Types of rsv virus

This age group would likely benefit from maternal vaccination or neutralizing mAbs administered at birth. The main goal of maternal vaccination is to boost neutralizing RSV titers and thereby transplacental antibody transfer. However, the optimal timing for vaccination 2nd or 3rd trimester and the durability of protection in the infant need to be defined. This coupled with the high prevalence of hypergammaglobulinemia in low- and middle-income countries, associated with HIV or malaria, which impairs transplacental antibody transfer, suggest the need for high maternal antibody titers to compete for transfer.

The limited data available in pregnant women are mostly derived from influenza surveillance studies with rates of RSV infection varying from 0. A number of RSV maternal vaccines are currently in clinical development Table 1. Based on the experience of the formalin-inactivated-RSV vaccine, within this age group those who are naive at the time of vaccination might be at risk of ERD with protein vaccines.

This target population would likely benefit most from live-attenuated or vectored vaccines. This population might benefit most from adjuvanted vaccines. The ideal vaccine should be able to prevent severe disease and limit transmission, but the lack of a standard definition of severe disease or precise markers to assess severity in infants has been a barrier for vaccine development.

Clinical endpoints that define a successful vaccine might be different depending on the target population. However, a standardized protective threshold has not been defined yet. Newer systems biology approaches are helping to define the optimal correlates of protection, which are complex and depend on multiple factors, rather than a single cutoff value in antibody assays, and will need to be adjusted to each target population.

Other cocorrelates of protection may include, F-specific epitope antibodies, mucosal IgA, interferon responses, antibody-dependent cell-mediated cytotoxicity and cell-mediated immunity. The lack of an ideal animal model has also slowed down RSV vaccine development.

Human challenge models mostly reproduce upper but not LRTI, limiting the generalizability of the results or the ability to assess the impact of vaccines on disease severity. Implementing robust multiplex polymerase chain reaction-based surveillance platforms could help to assess the impact of interventions on the burden of RSV disease, to identify possible escape mutants, or the contribution of other respiratory viruses causing RSV-like illnesses.

The most effective approach to protect young infants and children from severe RSV infection may be a combined strategy using passive and active immunization: either maternal vaccination with stabilized pre-F or virus-like particles containing the F protein or mAb against pre-F at birth; followed by pediatric active immunization with a live vaccine, either attenuated RSV or the pre-F protein expressed from a virus vector.

The recombinant adjuvanted RSV post-F nanoparticle vaccine is the most advanced vaccine in clinical development. Results from a phase-3 clinical trial that enrolled pregnant women on the third trimester demonstrated a decrease in RSV hospitalizations in the offspring; however, the study did not meet the primary endpoint defined as prevention of medically significant RSV LRTI. The potential approval of this vaccine is being evaluated. These vaccines consist of purified, adjuvanted proteins and use stabilized pre-F as the main antigen with promising results.

Other subunit vaccines in clinical or preclinical stages are using SH or G as main vaccine antigens. There are 5 vector-based vaccines in clinical development. The first 4 use adenovirus as a vector, while the other uses a modified vaccinia Ankara virus. Two of them are intended for use in pediatric seronegative patients.

LAVs represent an attractive alternative for older infants and young children. LAVs are administered intranasally and are able to elicit broad innate, humoral and cellular responses and replicate in the respiratory tract despite the presence of maternal antibodies.

Importantly, these vaccines have not been associated with ERD and are considered safer in infants. The use of reverse genetics has made possible to incorporate different mutations in the viral genome, making LAV sufficiently immunogenic and, except for rhinorrhea, not associated with adverse events.

During the study, RSV type B was the predominant circulating strain and developed escape mutations that conferred resistance to this mAb. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Disease or Condition of the Week. Section Navigation. Facebook Twitter LinkedIn Syndicate.

