RSV infection is one of the main reasons for infancy and young children worldwide [1]. In 2015 alone, 11,000 children under 5 years old died of respiratory syncytial virus infection. It is highly contagious and recurring. Even if infants and young children are cured, they are ver

Written by | Xiaoheilongou

Editor | Yihong

Respiratory syncytial virus (Respiratory syncytial virus, RSV) , also known as human respiratory syncytial virus (hRSV) , is a very common negative sense single-strand RNA virus. Since cells infected with RSV will fuse together to form a large cell structure called syncytial , hence the name respiratory syncytial virus .

RSV infection is one of the main reasons for infancy and young children worldwide 【1】. In 2015 alone, 11,000 children under 5 years old died of respiratory syncytial virus infection . It is highly contagious and recurring. Even if infants and young children are cured, they are very likely to be infected again in their future lives. RSV is mainly transmitted through droplets, which makes it prone to cause explosive infections in community and hospital settings, posing a great threat to public health and social stability.

Although we can currently prevent the outbreak of RSV by strengthening RSV virus detection, frequent hand washing, and avoiding close contact with infected people, there is currently no vaccine for RSV. In recent years, with the emergence of new immunization strategies, new methods for vaccine construction, and new technologies such as RSV neutralization antigen characterization, researchers have developed great interest in the development of RSV vaccines. The development process of the

RSV vaccine was full of twists and turns. In the 1960s, when researchers vaccinated the infants with a novel anti-RSV formalin inactivated vaccine against RSV (FIRSV) , they were infected with an atypical, enhanced RSV disease (ERD) . The hospitalization rate of infants caused by ERD is as high as 80%. Two babies were infected with ERD and eventually died due to RSV vaccination. The occurrence of these events has almost stopped the development of RSV vaccine 【2,3】. The process of screening and testing RSV candidate vaccines to determine the safety of vaccines is important and necessary. Given that the data on fatal cases of infants caused by RSV vaccines are very limited, in order to promote relevant research on RSV vaccines, the Kolls team from Tulane University in Louisiana, USA recently published an article in the journal Science Translational Medicine (Title: Fatal enhanced respiratory syncytial virus disease in toddlers), This study reveals the specific characteristics of lethal disease ERD in clinical characterization, immunopathology and transcriptional regulation, which is of great significance for us to understand RSV pathogen-enhanced diseases in general.

researchers first compared and analyzed the clinical characteristics of two boys who died of ERD in January 1967 and 25 babies who died of wild-type RSV (wtRSV) infection, and found that:

1. Two ERD children were significantly older than the wtRSV infection group;

2. No congenital heart disease in children, but statistics show that congenital risk factors in children with wtRSV are common. Among the 25 wtRSV children, there was congenital heart disease in (3 / 25), premature birth (7 / 24) and Down syndrome (1 / 25);

3. leukocyte count in children with ERD increased and neutrophil count in children with , but the opposite is that neutrophils in children with WtRSV decreased significantly (reduction rate was about 27%) ;

Table 1 The clinical manifestations of lethal ERD disease and wtRSV disease in infants

The specificity of neutrophils and eosinophils as ERD biomarkers has been debated for decades. The researchers compared the lung tissue sections of two infants with ERD with lung tissue sections of a young child infected with wtRSV and congenital heart disease, and found the following:

1. Diffuse alveolar consolidation, strong transmural bronchioles inflammation, and the cavity is filled with cells and granule debris. On the contrary, wtRSV infection is related to inflammatory responses, which are mainly concentrated in the bronchiole and mainly occur in the submuscular chamber of the bronchiole wall

2. The inflammatory infiltration of bronchiole caused by ERD is mainly neutrophils and eosinophils, accompanied by mixing monocytes. In contrast, in the symptoms caused by wtRSV infection, macrophages and lymphocytes dominate, while neutrophils only account for a secondary component in the inflammatory response.

Figure 1 The findings brought about by the immune section experiment of lung tissue conducted by researchers are consistent with and consistent with the pathology of wtRSV tissue

. Immediately afterwards, they performed lung transcriptional analysis on healthy young children who experienced ERD and were matched by age, gender and race. found that the type II lung cell transcripts (including the surfactant proteins SFPTA1, SFPTA2, SFPTB and SFPTC) of two children who died of ERD were severely defective in expression, while the genes associated with ion cells (CFTR and FOXI1) were downregulated, while the ciliary epithelial marker FOXJ1 was upregulated.

Figure 2 Comparative heat map of gene expression in children with ERD and children with ERD who had been infected with ERD but died of non-pulmonary causes

By analyzing the results of RNA-Seq, the researchers found that the transcriptional responses of genes such as CR1, CFH, FCGR 2 and C5 were significantly weakened [5,6]. In addition, during viral infection in children with ERD, the expression of the cell death mediator FASLG and AREG are significantly increased (AREG is an important lung repair mediator). The results showed that pathways related to enhanced vaccine response such as surfactant protein and type I interferon (I-IFN) were positive.

In summary, this study summarizes the characteristics of ERD diseases as follows:

1. High fever and bronchial-monocyte enrichment

2. Surfactant and type I interferon transcription signals significantly reduced

3. Type II immune response polarization in the lungs is manifested as lung eosinophilia and increased CCL 5 expression.

4. The eosinophil count in peripheral blood may be normal, but may also be invalid (as a clinical marker). The fatality of

ERD disease is a tragedy that has hindered the development of RSV vaccines for decades. In this study, the researchers showed us the comprehensive characteristics of lethal ERD diseases by conducting detailed analysis of the clinical characteristics, lung tissue immunopathology and transcriptome of children with ERD and wtRSV.By uncovering the fog of ERD diseases, it provides an important theoretical basis for the world to accelerate the research and development of safe RSV vaccines.

Original link:

https://www.science.org/doi/10.1126/scitranslmed.abj7843

Platformer: 11

References

[1] T. Shi, et al; RSV Global Epidemiology Network, Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: A systematic review and modelling study. Lancet 390, 946–958 (2017).

[2] H. W. Kim, J. G. Canchola, C. D. Brandt, G. Pyles, R. M. Chanock , K. Jensen, R. H. Parrott, Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 (1969).

[3] J. Chin, R. L. Magoffin, L. A. Shearer, J. H. Schieble, E. H. Lennette, Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am. J. Epidemiol. 89, 449–463 (1969).

[4] J. E. Johnson, R. A. Gonzales, S. J. Olson, P. F. Wright, B. S. Graham, The histopathology of fatal untreated human respiratory syncytial virus infection. Mod. Pathol. 20, 108–119 (2007)

[5] F. P. Polack, M. N. Teng, P. L. Collins, G. A. Prince, M. Exner, H. Regele, D. D. Lirman, R. Rabold, S. J. Hoffman, C. L. Karp, S. R. Kleeberger, M. Wills-Karp, R. A. Karron, A role for immunocomplexes in enhanced respiratory syncytial virus disease. J. Exp. Med. 196, 859–865 (2002).

[6] M. F. Delgado, S. Coviello, A. C. Monsalvo, G. A. Melendi, J. Z. Hernandez, J. P. Batalle, L. Diaz, A. Trento, H.-Y. Chang, W. Mitzner, J. Ravetch, J. A. Melero, P. M. Irusta, F. P. Polack, Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 15, 34–41 (2009).

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