Early-life viral encounters take the center stage

It remains a mystery why one infant is more prone to develop a respiratory tract infection than another. Our recent work adds another piece to this puzzle, indicating a central role for early-life viral infections, which are related to subsequent host-microbe crosstalk and risk of infections.
Early-life viral encounters take the center stage

Over the last decade, evidence accumulates that the microbial ecosystem in the nose has an important role in controlling pathogen overgrowth and modulating disease symptoms. Over the years, pathogen carriage and subsequent overgrowth – often a prerequisite for disease – is increasingly being thought of as ecosystem-wide, rather than a single pathogen problem. This line of research finds its origin in pneumococcal vaccine studies conducted over a decade ago. These studies showed that vaccinating against a selection of pneumococcal serotypes resulted in emergence of non-vaccine pneumococcal serotypes and other potential pathogens, like Staphylococcus aureus1. This is analogous with a waterbed mattress; pushing down the mattress in one place will inevitably cause the mattress to rise in another place, as the water cannot be compressed. 

Although these results were extremely valuable, they were highly controversial at the time, owing to the reluctance of journals and conferences to enable researchers to present their work. Regardless, these data provoked the idea that pneumococci may keep Staphylococcus at bay during homeostatic conditions, for example by competing for nutrients or direct metabolic interactions. Although through reductionist approaches researchers were aware of these types of interactions between specific bacteria, they could only shed light on small parts of a likely larger network of microbe-microbe and host-microbe interactions at the time. The broader availability of next-generation sequencing techniques around 2010 changed this, allowing members of our group to embark on a quest to further study the ecological landscape of the respiratory tract microbiota.

Fast forwarding in time, based on a combination of cross-sectional and longitudinal studies, we learned more and more on the upper airway microbiota. Especially the Microbiome Utrecht Infant Study (MUIS), a birth cohort study tracking microbiota development in over 110 infants, has massively contributed to our knowledge base. Our recent study is part of a series of MUIS-studies where we assessed upper airway, salivary and fecal microbiota development in infants over the first months of life2–5. With regard to the upper airway (nose) microbiota we previously showed how vaginal birth and breastfeeding impact microbial development, selecting for health-associated microbes, including lactic-acid producers like Dolosigranulum spp. In addition, we found that the typical upper airway microbiota development is characterised by early-life Staphylococcus enrichment (week 1 – month 1), followed by Dolosigranulum and Corynebacterium spp. abundance (month 2) and predominance of Moraxella spp. (month 2-3 and on). Although most children went through these stages, we found that those infants who ultimately develop a higher number of respiratory tract infections prematurely transition from a Staphylococcus into a Moraxella-dominated profile, skipping the intermediate stage with health-associated microbes. Signs of this premature development can already be detected within the first month of life, which is before the first symptomatic respiratory infections develop.

 This last observation puzzled us. Assuming direct ecological effects of the bacterial community composition on potential viral or bacterial pathogens, one would expect a more instantaneous relationship between microbiota imbalance and signs of infection. Given the time gap of 1-1.5 months, we reasoned this may signal indirect effects, for instance via the host immune system. This is why we set out to characterize the infant nose immune system by assessing gene expression of nasal cells (‘transcriptome’). In line with the microbiota data, we found strong dynamics over time, with specifically strong changes in gene expression just after birth. Highly expressed genes over the first days of life encompassed pattern recognition receptors, which are part of the innate immune system and capable of detecting molecules frequently found in pathogens. We found that first viral encounters resulted in a strong ‘jump’ in genes involved in interferon pathways (known antiviral immunity), yet what was interesting is that this did not directly relate to clinical symptoms of infections. Instead, we found that higher interferon pathway activity related to disadvantageous microbiota development, including early (premature) transition into a Moraxella-dominated profile and early enrichment of Haemophilus spp. In turn, as also shown in our previous work, these profiles are ultimately related to an increased number of respiratory infections over the first year of life. 

Although we could not confirm causality, we believe we unveiled an important pathway explaining infant infection susceptibility. First viral encounters trigger antiviral interferon pathways, which result in premature microbial development, setting off a self-enforcing circle of inflammation and further microbiota changes, rendering an infant more susceptible to subsequent (viral) infections. Alternatively, upon later first viral encounters, the respiratory microbiota already went through an age-appropriate development, possibly dampening downstream disadvantageous effects of interferon signaling (see Figure). As said, more work is required to further substantiate this plausible chain of events.

Fig 1 | Early versus late viral encounters and plausible chain of events. 

Concluding, our data indicate a central role for very early – often asymptomatic – viral encounters. These infections trigger a local interferon response, which in turn is associated with disadvantageous bacterial profiles and higher infection susceptibility over the first year of life.

References

  1. Bogaert, D. et al. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet 363, 1871–1872 (2004).
  2. Bosch, A. A. T. M. et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. EBioMedicine 9, 336–345 (2016).
  3. Bosch, A. A. T. M. et al. Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study. Am J Respir Crit Care Med 196, 1582–1590 (2017).
  4. Man, W. H. et al. Loss of Microbial Topography between Oral and Nasopharyngeal Microbiota and Development of Respiratory Infections Early in Life. American Journal of Respiratory and Critical Care Medicine 200, 760–770 (2019).
  5. Reyman, M. et al. Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life. Nat Commun 10, 4997 (2019).