Minus Related Pages. Wash Your Hands Often. Cover Your Cough and Sneeze. Avoid Sharing When Sick. Links with this icon indicate that you are leaving the CDC website. This clearly illustrates that RSV is the most frequent cause of hospitalizations for bronchiolitis, but it also underscores that other viruses can cause bronchiolitis, including rhinovirus, hMPV, corona, parainfluenza and influenza viruses, bocavirus and AdV [ 39 , 53 , 54 , 56 , 57 , 59 ].

The proportion with a discharge diagnosis of bronchiolitis is similar in patients with RSV, hMPV or rhinovirus infections [ 52 , 60 ]. It should be noted that, while RSV generally remains the most frequent viral agent in LRTI and particularly bronchiolitis severe enough to require hospitalizations, rhinovirus is emerging as the most frequent cause of acute respiratory illness in general and LRTI in particular in prospective community-based studies from Wisconsin, Western Australia, and the UK [ 17 , 41 , 62 ].

Two of these cohorts consisted of children at high risk of atopy, and atopy has been shown to predispose to rhinovirus-associated wheezy respiratory tract disease [ 63 , 64 ]. Consequently, these cohorts may not be fully representative of the general population.

However, in unselected cohorts, picornaviruses which include rhinovirus also were identified as the most frequent cause of acute respiratory episodes, including LRTI [ 62 ]. Well established host risk factors for hospitalizations are preterm birth, chronic lung disease CLD of prematurity, and hemodynamically significant congenital heart disease CHD [ 65 — 75 ] Table 2.

Infants with congenital or acquired immunodeficiencies are also at risk of severe disease [ 69 , 77 ]. Premature birth and underlying medical conditions not only increase the risk of hospitalization, but also of more severe clinical disease manifestations, as indicated by more frequent requirement for mechanical ventilation, admission to the ICU, longer duration of hospitalization, and increased mortality [ 46 , 58 , 69 , 70 ]. In spite of the increased hospitalization risk associated with the above risk factors, at least half of all infants hospitalized with RSV infection are previously healthy without any of these established medical risk factors [ 42 , 65 ].

In the USA, ancestry or ethnicity and health insurance status also influence the hospitalization rates. As already mentioned, Alaska Native and American Indian infants are hospitalized due to RSV infection much more frequently than the general US infant population [ 44 , 47 ].

However, in a Tennessee Medicaid cohort, European ancestry was an independent risk factor for hospitalization due to RSV infection [ 65 ]. Others also found that non-Hispanic patients of European extraction were more likely to be treated as inpatients than as outpatients, to have private health insurance and to be younger than 6 months of age [ 42 ].

Only younger age and prematurity were identified as independent risk factors in this investigation. Among hospitalized patients, African ancestry was protective, with black infants showing higher oxygen saturation and a shorter duration of hospitalization [ 79 ]. Most of these risk factors have been reported quite consistently in numerous studies, both in term and preterm infants; however, only a few of them are generally identified in each individual study population, and even analyses of quite similar cohorts e.

There are even studies that are unable to detect a significant association of disease severity or hospitalization with any of these factors [ 88 ]. This suggests that other host factors play a primary role in such cohorts. These include the host immune response to RSV infection and the genetic susceptibility of the host, possibly including an atopic predisposition.

These aspects will be discussed in greater length in later sections. To date, only two protective factors have been identified. One is breast feeding [ 40 , 42 , 81 , 83 , 85 ]. The other is the level of maternally derived antibodies, which are present in essentially all neonates, though at vastly varying titers [ 89 , 90 ]. In numerous studies, the titers of maternally derived neutralizing antibodies are inversely associated with RSV infection overall [ 91 , 92 ], or with the severity of RSV disease [ 16 , 93 — 96 ], although at least one study did not find the relationship to be linear [ 78 ].

Whether viral load correlates with disease severity remains controversial since some analyses of hospitalized children show a significant association [ 97 — ], whereas others do not [ , ]. The method used for viral quantification does not account for these differences since both quantitative RT-PCR and plaque assays have yielded positive as well as negative results.

