Making a bed for viral infections

doi:10.1126/science.abe3685

GSTDTAP > 气候变化

DOI	10.1126/science.abe3685
	Making a bed for viral infections
	Ananda S. Mirchandani; Sarah R. Walmsley
	2020-10-09
发表期刊	Science
出版年	2020
英文摘要	In the past 100 years, humans have harnessed the power of antibiotics to save countless lives from bacterial infection, however, our capacity to treat viral illnesses lags far behind. Prevention through vaccination has been the most effective method to tackle viral infections, yet vaccines have not always been achievable, as in the case of respiratory syncytial virus (RSV) ([ 1 ][1]). In most people, RSV infection causes a mild “cold”-like illness, and by age 2, most children will have been infected by RSV ([ 2 ][2]). Although most develop only mild symptoms, some children will develop severe lung inflammation (bronchiolitis) that can be fatal. Therefore, determining the risk of severe illness would transform the management of RSV. On page 188 of this issue, Habibi et al. ([ 3 ][3]) identified an inflammatory signature in adults susceptible to symptomatic RSV infection, which they ascribe to activated neutrophils. Their findings suggest that the immune environment in which the virus is received may dictate the outcome. Neutrophils are often overlooked as mediators of the immune response to viruses, even though they are the predominant immune cell in the lungs of individuals with RSV-induced bronchiolitis ([ 4 ][4]) and despite measurements of neutrophil-associated mediators in the lung correlating with RSV disease severity ([ 5 ][5]). Neutrophils have been shown to exacerbate epithelial cell damage but reduce viral titers in RSV infection in vitro, demonstrating how their presence can alter the course of the infection once it has commenced ([ 6 ][6]). Furthermore, neutrophils express most Toll-like receptors ([ 7 ][7]), which recognize pathogens, and they have been shown to respond to other single-stranded RNA viruses, such as influenza A virus ([ 8 ][8]). Thus, it is likely that neutrophils can play an active part in immune responses to other viral infections, including RSV. The timing of neutrophil presence in tissues, as well as their activation status, appears to be key. It has been demonstrated that depletion of nonactivated neutrophils before infection and thereafter, or enhancement after infection, does not worsen RSV outcomes in mice ([ 9 ][9]). Habibi et al. inoculated 58 healthy adults with RSV and assessed the preinfection transcriptional landscape of their nasal mucosa, identifying a specific inflammatory milieu in those who developed symptomatic RSV infection. In mouse models, preinfection expansion of lung neutrophil numbers with C-X-C motif chemokine ligand 1 (CXCL1) led to increased RSV infection–associated weight loss, which was partially rescued by blocking neutrophil recruitment to the lung. This suggests that an aberrant inflammatory milieu created by activated neutrophils is necessary to drive symptomatic RSV infection. This is supported by the finding of higher preinoculation levels of the neutrophil-associated proteases lipocalin-2 (LCN2) and myeloperoxidase (MPO) in the nasal mucosa of the individuals who developed RSV infection. Moreover, CXCL1 enhanced MPO production in mice, beyond the levels seen in RSV infection alone, suggesting that CXCL1 per se was altering the lung niche. ![Figure][10] Mucosal niches The presence of inflammatory mediators such as the neutrophil chemokine interleukin-17 (IL-17) and the neutrophil-associated proteases lipocalin-2 (LCN2) and myeloperoxidase (MPO) in the nasal mucosa of adults is associated with symptomatic respiratory syncytial virus (RSV) infection. Dissecting the mechanisms and immune responses that also allow asymptomatic infection and viral shedding is an important future aim. GRAPHIC: A. KITTERMAN/ SCIENCE While the timing of the inflammatory milieu appears to be important in allowing the establishment of a symptomatic RSV infection, the dynamic changes in the immune responses recorded in the cohort by Habibi et al. are also insightful. Those who developed RSV infection had lower intranasal levels of the archetypal “cytokine storm” cytokines, interleukin-1β (IL-1β), IL-10, and IL-6, in the presymptomatic phase of the infection. This finding emphasizes that immune responses are dynamic and that snapshots in disease processes may be misleading, especially when cross-talk between innate and adaptive immune responses is being ascertained. Furthermore, although an increased preinfection IL-17 level in nasal mucosa was associated with RSV infection, this cytokine was diminished during the incubation period in these people, again underpinning the importance of the timing of these responses in dictating outcomes. The role of IL-17 as an indirect neutrophil chemoattractant is established, however, the exact source of this cytokine in the nasal mucosa was not determined by Habibi et al. Both innate (e.g., γδ T cells) and adaptive (e.g., CD4+ T cells) lymphocytes have been shown to be the predominant producers of IL-17 ([ 10 ][11]), and airway epithelial cells express the IL-17 receptor. A role for IL-17 in immune responses to bacterial infection has been shown ([ 11 ][12]). Yet, whether IL-17 (unlike its close relative IL-22) has a role in epithelial homeostasis remains unclear. Further studies to determine whether IL-17 plays an active role in mucosal homeostasis and in creating an RSV-permissive milieu is warranted, especially as it could allow patient risk stratification. The capacity to determine the susceptibility to viral infection on an individual level has never been so attractive, given the global impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Undoubtedly, a number of similarities can be drawn between the viral illnesses induced by RSV and SARS-CoV-2. Both of these enucleated RNA viruses cause a more severe infection in men, patients with underlying immunosuppression, and those with chronic cardiovascular disease ([ 12 ][13], [ 13 ][14]). However, the age distribution of the severe spectrum of disease is somewhat different. Although both viruses can severely affect older people, SARS-CoV-2 does not appear to be as pathogenic in younger children, albeit infants are still at risk ([ 14 ][15], [ 15 ][16]). Whether the findings of Habibi et al. therefore apply to other respiratory viruses, or indeed other age groups, remains to be elucidated. Much of our understanding of immune responses to pathogens, including viral pathogens, has been dissected during infection stages. From a population perspective, however, prevention and risk stratification remain the cornerstone for improving outcomes, whether from established and endemic pathogens such as influenza viruses and RSV, or from emerging pathogens such as SARS-CoV-2. This study also identified a subgroup of people who developed asymptomatic RSV replication. Dissecting the mechanisms and immune responses that also allow this outcome would greatly enhance our capacity to control the spread of viral pathogens on a global scale. The findings of Habibi et al. provide a strong start to further our understanding of how the immune landscape before an insult is just as important in shaping outcomes as the responses to the pathogen itself (see the figure). It is a reminder too, of the dynamic complexity of the immune system, and of the work that lies ahead. 1. [↵][17]1. P. L. Acosta, 2. M. T. Caballero, 3. F. P. Polack , Clin. Vaccine Immunol. 23, 189 (2015). [OpenUrl][18] 2. [↵][19]1. W. P. Glezen, 2. L. H. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/298083
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Ananda S. Mirchandani,Sarah R. Walmsley. Making a bed for viral infections[J]. Science,2020.
APA	Ananda S. Mirchandani,&Sarah R. Walmsley.(2020).Making a bed for viral infections.Science.
MLA	Ananda S. Mirchandani,et al."Making a bed for viral infections".Science (2020).