Virology 297, 1–7 (2002) doi:10.1006/viro.2002.1431 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector MINIREVIEW Respiratory Syncytial Virus Immunobiology and Pathogenesis Barney S. Graham,1 John A. Rutigliano, and Teresa R. Johnson Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3017 Received February 22, 2002; accepted February 21, 2002 Respiratory syncytial virus (RSV) is a pneumovirus in though underlying asthma and chronic bronchitis can be the family Paramyxoviridae. It is a pleomorphic envel- exacerbated during infection. However, in the institution- oped virus about 150 nm in diameter, transmitted by alized elderly, disease can be severe and in some stud- large particle aerosol and fomites, resulting in yearly ies has been associated with as much excess mortality epidemics ofrespiratory disease. RSV infectsnearly 70% as influenza (Falsey et al., 1995). The pathology is less of infants in their first year of life and everyone by age distinctive in this setting and is often complicated by three (Glezen and Denny, 1973). Reinfection is common. chronic lung disease, heart failure, and bacterial super- About 50% of children infected in the first year of life are infection. Therefore, it is difficult to ascribe disease reinfected in the second year of life, and everyone is pathogenesis to a direct manifestation of virus-mediated reinfected every two to three years throughout life. cytopathology and virus-induced inflammation, or to ex- RSV disease syndromes. There are several distinct acerbation ofunderlying conditions. disease syndromes associated with RSV infection. While RSV infection is associated with high mortality in pa- most infants have mild disease, about 5% of those less tients with immunodeficiency. This is particularly true in than one year ofage require hospitalization. The peak the setting ofsevere combined immunodeficiencydis- hospitalization rate is in infants between 2 and 3 months ease (Fishaut et al., 1980), and in patients following ofage. Those with bronchopulmonary dysplasia and allogenic bone marrow (Hertz et al., 1989) or lung trans- congenital heart disease are at greatest risk, but most plantation (Krinzman et al., 1998). Solid organ transplant hospitalized children have no apparent underlying con- recipients, patients with malignancies, or persons with dition. The virus infects both ciliated and nonciliated other selected immune deficiencies have milder disease. cells in small (75–300 ␮m in diameter) airways, resulting The disease syndrome is a giant cell pneumonia with in a bronchiolitis characterized clinically by wheezing. widespread syncytium formation in epithelial cells, pre- Bronchoalveolar lavage (BAL) reveals a predominance of sumably a direct result ofvirus-induced cytopathology. polymorphonuclear leukocytes in respiratory secretions. Finally, RSV has a legacy ofvaccine-enhanced dis- However, tissue sections reveal a predominance oflym- ease. Four studies using a Formalin-inactivated, alum- phocytes in the peribronchiolar and perivascular spaces, precipitated whole virus vaccine (FI-RSV) were per- and small airways containing fibrin, mucus, and a mix- formed in children in the mid-1960s. Vaccine-induced ture ofsloughed epithelial cells and inflammatory cells. immune responses did not protect against subsequent In addition, RSV infects the alveolar epithelium, particu- natural infection, and disease severity was increased. larly Type 1 alveolar pneumocytes. This component of Among vaccinated children in the youngest age group, RSV pathology is underappreciated despite signs of 80% required hospitalization and some died (Kim et al., lower airway disease such as hypoxia that are com- 1969). This tragedy has motivated extensive study of monly found even in asymptomatic patients. disease pathogenesis in animal models over the last 25 Most normal children and adults experience mild up- years and led to the current paradigms that guide vac- per respiratory disease during reinfection with RSV, al- cine development and approaches to therapy. Serological studies in the children with RSV vaccine- enhanced illness showed poor neutralizing activity and 1 To whom correspondence and reprint requests should be addressed fusion-inhibiting activity in the antibody response to vac- at Building 40, Room 2502, 40 Convent Drive, MSC-3017, Bethesda, MD cine (Murphy et al., 1986, 1988), perhaps explaining the 20892-3017. Fax: (301) 480-2771. E-mail: [email protected]. lack of protection from natural infection. However, this 1 0042-6822/02 2 MINIREVIEW does not explain why illness was enhanced. They were sponses induced by RSV has distinct advantages be- also found to have high lymphoproliferative