In ambulatory subjects with a first episode of RSV infection, there was no significant difference in viral load between patients with bronchiolitis and those experiencing only URTI [ 11 ]. In contrast, the results from another prospectively followed birth cohort indicate a moderate correlation between viral load and disease severity in patients infected with RSV alone, but not in those co-infected with another respiratory virus [ ]. However, the authors point out that the viral loads in these outpatient episodes were similar to those they had previously found in infants hospitalized with severe RSV LRTI, indicating that viral load is not the only factor determining disease severity.

Several investigations showed RSV subtype A to be associated with more severe disease compared to subtype B, and this risk persisted after adjusting for age, prematurity, and other risk factors [ 3 , 4 , 75 , ]. Conversely, a greater severity in subtype B compared with subtype A infections has only been reported in one study [ ]. To add to the confusion, other studies were unable to detect a significant association at all [ 98 , , ].

Clade or genotype may be a more important determinant of disease severity than subtype [ 5 , , — ], although a significant association with genotype is not consistently seen either [ ]. These discrepancies are likely due to the fact that several different strains generally co-circulate in any given RSV season [ 5 , 6 ], and some of the studies may simply lack the statistical power to detect significant differences in disease severity between individual RSV genotypes. This supports the finding of greater disease severity in subtype A compared to subtype B infections.

Studies in cell culture and in vivo models also provide clear evidence that individual RSV type A isolates differ substantially in their infectivity, virulence, and immunopathogenicity [ — ]. Together, these findings strongly suggest that viral characteristics—in interaction with host susceptibility factors—determine disease phenotype, including severity. Several analyses show simultaneous infection with more than one respiratory virus to be associated with increased disease severity in infants [ 39 , 60 , — ], although this is not a consistent finding [ 53 , 57 ].

In a Dutch community-based study, viral load was significantly associated with disease severity when RSV was the only pathogen detected, but such an association was not evident in infants co-infected with RSV and another respiratory virus [ ].

In this study, it was decided to designate the viral agent that was present in higher quantities as the primary pathogen. It remains to be determined, however, whether this is a valid assumption. As a matter of fact, a detailed analysis of clinical characteristics in co-infections compared to single infections showed RSV to dictate the prevalence and severity of clinical features such as obstructive airway disease and hypoxia as well as overall duration of hospitalization, regardless of whether the co-infection involved rhinovirus or adenovirus AdV [ ].

In contrast, dual infections involving rhinovirus in combination with AdV or influenza virus more often yielded significant differences in the prevalence of individual clinical characteristics. This suggests that simultaneous detection of two or more viruses by RT-PCR is not simply the reflection of lingering viral nucleic acids from a past infection, but truly reflects the simultaneous presence of two or more pathogens.

Other data suggest that the localization of the virus may also play a role. This raises the question of whether the viral agent detected in nasopharyngeal secretions NPS is necessarily the agent responsible for lower respiratory symptoms.

Viral etiologies of acute respiratory illness and bronchiolitis in hospitals and emergency departments. The management of acute bronchiolitis severe enough to require hospitalization largely consists of supportive care, such as nasal suction, nasogastric or intravenous fluids, supplemental oxygen, and nasogastric feeding.

Evidence in support of a meaningful effect of inhaled or systemic corticosteroids in the treatment of severe bronchiolitis is also lacking [ ], and their routine use is not recommended. The results of a recent randomized controlled trial suggest that the combination of nebulized epinephrine with high-dose oral corticosteroids reduced the hospital admission rate in infants presenting at the emergency department [ ].

There is considerable cause for concern over the high dose of dexamethasone that was used in this trial, and independent confirmation of the results should be obtained before adopting this approach. Also note that plasma cortisol levels were found to be significantly elevated in infants with mild bronchiolitis compared to healthy controls and were further elevated in patients with severe RSV bronchiolitis requiring hospitalization [ ]. There was also evidence that this endogenous cortisol production was associated with the suppression of cytokines that are considered to be key mediators of antiviral responses.

