Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection

doi:10.1126/science.aba9301

GSTDTAP > 气候变化

DOI	10.1126/science.aba9301
	Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection
	Maximillian S. Habibi; Ryan S. Thwaites; Meiping Chang; Agnieszka Jozwik; Allan Paras; Freja Kirsebom; Augusto Varese; Amber Owen; Leah Cuthbertson; Phillip James; Tanushree Tunstall; David Nickle; Trevor T. Hansel; Miriam F. Moffatt; Cecilia Johansson; Christopher Chiu; Peter J. M. Openshaw
	2020-10-09
发表期刊	Science
出版年	2020
英文摘要	Why some individuals come down with a cold in any given year, whereas others are spared, is poorly understood. Habibi et al. exposed volunteers to respiratory syncytial virus (RSV), one of the pathogens responsible for the common cold, and then followed them over the ensuing 2 weeks (see the Perspective by Mirchandani and Walmsley). The main factor distinguishing the infected from the noninfected was that the former showed signs of airway neutrophil activation before exposure to RSV. Conversely, protected individuals showed enhanced interleukin-17 signaling soon after virus inoculation. Similarly, mice pretreated with a neutrophil chemoattractant were more susceptible to RSV infection and CD8+ T cell–driven disease. Neutrophil proteases, which can modulate cytokine activity, may explain the disparity and could provide therapeutic targets for RSV and other respiratory infections. Science , this issue p. [eaba9301][1]; see also p. [166][2] ### INTRODUCTION Even with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood. ### RATIONALE We reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection. ### RESULTS After nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient boost in mucosal markers of innate immune activation for several days after viral administration and no subsequent viral replication. In mice, chemokine-induced neutrophil recruitment to the airway before viral exposure transiently enhanced viral replication immediately after inoculation. As with human subjects, this was associated with decreased expression of some innate mediators in the respiratory tract, which was then followed by enhanced disease driven by CD8+ T cells. ### CONCLUSION Although reinfection with a respiratory virus can be partially explained by the waning of antibody titers and T cell numbers, neutrophilic inflammation in the airway at the time of pathogen exposure also predisposes individuals to symptomatic infection. After exposure, the response of the mucosa diverges: A mild and transient increase in nasal inflammatory mediators is accompanied by termination of viral infection, whereas failure to mount this response is followed by viral success. The state of innate immune preparedness of the respiratory mucosa is thus a major determinant of susceptibility to viral challenge. Our results show the importance of understanding the mucosal microenvironment in studies of respiratory infection and highlight targets for local intervention, which may enhance protection against a range of respiratory pathogens. ![Figure][3] Mucosal neutrophilic inflammation before viral exposure inhibits the early type-17 inflammatory response that would otherwise abort infection. Airway neutrophil activation is predictive of subsequent symptomatic RSV infection and disease-associated influx of CD8+ T cells. During the presymptomatic phase, enhanced cytokine secretion (particularly of IL-17 and associated mediators) is associated with protection from RSV infection. GRAPHICS: N. CARY/ SCIENCE The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17– and tumor necrosis factor–related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure. [1]: /lookup/doi/10.1126/science.aba9301 [2]: /lookup/doi/10.1126/science.abe3685 [3]: pending:yes
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/298093
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Maximillian S. Habibi,Ryan S. Thwaites,Meiping Chang,et al. Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection[J]. Science,2020.
APA	Maximillian S. Habibi.,Ryan S. Thwaites.,Meiping Chang.,Agnieszka Jozwik.,Allan Paras.,...&Peter J. M. Openshaw.(2020).Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection.Science.
MLA	Maximillian S. Habibi,et al."Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection".Science (2020).