Human milk glycosaminoglycans inhibit cytomegalovirus and respiratory syncytial virus infectivity by impairing cell binding

Rachele Francese; Manuela Donalisio; Massimo Rittà; Federica Capitani; Veronica Mantovani; Francesca Maccari; Paola Tonetto; Guido E Moro; Enrico Bertino; Nicola Volpi; David Lembo

doi:10.1038/s41390-022-02091-y

Human milk glycosaminoglycans inhibit cytomegalovirus and respiratory syncytial virus infectivity by impairing cell binding

Pediatr Res. 2022 May 5. doi: 10.1038/s41390-022-02091-y. Online ahead of print.

Authors

Rachele Francese^#¹, Manuela Donalisio^#¹, Massimo Rittà¹, Federica Capitani^{2

3}, Veronica Mantovani^{2

3}, Francesca Maccari², Paola Tonetto⁴, Guido E Moro⁵, Enrico Bertino⁴, Nicola Volpi⁶, David Lembo⁷

Affiliations

¹ Department of Clinical and Biological Sciences, Laboratory of Molecular Virology and Antiviral Research, University of Turin, Orbassano (TO), Italy.
² Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
³ Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
⁴ Department of Public Health and Pediatrics, Neonatal Intensive Care Unit, University of Turin, Turin, Italy.
⁵ Italian Association of Human Milk Banks (AIBLUD), Milan, Italy.
⁶ Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. volpi@unimo.it.
⁷ Department of Clinical and Biological Sciences, Laboratory of Molecular Virology and Antiviral Research, University of Turin, Orbassano (TO), Italy. david.lembo@unito.it.

^# Contributed equally.

PMID: 35513714
DOI: 10.1038/s41390-022-02091-y

Abstract

Background: The antiviral role of glycosaminoglycans in human milk (HM-GAGs) has been poorly investigated. They are highly sulfated polysaccharides, which were proposed to act as decoy receptors according to their structure. The aim of this study is to evaluate the antiviral potential and the mechanism of action of total and individual HM-GAGs against three pediatric clinically relevant viruses: respiratory syncytial virus (RSV), cytomegalovirus (HCMV), and rotavirus.

Methods: HM-GAGs were isolated from HM and a library of individual GAGs, structurally related to HM-GAGs, was prepared. The antiviral activity of HM-GAGs and the impact of thermal treatment were investigated in vitro by specific antiviral assays.

Results: We demonstrated that HM-GAGs are endowed with anti-HCMV and anti-RSV activity and that they act by altering virus attachment to cell. We clarified the contribution of individual HM-GAGs, showing a specific structure-related activity. We did not observe any alteration of HM-GAG antiviral activity after thermal treatment.

Conclusions: We showed that HM-GAGs contribute to the overall antiviral activity of HM, likely exerting a synergic action with other HM antiviral agents. HM-GAGs can now be added to the list of endogenous factors that may reduce breast-milk-acquired HCMV symptomatic infections and protecting infants from respiratory tract infections by RSV.

Impact: HM-GAGs have been poorly investigated for their antiviral action so far. We demonstrated that HM-GAGs are endowed with significant anti-HCMV and anti-RSV activity and that they are able to alter virus binding to the cell. The contribution of individual HM-GAGs is mainly exerted by the FMHep and is not based on a simple charge interaction between the virus and sulfate groups but involves a specific GAG structural configuration. Our results contribute to identifying the multiple factors synergically acting in mediating HM antiviral properties and to clarifying their specific mechanism of action.