This strongly suggests that systemic corticosteroid treatment may not be advisable in severe RSV disease. Many infants experience recurrent wheezing episodes after hospitalization for bronchiolitis. However, inhaled corticosteroids during the acute phase of RSV bronchiolitis did not demonstrate prevention preventative effect on post-bronchiolitis wheezing [ , ]. Ribavirin is a broad-spectrum antiviral agent approved by the FDA for use in nebulized form in the treatment of infants and children with severe bronchiolitis.

The results of a meta-analysis indicate that it may be effective in reducing the duration of ventilation and length of hospitalization, but the available studies are too small and their quality is too variable to allow any firm conclusions [ ].

Current AAP guidelines do not recommend its routine use because of uncertainties regarding its effectiveness, concern over potential health risk for caregivers, and its high cost [ 27 ]. However, it may be considered in high-risk infants with severe disease [ 27 ]. Despite considerable evidence that concurrent bacterial infections in infants and children hospitalized for RSV-related illness are very infrequent, antibiotics are still often prescribed [ 31 , 34 , ].

Antibiotic therapy in randomized controlled trials has not been shown to result in improved outcome [ ] and its use should be carefully evaluated because of the potential risk of adverse events and the growing threat of bacterial antibiotic resistance.

In other words, a benefit—risk analysis should be performed in each case. In a mouse model, treatment with antibiotics for 15 days after RSV infection resulted in increased airway hyperresponsiveness AHR on the last day of treatment, but this was not seen after RSV infection alone or antibiotic treatment alone at this time point [ ].

In addition, antibiotic treatment interfered with the RSV-induced upregulation of pulmonary regulatory T cells Tregs and immunomodulatory cytokines that have been shown to play an important role in limiting the immunopathology of RSV infection in mice [ — ].

In summary, there is great variability in the management of acute bronchiolitis not only at the international level, but also within countries and even between centers [ 22 , ].

This reflects the lack of conclusive evidence that any of the therapies in current use for the treatment of bronchiolitis have a positive impact on disease outcome.

FDA approval was based on the results of two randomized clinical trials of prophylaxis with palivizumab [ , ]. The results of a number of observational studies confirm that palivizumab is effective in premature infants with or without CLD and in infants with hemodynamically significant CHD [ 58 , — ], although they also highlight that compliance with current recommendations for the dosing of palivizumab is suboptimal [ , ].

There is considerable variation in the actual RSV epidemic season within different regions or areas of the US.

In particular, the season is more difficult to predict and lasts longer in Florida, southwestern Alaska [ ], and the Pacific Northwest unpublished data. Consequently, there have been several attempts to develop models that predict which high-risk infants would benefit most from palivizumab prophylaxis [ 71 , , ]. In Canada, use of palivizumab according to the Canadian Risk-Scoring Tool [ ] in infants with a GA of 32—35 weeks has been shown to be cost-effective [ ] and convenient [ ].

It should be noted, however, that there may be another approach to improving the effectiveness of palivizumab and simultaneously reducing cost. Of course, this dosage regimen would have to be tested before being adopted, but it does have the potential for enormous cost savings. Reinfections with RSV are common throughout life, even though antigenic diversity among RSV strains is rather limited compared to other respiratory viruses, suggesting that protective immunity is incomplete and short-lived.

This is at least partly due to the fact that RSV, like other viruses, has developed numerous mechanisms to evade or subvert the host immune response [ ] Fig. The G protein, which together with the F protein is the only RSV antigen inducing neutralizing antibodies, is heavily glycosylated, and this has been shown to interfere with antibody recognition [ , ]. Another immune evasion mechanism involves the ability to produce the G protein not only in full-length membrane-bound, but also in a truncated secreted form Fig.

