Neonatal Immune Responses to Respiratory Viruses

Abstract

Respiratory tract infections are a leading cause of morbidity and mortality in newborns, infants, and young children. These early life infections present a formidable immunologic challenge with a number of possibly conflicting goals: simultaneously eliminate the acute pathogen, preserve the primary gas-exchange function of the lung parenchyma in a developing lung, and limit long-term sequelae of both the infection and the inflammatory response. The latter has been most well studied in the context of childhood asthma, where multiple epidemiologic studies have linked early life viral infection with subsequent bronchospasm. This review will focus on the clinical relevance of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and rhinovirus (RV) and examine the protective and pathogenic host responses within the neonate.

Keywords: RSV; human metapneumovirus; lung; neonate; respiratory virus; rhinovirus.

Figure 1

Baseline differences in the neonatal innate immune system. Several areas of the innate response are blunted in neonates, including macrophage response to TLR signals, neutrophil/monocyte extravasation, and poor function of antigen-presenting cells (monocytes/dendritic cells). Anti-inflammatory signals are also produced by the innate system, with IL-10 production via macrophages. Dendritic cells express PD-L1, a co-inhibitory receptor, shortly after birth and produce less pro-inflammatory IL-12. NK cells show reduced effector function and increased expression of inhibitory receptors (e.g. NKG2A). Eosinophils accumulate in the lung within the first two weeks of life in mice. Created with biorender.com.

Figure 2

Baseline differences in the neonatal adaptive immune system. The neonatal CD4⁺ T cell compartment is skewed towards Th2 (due to hypomethylation of critical Th2 regulatory regions) and Treg development. There is less differentiation towards Th1 due to reduced IL-12 in the milieu, coupled with increased Th1 apoptosis due to IL-4 signaling. Tfh cells, while stimulated by IL-4 to differentiate, have arrested development, with generation of short-lived pre-Tfh cells. IL-4 signaling on Tfh cells also limits IL-17 production and skews the humoral response towards IgE production. Both neonatal Tfh and B cells have poor migration to germinal centers, which structurally demonstrate poor organization. B cells also have increased production of IL-10 and spontaneous secretion of IgM. CD8⁺ T cells show radically different properties in neonates compared to adults, with increased proliferation, generation of reactive oxygen species (ROS) and antimicrobial peptides (AMPs), and reduced cytotoxicity and memory formation. Created with biorender.com.

Figure 3

The immune response to respiratory viruses in neonates. The neonatal response favors a type II response, with increased IL-33, IL-25 and TSLP released from the epithelium, increased type 2 innate lymphoid cells (ILC2), increased type 2 helper T cells (Th2), and differentiation of M2-like alveolar macrophages (M2). CD8 T cells have reduced T cell receptor (TCR) avidity, while both CD8 T cells and natural killer (NK) cells show reduced effector functions. Germinal center (GC) reactions are diminished in neonates, with less T follicular helper (Tfh) cell differentiation and less IgG production from GC B cells. Created with biorender.com.