Author Correction: Regulatory review of benefits and risks of preventing infant RSV disease through maternal immunization
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Respiratory syncytial virus glycoprotein G impedes CX3CR1-activation by CX3CL1 and monocyte function
The soluble form of the Respiratory Syncytial Virus (RSV) G protein (sG) bears resemblance to the chemokine fractalkine (CX₃CL1). Both RSV sG and CX3CL1 possess a mucin-like domain and a CX3C motif, exist in membrane-associated and soluble forms, and bind to the CX₃CR1 receptor expressed on immune and epithelial cells. To explore the biological significance of RSV sG and CX₃CR1 interaction, we produced wild type (WT) and CX₃C motif-deficient (CX3CMut) RSV sG proteins and determined their effects on CX₃CR1 signaling in monocytic cells. Both CX3CMut– and WT RSV sG failed to activate CX₃CR1 signaling directly. However, WT sG competed with CX₃CL1 for CX₃CR1 binding and reduced CX3CL1-induced CX₃CR1-activation, monocyte migration, and adhesion. The CX₃C motif of sG was crucial for competitive blocking of CX3CL1-mediated activation, as CX₃CMut sG did not affect these CX₃CR1 functions significantly. Thus, blockade of CX₃CR1 signaling by sG may allow RSV to dampen host immune responses.
Modulating cytokine microenvironment during T cell activation induces protective RSV-specific lung resident memory T cells in early life in mice
Maternal immunisation against respiratory viruses provides protection in early life, but as antibodies wane, there can be a gap in coverage. This immunity gap might be filled by inducing pathogen-specific lung tissue-resident T cells (TRM). However, the neonatal mouse lung has a different inflammatory environment to the adult lung which affects T cell recruitment. We compared the factors affecting viral-specific TRM recruitment in the lungs of adult or neonatal mice. In contrast to adulthood, we demonstrated that RSV or influenza infection in neonatal mice recruited fewer TRM to the lungs. This was associated with reduced lung levels of CCL5 and CXCL10. Co-administration of CCL5 or CXCL10 at the time of primary T cell activation significantly increased RSV-specific TRM in the lung, protecting mice upon reinfection. These chemokine differences were reflected in responses to infection in human cord blood. Here we show a critical role for CCL5 and CXCL10 in the induction of lung TRM and a possible strategy for boosting responses.
Maternal effects in the model system Daphnia: the ecological past meets the epigenetic future
Maternal effects have been shown to play influential roles in many evolutionary and ecological processes. However, understanding how environmental stimuli induce within-generation responses that transverse across generations remains elusive, particularly when attempting to segregate confounding effects from offspring genotypes. This review synthesizes literature regarding resource- and predation-driven maternal effects in the model system Daphnia, detailing how the maternal generation responds to the environmental stimuli and the maternal effects seen in the offspring generation(s). Our goal is to demonstrate the value of Daphnia as a model system by showing how general principles of maternal effects emerge from studies on this system. By integrating the results across different types of biotic drivers of maternal effects, we identified broadly applicable shared characteristics: 1. Many, but not all, maternal effects involve offspring size, influencing resistance to starvation, infection, predation, and toxins. 2. Maternal effects manifest more strongly when the offspring’s environment is poor. 3. Strong within-generation responses are typically associated with strong across-generation responses. 4. The timing of the maternal stress matters and can raise or lower the magnitude of the effect on the offspring’s phenotype. 5. Embryonic exposure effects could be mistaken for maternal effects. We outline questions to prioritize for future research and discuss the possibilities for integration of ecologically relevant studies of maternal effects in natural populations with the molecular mechanisms that make them possible, specifically by addressing genetic variation and incorporating information on epigenetics. These small crustaceans can unravel how and why non-genetic information gets passed to future generations.
Syrian hamsters (Mesocricetus auratus) as an upper respiratory tract model for respiratory syncytial virus infection
Respiratory syncytial virus (RSV) is one of the leading causes of respiratory tract infection in children, immunocompromised individuals and older adults. Vaccines have recently been approved for use in adults and although further efforts to develop suitable interventions for children are ongoing, there are limited animal models for RSV infection. For preclinical efficacy testing of prophylactic and therapeutic treatments cotton rat and ferret models can be used. However, these can be expensive, difficult to source and house, and often have limitations such as insufficient virus replication in the respiratory tract and/or lack of horizontal transmission. In this study, Syrian hamsters (Mesocricetus auratus), which are relatively cheap, easy to source and house, were inoculated intranasally with a recombinant RSV-A-0594 strain expressing EGFP and using virological and pathological analyses. Viral replication was assessed and compared to viral replication in the ferret model. Although there was limited virus infection of the lower respiratory tract of Syrian hamsters, we show that a contemporary recombinant RSV-A strain replicates efficiently in the upper respiratory tract of Syrian hamsters (titers up to 4.5 Log10 TCID50/g and 12 Log10 RNA copies/g). These titers are comparable to those found in the ferret upper respiratory tract tissues post-infection with the same virus strain (up to 6.0 Log10 TCID50/g and 12 Log 10 RNA copies/g). Fluorescent regions indicating virus infection were macroscopically visible under UV-light in the nasal turbinates and histological assessment showed mucosal inflammation with necrotic cells in this tissue. In summary, Syrian hamsters generally displayed less severe systemic and pulmonary changes than ferrets, but do appear to be a promising model for upper respiratory tract infection with RSV.
Analysis of microbial composition and sharing in low-biomass human milk samples: a comparison of DNA isolation and sequencing techniques
Human milk microbiome studies are currently hindered by low milk bacterial/human cell ratios and often rely on 16S rRNA gene sequencing, which limits downstream analyses. Here, we aimed to find a method to study milk bacteria and assess bacterial sharing between maternal and infant microbiota. We tested four DNA isolation methods, two bacterial enrichment methods and three sequencing methods on mock communities, milk samples and negative controls. Of the four DNA isolation kits, the DNeasy PowerSoil Pro (PS) and MagMAX Total Nucleic Acid Isolation (MX) kits provided consistent 16S rRNA gene sequencing results with low contamination. Neither enrichment method substantially decreased the human metagenomic sequencing read-depth. Long-read 16S-ITS-23S rRNA gene sequencing biased the mock community composition but provided consistent results for milk samples, with little contamination. In contrast to 16S rRNA gene sequencing, 16S-ITS-23S rRNA gene sequencing of milk, infant oral, infant faecal and maternal faecal DNA from 14 mother-infant pairs provided sufficient resolution to detect significantly more frequent sharing of bacteria between related pairs compared to unrelated pairs. In conclusion, PS or MX kit-DNA isolation followed by 16S rRNA gene sequencing reliably characterises human milk microbiota, and 16S-ITS-23S rRNA gene sequencing enables studies of bacterial transmission in low-biomass samples.
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