The secreted protein may act as a decoy for neutralizing antibodies [ ]. In addition, the central conserved region of the G protein contains a CX3C motif, which endows it with the ability to signal through the CX3CR1 receptor and to exert chemotactic activity similar to that of fractalkine CX3CL1.

Whether this interferes or enhances leukocyte recruitment to the infected lung in vivo is unclear from the available data [ ]. Similarly, human RSV G protein-specific T-cell lines produce interleukin IL -4 and IL, whereas the cytokine profile of F protein-specific T-cell lines is Th1-dominated and similar to that induced by live virus [ ].

This implies that the RSV G protein has the potential to downregulate cellular immune responses. There are also data suggesting that the G protein can downregulate inflammatory responses by antagonizing signaling through toll-like receptors TLRs [ , ]. Primary RSV infection most often occurs during the first few months of life.

While the immune system of neonates and young infants is capable of producing adult-like responses under certain conditions, both innate and adaptive immune responses are often characterized by quantitative or functional deficiencies [ ].

Compared to adults, macrophages from neonates and young infants and children frequently show markedly lower production of a variety of cytokines. This is at least in part due to the diminished expression of pathogen-associated pattern recognition receptors or their decreased upregulation upon activation. DC numbers are reduced in neonates compared to adults and differ in their subset distribution. They show signs of impairment in antigen presentation and T cell stimulation due to decreased expression of MHC class I and II and co-stimulatory molecules and reduced production of cytokines, in particular ILp The most striking characteristic of neonatal T cell responses is their extraordinary plasticity, ranging from relative unresponsiveness to stimuli that provoke strong responses in adult T cells to the capacity to generate adult-like responses if and when the appropriate stimuli are provided.

Neonatal B cell antibody production is often characterized by delayed onset, decreased peak titers, and diminished duration, although higher antibody titers to certain vaccines have been noted in some circumstances [ , ]. In addition, infant B cells show little evidence of somatic hypermutations after encounter of their cognate antigen [ ], resulting in lower affinity and decreased heterogeneity of the antibody repertoire [ ].

There is limited information on the normal human immune response to primary RSV infection. This is due to several factors.

For one, laboratory confirmation generally is sought only in the most severe cases that require hospitalization, which may not be representative of the milder disease seen in the vast majority of patients. In addition, primary RSV infection occurs at such a young age that sampling is generally limited to the nasal lavage or nasopharyngeal aspirates NPA routinely taken for diagnostic or therapeutic purposes and nonbronchoscopic BAL fluid obtained from mechanically ventilated patients. Therefore, much of the information currently available on the human immune response to RSV infection comes from experimental models.

The primary targets of RSV infection are bronchial and bronchiolar ECs, particularly those that are ciliated [ , ]. The most common in vitro models for the study of airway EC responses to RSV infection are immortalized respiratory epithelial cell lines. However, evidence is emerging that their responses to RSV infection differ substantially from those of primary airway ECs, including different kinetics of viral replication and lower viral titers, decreased cytotoxic responses and reduced production of pro-inflammatory cytokines compared to primary airway ECs [ ].

In addition, primary respiratory ECs retain the donor characteristics, i. Well-differentiated human airway epithelial cultures probably represent the most faithful in vitro model for the study of the interaction of RSV with host cells.

Primary human respiratory ECs, when cultured at an air—liquid interface, regrow into polarized pseudostratified airway epithelium that contains all the cell types and exhibits all the morphological and functional characteristics of normal respiratory epithelium, including mucus production, ciliary motion, and cytokine and chemokine production [ — ]. This model has been used to confirm that RSV infects the airway epithelium from the apical side only and targets almost exclusively ciliated epithelial cells [ , ], as already seen in autopsy studies and polarized epithelial cells [ , ].

