Mother-to-Child Transmission of Arboviruses during Breastfeeding: From Epidemiology to Cellular Mechanisms

Abstract

Most viruses use several entry sites and modes of transmission to infect their host (parenteral, sexual, respiratory, oro-fecal, transplacental, transcutaneous, etc.). Some of them are known to be essentially transmitted via arthropod bites (mosquitoes, ticks, phlebotomes, sandflies, etc.), and are thus named arthropod-borne viruses, or arboviruses. During the last decades, several arboviruses have emerged or re-emerged in different countries in the form of notable outbreaks, resulting in a growing interest from scientific and medical communities as well as an increase in epidemiological studies. These studies have highlighted the existence of other modes of transmission. Among them, mother-to-child transmission (MTCT) during breastfeeding was highlighted for the vaccine strain of yellow fever virus (YFV) and Zika virus (ZIKV), and suggested for other arboviruses such as Chikungunya virus (CHIKV), dengue virus (DENV), and West Nile virus (WNV). In this review, we summarize all epidemiological and clinical clues that suggest the existence of breastfeeding as a neglected route for MTCT of arboviruses and we decipher some of the mechanisms that chronologically occur during MTCT via breastfeeding by focusing on ZIKV transmission process.

Keywords: Chikungunya virus; West Nile virus; Zika virus; arboviruses; barrier crossing mechanisms; breast milk; breastfeeding; dengue virus; intestinal epithelium; mammary epithelium; mother-to-child transmission; viral transmission; yellow fever virus.

Figure 1

A chronology of the three main events occurring during viral mother-to-child transmission by breastfeeding. The first event consists of viral dissemination to mother’s mammary glands where viral infectious entities need to cross the mammary epithelium to be excreted in breast milk (red box). Then, viral infectious entities that could be either cell-associated viruses (CAVs), free viruses (FVs) or vesicle-cloaked viruses (VCVs) transit in breast milk in the presence of diverse components such as milk fat globules (MFGs) or immunoglobulins A (IgA). At this stage, conservation of viral infectivity needs to be ensured in breast milk (blue box). Finally, viral infectious entities can cross tonsillar (TE), respiratory (RE), and/or intestinal (IE) epithelia to infect the breastfed newborn. As an example, viral infectious entities present in the small intestine’s lumen need to cross the monostratified intestinal epithelium to reach the lamina propria (LP) (green box).

Figure 2

General organization of the mammary gland and its epithelium. The mammary epithelium (pink) is a ramified structure embedded in a fibro-adipose connective tissue: the mammary stroma (yellow). The epithelial structure is ramified into different levels of lactiferous ducts leading to milk-producing alveoli. The bistratified mammary epithelium (black box) is composed of luminal cells (pink) in contact with the lumen (white) and myoepithelial cells (orange) in contact with both the basement membrane (blue) and the stroma.

Figure 3

Hypothetical mechanisms of blood–milk barrier crossing by Zika Virus (ZIKV). In order to explain the presence of ZIKV particles in breast milk of infected mothers, several mechanisms could occur. Free viral particles (dark red) present in the bloodstream could sequentially infect myoepithelial cells (orange) and luminal cells (pink), resulting in the production of free viral particles in breast milk. Infected immune cells from the bloodstream (blue) could cross the epithelial barrier via the paracellular route by the « Trojan horse » mechanism, resulting in the presence of infected cells in breast milk that could produce viral particles. The viral particles produced could productively infect the luminal cells of the epithelium resulting in the presence of both cell-free and cell-associated ZIKV in breast milk. Infected epithelial cells could also be found in breast milk after being split off from the epithelium. Finally, it cannot be excluded that vesicles containing multiple virions could be produced by the mammary epithelium.

Figure 4

Inhibitory mechanisms of viral infectivity by breast milk components. Human breast milk contains components of different natures such as maternal cells (in green), the cream fraction (in yellow), the skim milk fraction composed of lactoserum (in blue) and casein micelles (in brown) (Figure 4). The cream fraction contains milk fat globules, free fatty acids (free FAs), and prosta-glandins. The lactoserum contains carbohydrates such as lactose, mineral salts, and a high diversity of proteins such as immunoglobulins (Ig), lactalbumin (LA), vitamin A, monolaurin, lactoferrin (LF), soluble viral receptors, and others. Lipases contained in breast milk digest triglyceride hearts of MFG when the milk fat globule membrane (MFGM) is altered, generating free FA (yellow box). Free FA inactivate enveloped viruses such as Herpes simplex virus type 1 (HSV-1), Vesicular stomatitis virus (VSV), Maëdi–Visna virus (MVV), Sendaï virus (SeV), Newcastle disease virus (NDV), type A Influenza virus (IAV), Measles virus (MV), Hepatitis C virus (HCV), and arboviruses (red) such as Sindbis virus (SINV), West Nile virus (WNV), Semliki forest virus (SFV), Ross river virus (RRV), Getah virus (GETV), and Zika virus (ZIKV) by interacting with the viral envelope and altering viral particle integrity (yellow box). Soluble viral receptors present in breast milk inhibit viral entry of viruses such as Cytomegalovirus (CMV) by interacting with viral par-ticles contained in breast milk, thus inhibiting viral binding to cell receptors on target cells (blue box, dashed line). LF inhibits viral entry by binding either to viral particles or to target cells (blue boxes, full line, first row). LF binds to HCV, Rotavirus (RV), Poliovirus (PV), type 1 Human immunodeficiency virus (HIV-1), HSV-1, Herpes simplex virus type 2 (HSV-2), or CMV. LF binds to target cells, inhibiting infection by PV, CMV, and arboviruses (red) such as SINV, SFV, Japanese encephalitis virus (JEV), Mayaro virus (MAYV), dengue virus (DENV), Toscana virus (TOSV), Chikungunya virus (CHIKV), or ZIKV. LF supposedly inhibits intracellular steps of the viral cycle like reverse transcription (RT), antigen synthesis, or proviral integration into the host cell genome by yet unknown mechanisms (blue boxes, full line, second and third rows). Maternal Igs present in breast milk can bind to viral particles, thus inhibiting their infectivity either by antibody-dependent cell-mediated cytotoxicity (ADCC) or by neutralizing (black boxes, full line) arboviruses (red) such as GETV, RRV, and SFV.

Figure 5

The intestinal barrier: anatomy and viral crossing. (A) The intestinal barrier is a monostratified epithelium composed of different cell types that all differentiate from pluripotent stem cells (yellow) located at the bottom of the crypts: enterocytes (orange), goblet cells (pink), Paneth cells (blue), and microfold cells (M cells) (green). Underlying the epithelium, the gut-associated lymphoid tissue is composed of free and anchored immune cells. Over the lymphoid follicles, the follicle-associated epithelium is enriched by M cells. (B) The intestinal barrier can be crossed by paracellular crossing by Rotavirus (RV), by enterocyte infection by RV (*: after paracellular crossing), Human immunodeficiency virus (HIV), Hepatitis A virus (HAV), and Zika virus (ZIKV), by transcytosis through enterocytes by HIV, type 1 Human T-cell lymphotropic virus (HTLV-1), and Tick-borne encephalitis virus (TBEV), or by transcytosis through M cells by HIV, Poliovirus (PV), and Norovirus (NV). The only arboviruses (red) that were reported to cross the intestinal barrier are TBEV and ZIKV.