Could RSV Be Transmitted Through the Placenta into Developing Fetal Lungs?

By Giovanni Piedimonte, MD

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants and young children. Strong epidemiologic evidence suggests that when infants are infected, they are predisposed to chronic respiratory dysfunction and asthma, possibly due to persistence of the virus or its effects on lung development.

For many years, it has been generally accepted that the pathophysiology of RSV bronchiolitis is driven by the inflammatory response mounted by horizontal (i.e., interpersonal) transmission of the virus in the first few months after birth.

However, my colleagues and I recently published an animal study in PLOS ONE1 that has brought to the forefront a striking new idea: RSV may be transmitted vertically from the respiratory tract of the mother to the lungs of the fetus. Until now, we believed that when a pregnant woman got a cold, the developing fetus was protected by the placenta from RSV and other respiratory viruses.

Intriguing findings: Transplacental transmission and beyond

In our study, pregnant rats were inoculated with recombinantRSV. The RSV genome was subsequently found in 30 percentof fetuses (Figure 1) and in the lungs of 40 percent of newbornrats and 25 percent of rats born to inoculated mothers whentested in adulthood (10 weeks after birth). These data supporttransplacental transmission of RSV from mother to offspring and the persistence of vertically transmitted virus in lungs after birth.

Figure 1. Propagation of vertically transmitted RSV in the rat. Magnified at 60×, extracts of whole fetuses are shown that were delivered from dams inoculated with recombinant RSV (rrRSV; bottom row) or from pathogenfree controls (top row) and co-cultured with human airway epithelial cells. The micrographs show red fluorescence in the cytoplasm of cells exposed to fetal extracts from rrRSV-infected dams, confirming the presence of actively replicating infectious virus associated with markedly increased green nerve growth factor (NGF) immunoreactivity. Reprinted from Piedimonte et al, PLOS ONE.1

Notably, we also found that exposure to RSV in utero changes the way that lungs function through dysregulation of neurotrophic pathways, thereby predisposing the subject to the postnatal airway hyper reactivity that is the hallmark of asthma.

Rethinking RSV transmission

While this is the first time to our knowledge that vertical transmission of RSV — or any common respiratory virus —has been reported, a number of infectious agents, including herpes viruses and retroviruses, have been shown to cross the placenta and establish persistent infection in offspring.

Our research was driven by two key factors:

• Human and animal research showing that while RSV primarily targets the lungs, the virus can spread to extrapulmonary sites, which can have systemic implications. We postulated that if RSV can spread beyond the lungs, it is possible that the virus also could penetrate the placenta.
• The possibility that some infections, such as RSV, once regarded as temporary may be longer-lasting and more pervasive than we thought. While the acute phase of an RSV infection typically resolves in a few weeks, my colleagues and I found in a separate study that RSV’s molecular signature persists in the bone marrow long after the virus has cleared— even well into adulthood.2 This finding has implications for both mother and fetus in terms of the potential for in utero transmission and its sustained effects.

Potential implications: A new focus on prevention in pregnancy?

If our recent findings1 can be confirmed in human studies, we may have to rewrite the books on RSV transmission. The general idea we have been working under for decades in pulmonology is that nothing bad happens in the lungs until the baby is born — even with serious conditions such as cystic fibrosis. This study suggests that a certain percentage of patients who develop asthma may do so because of viral exposure in utero.

The next step in our research will be to see if these observations are replicated in ex vivo studies of human cells. Eventually, research will focus on in vivo human studies in mothers naturally infected with RSV. Cleveland Clinic Children’s plans to work closely with our colleagues in Cleveland Clinic’s Ob/Gyn & Women’s Health Institute to carefully administer these studies.

If human studies replicate our findings from animal models, our understanding of the pathogenesis of RSV infections would be completely changed. It would turn back the clock of respiratory developmental diseases by months and mean that we would need to start thinking about lung development and pathology during pregnancy rather than at birth. This could create a paradigm shift by extending our focus on prevention from the first few years after birth to also include the last few months before birth.

About the Author

Dr. Piedimonte, a pediatric pulmonologist, is Chairman and Physician-in-Chief of Cleveland Clinic Children’s. He can be reached at 216.444.2344 or piedimg@ccf.org.

References

1. Piedimonte G, Walton C, Samsell L. Vertical transmission of respiratory syncytial virus modulates pre- and postnatal innervation and reactivity of rat airways. PLOS ONE. 2013;8(4):e61309.
2. Rezaee F, Gibson LF, Piketel D, Othumpangat S, Piedimonte G. Respiratory syncytial virus infection in human bone marrow stromal cells. Am J Respir Cell Mol Biol. 2011;45(2):277-286.