Budding and release of the virus also occurs from the apical surface, with subsequent spread via ciliary motion [ ]. This results in patchy infection, suggesting that not all ciliated cells are susceptible to RSV infection. Although there is some disagreement over the extent of cytopathology induced by RSV infection, including syncytia formation [ , , ], it has been demonstrated that this model quite faithfully captures many of the features of severe RSV infection in human infants, including apoptosis and sloughing of ECs, mucus hypersecretion due to goblet cell hyperplasia or metaplasia, and the production of various chemokines and cytokines [ , ].

The RSV receptor has not yet been identified, but nucleolin has recently been identified as a promising candidate [ ]. The discrepancies may be related to the use of epithelial cell lines compared to primary human ECs, which show differential responses to infection with the same RSV strain [ ].

In addition, individual strains of RSV differ markedly in their ability to induce some of these cytokines and chemokines and [ , ], epithelial cells from different donors show marked variability in the cytokine and chemokine responses to infection with the same RSV strain [ ], and both constitutive production and upregulation following RSV infection are dependent on the localization of the epithelial cells in the airways [ , ].

Either in response to transient infection or to activating signals received from bronchial ECs [ , ], alveolar macrophages can further enhance the chemokine and cytokine release of bronchial ECs and can themselves contribute to their production [ , , ].

Animal models of human RSV disease include a variety of heterologous hosts that are only semi-permissive to infection with hRSV. They comprise chimpanzees, rhesus monkeys, sheep, cotton rats, guinea pigs, and mice [ ], with guinea pigs being somewhat unusual in that they develop persistent or even latent infection [ ], while there is as yet no clear evidence for persistence of RSV in humans.

The bovine model has the advantage over murine models that BRSV is a pathogen for calves and as such creates a disease that is in most ways identical to RSV in human children.

The clinical and pathological features of the bRSV model are described [ ]. The most widely used models of hRSV infections are inbred laboratory mouse strains, because of the ease of housing and handling them, the availability of a wide variety of transgenic and gene-deletion mice as well as immunological reagents for characterizing immunopathological pathways [ ].

However, they are at best a semi-permissive hosts, their lung anatomy is much simpler compared to humans, and the more obvious clinical signs of illness in mice are non-specific and include weight loss, lethargy, and ruffled fur. For comparison, adult humans can develop symptomatic infections with an inoculum of as little as 1, PFU [ ]. Peak viral titers in the airways or lungs of mice are seen 4—5 days after inoculation depending on the size of the inoculum and the virus becomes undetectable by plaque assay by day 7 or 8 postinfection [ , ].

Their induction is rapid and generally peaks early, although the individual mediators vary markedly in their kinetics and peak concentrations.

In addition, macrophage depletion significantly reduced the recruitment and activation of natural killer NK cells, but did not affect the recruitment of CD4 and CD8 T cells to the lungs. In addition, they play a central role in the activation of effector cells. The concerted action of chemokines and pro-inflammatory cytokines in the initial phases of RSV infection is associated with marked changes in the cellular composition of BAL fluid and lung tissue.

After inoculation of mice with hRSV, there is an early rise in the numbers of neutrophils cells in BAL and lungs [ , , , — ]. However, the magnitude and the kinetics of these changes vary widely between studies and also between mouse strains [ ].

NK cell activity reached a maximum on day 3 and was undetectable by day 8 [ ]. NK cells play an important role in viral clearance in the early phase of RSV infection [ ].

There are, however, experimental systems in which a small but significant increase in the number of eosinophils is observed in BAL and among isolated lung cells of RSV-infected mice [ — ]. In some systems, eosinophils also constitute a minor, but significant component of the lung infiltrate [ ]. Macrophages always are the major cell type in BAL of mice, and may be further upregulated by RSV infection, although some noted the largest increases by day 6 and not in the early phase [ ].

The importance of some of these chemoattractants in the recruitment of effector cells to the lung has been confirmed through blockade or deletion of specific chemokines or chemokine receptors. However, it is equally evident that both T lymphocyte subsets contribute to the pathology of RSV infection since clinical illness is markedly reduced after depletion of either CD4 or CD8 T cells and is essentially absent in mice depleted of both [ ].

