruses in the context of breast-feeding. Breast-milk is a complex biofluid to nourish infants, support their growth and to protect them from numerous diseases, but it also represents a transmission route of several infections. It has been reported that flaviviruses can occasionally be detected in breast-milk, with limited information existing about their possible transmission through breast-feeding. We therefore explored the intrinsic protective role of human milk against ZIKV and USUV infections in vitro and we also assessed the contribution of specific components in mediating this activity. We demonstrated that human milk is endowed with anti-ZIKV and anti-USUV activity at all maturation stages and that it acts by altering virus attachment to the host cell. This activity is mostly due to non-specific bioactive factors, including extracellular vesicles and glycosaminoglycans. Our findings support the use of fresh milk (or from donor banks) as the food of choice for nutrition and protection of newborns in a possible context of ZIKV or USUV epidemics.

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