responses to cause ofthe wealth ofimmunological reagents and ge- RSV antigens (Kim et al., 1976) and a relatively high netically defined strains available. frequency of eosinophilia (Chin et al., 1969). Tissue sec- The Th2 hypothesis of RSV pathogenesis. In mice tions from the children who died demonstrate a typical immunized with FI-RSV and then challenged with RSV, distribution ofinflammationaround the small airways, one sees an inflammatory infiltrate composed of mono- but the composition of the infiltrate is different from cytes, lymphocytes, and numerous eosinophils demon- primary infection with an abundance of eosinophils and strated by their large cytoplasmic granules (Fig. 2C). This neutrophils in addition to mononuclear cells (Fig. 1). is reminiscent ofthe pathology seen in infantswith There was no evidence ofextensive, virus-induced cyto- FI-RSV vaccine-enhanced disease. The pathology is de- pathology. These observations suggested a virus-spe- pendent on CD4ϩ T cells. Lung extracts from mice chal- cific cell-mediated immune process was responsible for lenged with RSV after FI-RSV immunization show a dom- the enhanced illness. inant IL-4 mRNA pattern, whereas the dominant re- The findings in animal models that relate to the syn- sponse in mice immunized with live RSV given drome ofthe RSV vaccine-enhanced illness will be re- intramuscularly or intranasally is IFN-␥ (Graham et al., viewed. In particular, how the current understanding of 1993). These findings suggested that an aberrant CD4ϩ vaccine-enhanced illness pathogenesis can inform our Th2 response may be the basis for the RSV vaccine- understanding ofdisease associated with primary RSV enhanced illness syndrome. The mechanism by which infection will be addressed. The central focus will be on this occurs is still controversial as discussed below. how prior antigen exposure can induce aberrant adap- When the RSV vaccine-enhanced illness was associ- tive immune responses, and how those responses can ated with CD4ϩ Th2 responses, it promoted an interest in cause disease. The pathogenesis ofRSV in the institu- the role ofType 2 cytokines in the pathogenesis of tionalized elderly or immunocompromised patients will primary RSV infection. Primary RSV infection is associ- not be discussed in detail. ated with wheezing, and severe disease requiring hos- Murine model of RSV. A murine model ofRSV has been pitalization is associated with a higher incidence ofsub- used to study the pathogenesis ofvaccine-enhanced sequent childhood asthma (Sigurs et al., 1995). Some illness. Most work has been done in BALB/c mice that groups have shown RSV-specific IgE can be found in are relatively permissive to RSV replication compared to respiratory secretions ofchildren with severe disease other strains. However, the murine model has some (Welliver et al., 1981), and others have shown an increase limitations that should be recognized in the interpretation ofeosinophilic cationic protein (Garofalo et al., 1992), ofresults. The infectionis initiated in anesthetized mice findings consistent with Type 2 cytokine activity. How- by intranasal inoculation ofa large volume ofhigh titer ever, others have shown children with severe disease virus. The inoculum is aspirated directly into lung. Virus have a dominant IFN-␥ response without direct evidence replication occurs primarily in the alveolar parenchyma ofthe classical Type 2 cytokines IL-4 or IL-5 (Branden- in Type 1 pneumocytes (Figs. 2A and 2B). There is evi- burg et al., 2000). dence ofbronchiolar cytopathology in some strains, and How is the RSV-specific Th2 response induced in FI- immune infiltration occurs around arterioles and bron- RSV vaccine-enhanced illness? The RSV G glycoprotein chioles, as well as in the alveolar interstitium. Illness is is part ofthe envelope spike on the surfaceofthe virus mediated predominantly by the T cell response to infec- and is the putative attachment protein. G has a number tion (Graham et al., 1991b). Therefore, the murine model ofinteresting structural features.It is a type II integral provides a good system to ask how the composition of membrane protein anchored at the amino terminus. the inflammatory infiltrate is regulated in response to About 50% ofthe protein produced is secreted fromthe RSV infection. It is not a good model for studying disease infected cell because of an alternative initiation codon in caused by virus-induced cytopathology in airway epithe- the transmembrane domain (Roberts et al., 1994). About lium. It is also not a good system for studying the kinetics 60% ofthe molecular weight is O-glycosylation, and there ofprimary RSV infectionor the role ofearly events me- is a high serine