Conversely, the transfer of RSV-specific CTL results in rapid viral clearance in immunocompromised irradiated and immunocompetent animals, with the rate of viral clearance depending on the number of transferred cells [ ]. At the same time, recipients of high numbers of RSV-specific CTL developed weight loss, ruffled fur, and respiratory distress in association with increased pulmonary inflammation.

At the highest CTL numbers, almost all recipients died. From the currently available data, it is clear that there is an early influx of both conventional and plasmacytoid DCs cDCs and pDCs into the lungs and lung-draining lymph nodes of RSV-infected mice [ — ].

However, the kinetics of this influx and the persistence of individual DC subsets in the lungs remain highly controversial. Some data indicate that the increase in pDC numbers is sustained until at least day 21 postinfection [ , ]. In marked contrast, other investigators report only a transient early increase in pDCs, whereas cDCs remained elevated until at least day 18 in the lung, though they had returned to baseline levels on day 14 in the lymph nodes [ ].

Depletion of pDCs results in decreased viral clearance, enhanced inflammation in the airways and lung parenchyma, increased mucus production and prolonged RSV-induced AHR [ , ]. This indicates that pDCs play an essential role in limiting viral replication and regulating inflammatory responses and changes in lung function.

While a major function of pDCs is to produce the antiviral type I IFNs, cDCs are vital for antigen presentation and inducing the appropriate polarization of the ensuing T cell response. NK cells are the major source of this cytokine in the early phase of infection [ , , ].

In addition, they exhibit elevated Th2 cytokine levels IL-4 and IL , tissue eosinophil infiltration, and IgE production [ ], although reportedly there was no effect of NK cell depletion on the RSV-induced cytokine profile in another study [ ]. Mice incapable of responding to IFN type I or type II because of STAT1 deficiency had enhanced disease with earlier peak viral load, greater inflammatory infiltrate that contained neutrophils and eosinophils instead of the predominantly lymphocytic infiltrate of wild-type mice.

Nonetheless, comparison of mouse strains that differ in their susceptibility to RSV-induced AHR led to the identification of IL as an important mediator of protection from pulmonary inflammation, mucus production, and AHR in B6 mice, and this was confirmed through the use of neutralizing anti-IL antibodies [ ].

However, the generation of virus-specific CTL and their functional activities were not affected by ILp40 deficiency. When mice were infected with a recombinant RSV expressing murine IL, viral clearance was enhanced in association with increased recruitment of NK cells, but weight loss was also much more pronounced [ ].

All of the above studies were conducted in adult mice. Mice infected as weanlings 3 weeks old developed AHR upon primary infection, but not when reinfected 5 weeks later despite evidence of increased airway inflammation.

The role of IL has been investigated primarily in the context of RSV-induced AHR, because of the central role of this cytokine in allergic inflammatory airway disease [ ]. There is strong evidence that individual laboratory strains and clinical isolates of RSV differ markedly in their ability to upregulate IL production in the lungs of mice [ — ].

They also showed differential induction of AHR, but this did not appear to be directly correlated with the pulmonary levels of IL This was associated with a significant increase in IL in lung supernatants and decrease in mucus production, which has been observed in other studies of RSV infection in mice [ ] and is consistent with the known ability of IL to induce goblet cell hyperplasia and mucus production [ ]. It does not explain, however, why other researchers did not see a reduction in RSV-induced AHR after inhibition of IL signaling or in ILdeficient mice, even though the strain they used greatly upregulated IL levels in the lung [ ].

The regulatory cytokine IL is upregulated in the airways and lung parenchyma of RSV-infected mice [ , ]. There is consensus, however, that the absence of IL signaling either due to genetic IL deficiency or IL receptor ILR blockade increases disease severity and inflammation. Specifically, it enhances the recruitment of monocytes, neutrophils and effector lymphocytes [ , ]. Indeed, very similar effects have been observed following the depletion of Tregs.

