Differential anti-viral response to respiratory syncytial virus A in preterm and term infants

Jeremy Anderson; Samira Imran; Yan Yung Ng; Tongtong Wang; Sarah Ashley; Cao Minh Thang; Le Quang Thanh; Vo Thi Trang Dai; Phan Van Thanh; Bui Thi Hong Nhu; Do Ngoc Xuan Trang; Phan Thi Phuong Trinh; Le Thanh Binh; Nguyen Thuong Vu; Nguyen Trong Toan; Boris Novakovic; Mimi L K Tang; Danielle Wurzel; Kim Mulholland; Daniel G Pellicci; Lien Anh Ha Do; Paul V Licciardi

doi:10.1016/j.ebiom.2024.105044

Differential anti-viral response to respiratory syncytial virus A in preterm and term infants

EBioMedicine. 2024 Apr:102:105044. doi: 10.1016/j.ebiom.2024.105044. Epub 2024 Mar 6.

Authors

Jeremy Anderson¹, Samira Imran², Yan Yung Ng², Tongtong Wang³, Sarah Ashley², Cao Minh Thang⁴, Le Quang Thanh⁵, Vo Thi Trang Dai⁴, Phan Van Thanh⁴, Bui Thi Hong Nhu⁵, Do Ngoc Xuan Trang⁵, Phan Thi Phuong Trinh⁵, Le Thanh Binh⁵, Nguyen Thuong Vu⁵, Nguyen Trong Toan⁵, Boris Novakovic², Mimi L K Tang⁶, Danielle Wurzel⁷, Kim Mulholland⁸, Daniel G Pellicci⁹, Lien Anh Ha Do¹⁰, Paul V Licciardi¹¹

Affiliations

¹ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: jeremy.anderson@mcri.edu.au.
² Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia.
⁴ Pasteur Institute of Ho Chi Minh City, Vietnam.
⁵ Tu Du Hospital, Ho Chi Minh City, Vietnam.
⁶ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Allergy and Lung Health Unit, University of Melbourne, Melbourne, Australia.
⁷ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Allergy and Lung Health Unit, University of Melbourne, Melbourne, Australia; Royal Children's Hospital, Melbourne, Australia.
⁸ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; London School of Hygiene and Tropical Medicine, London, United Kingdom.
⁹ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia.
¹⁰ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: lienanhha.do@mcri.edu.au.
¹¹ Infection, Immunity and Global Health, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: paul.licciardi@mcri.edu.au.

Abstract

Background: Preterm infants are more likely to experience severe respiratory syncytial virus (RSV) disease compared to term infants. The reasons for this are multi-factorial, however their immature immune system is believed to be a major contributing factor.

Methods: We collected cord blood from 25 preterm (gestational age 30.4-34.1 weeks) and 25 term infants (gestation age 37-40 weeks) and compared the response of cord blood mononuclear cells (CBMCs) to RSVA and RSVB stimulation using neutralising assays, high-dimensional flow cytometry, multiplex cytokine assays and RNA-sequencing.

Findings: We found that preterm and term infants had similar maternally derived neutralising antibody titres to RSVA and RSVB. Preterm infants had significantly higher myeloid dendritic cells (mDC) RSV infection compared to term infants. Differential gene expression analysis of RSVA stimulated CBMCs revealed enrichment of genes involved in cytokine production and immune regulatory pathways involving IL-10, IL-36γ, CXCL1, CXCL2, SOCS1 and SOCS3 in term infants, while differentially expressed genes (DEGs) in preterm infants were related to cell cycle (CDK1, TTK, ESCO2, KNL1, CDC25A, MAD2L1) without associated expression of immune response genes. Furthermore, enriched genes in term infants were highly correlated suggesting an increased co-ordination of their immune response to RSVA. When comparing DEGs in preterm and term infants following RSVB stimulation, no differences in immune response genes were identified.

Interpretation: Overall, our data suggests that preterm infants have a more restricted immunological response to RSVA compared with term infants. While further studies are required, these findings may help to explain why preterm infants are more susceptible to severe RSV disease and identify potential therapeutic targets to protect these vulnerable infants.

Funding: Murdoch Children's Research Institute Infection and Immunity theme grant.

Keywords: Immune response; Infants; Inflammation; Preterm; RSV; Transcriptome.

MeSH terms

Acetyltransferases
Antiviral Agents
Child
Chromosomal Proteins, Non-Histone
Cytokines / metabolism
Humans
Infant
Infant, Newborn
Infant, Premature
Respiratory Syncytial Virus Infections*
Respiratory Syncytial Virus, Human*

Substances

Cytokines
Antiviral Agents
ESCO2 protein, human
Acetyltransferases
Chromosomal Proteins, Non-Histone