Whether this accelerates viral clearance is somewhat controversial. The results from the hybrid CB6F1 model further suggest that Tregs also play a role in moderating disparities in epitope dominance [ ].

As a result, Tregs are central in diminishing disease severity, including overall morbidity and weight loss [ , , ]. Interestingly, the depletion of Tregs in CB6F1 mice was associated with increased pulmonary levels of IL [ ], suggesting that IL alone is not sufficient for suppression of the RSV-induced immunopathology and that the effects of IL deficiency or ILR blockade are largely mediated by the failure to maintain adequate numbers of Tregs [ ].

While weight loss was even more dramatic in these mice, the overall results were similar, with the notable difference that viral load was decreased in Treg depleted mice [ ]. Conversely, increasing the number of Tregs via IL-2 immune complexes decreased inflammation and accelerated recovery. Interestingly, the Tregs in the lung parenchyma and airways of RSV-infected mice were found to express granzyme B, and this was found to be essential for the regulatory function of Tregs in RSV infection.

IL designates a group of cytokines that play a central role in adaptive immune responses to bacteria and fungi, but are also able to induce pro-inflammatory responses. There also was an increase in the transcript levels of IL-6 and ILp19, which are involved in the differentiation and maintenance of Th17 cells.

Furthermore, IL was shown to upregulate mucus production and to inhibit CD8 T cell effector functions, thereby reducing viral clearance. In this study, it was shown that signaling through the receptor of the complement anaphylatoxin C3a C3aR induces production of the tachykinins, substance P and hemokinin This was associated with markedly reduced pulmonary inflammation and a different composition of the inflammatory infiltrate decreased neutrophils, and increased macrophages and lymphocytes compared to wild-type controls.

Prophylactic blockade of NK-1R signaling was accompanied by reduced airway lymphocytic inflammation. In addition, it prevented the RSV-induced development of airway smooth muscle responsiveness to electric field stimulation. This suggests that substance P plays a dual role in the development of AHR during acute RSV infection, namely proinflammatory and neurogenic. Others found both prophylactic and therapeutic neutralization of substance P to be effective in reducing lung inflammation, and addition of anti-F protein antibodies did not significantly enhance this effect [ ].

The involvement of substance P in neurogenic inflammation is supported by a variety of studies in RSV-infected rats and other animals [ ]. The results from these experiments implicate the RSV-induced upregulation of nerve growth factor NGF and its receptors and the subsequent increase in the expression of NK-1R at least at the transcript level along with functional interactions between substance P-containing neurons and mast cells and their inflammatory mediators in the exaggerated neurogenic inflammation [ ].

The role of cytokines and chemokines is summarized in Table 4. The F and G proteins are the dominant RSV antigens containing epitopes that induce neutralizing antibodies. In the absence of humoral responses, viral clearance is not affected, but lung inflammation is more severe and viral replication and clinical illness after rechallenge with RSV are more pronounced compared to animals with an intact B cell compartment [ ]. Whether elaboration of RSV-specific antibodies or administration of passive antibodies suppresses viral replication in the lower respiratory tract only or also in the upper respiratory tract appears to depend on the specific animal model [ , ].

Some experimental mice infected with RSV develop RSV-specific IgE antibodies [ ], although this was not observed in a similar experimental system [ ]. Guinea pigs are capable of producing IgE antibodies. Indeed, in neonatally infected mice, virus-specific IgE was shown to play a central role in mediating enhanced AHR upon reinfection [ ].

Many of the chemokines that are present early in the course of RSV infection in the lungs of mice have also been detected in non-bronchoscopic BAL fluid, tracheal aspirates, or nasal secretions obtained from severely RSV-infected infants, and are found at higher levels compared to controls. Fewer data are available on their role in less severe RSV infection not requiring hospitalization, but some of them are also detected in nasal secretions of infants and children with URTI [ , , ] and experimentally infected adults [ , ].