T Helper 1 Background Protects Against Airway Hyperresponsiveness and Inflammation in Guinea Pigs With Persistent Respiratory Syncytial Virus Infection

Abstract

A family history of allergy has been implicated in children who develop post-bronchiolitis wheezing and asthma. In a guinea pig model of respiratory syncytial virus (RSV) lung infection, we evaluated the role of host Th1 background (either genetic or induced) on the development of a persistent infection, nonspecific airway hyperresponsiveness (AHR) and airway inflammation. Allergy resistant/T helper 1 (Th1)-skewed strain 2 guinea pigs (STR2) and cytosine phosphate guanine oligodeoxynucleotides (CpG-ODN) (Th1 stimuli) pretreated Cam Hartley guinea pigs (CH) were inoculated with RSV and compared with virus-inoculated allergysusceptible/Th2-skewed CHs and to sham-inoculated STR2 and CH, 60 d post-inoculation. We measured titers of intrapulmonary RSV, lung interferon (IFN)-␥ and interleukin (IL)-5 mRNA expression, AHR and airway T cells and eosinophils. All virus-inoculated groups of animals showed evidence of persistent RSV lung infection; however, Th2-skewed guinea pigs had virus-associated AHR and significantly greater levels of airway T cells and eosinophils. In conclusion, RSV can establish persistent infection of the guinea pig lung regardless of host Th1/Th2 background; however; a host Th1 background limits the extent of virus-associated AHR and airway inflammation. Heterogeneity in virus-host interactions may be relevant to understanding why some children hospitalized for RSV bronchiolitis go on to develop recurrent wheezing/asthma symptoms. R SV is the most common cause of acute bronchiolitis, the leading cause of infant hospitalization in the developed world (1). A proportion of children hospitalized with acute bronchiolitis develop sequelae of recurrent wheezing and features of asthma for which allergic mechanisms (2-5) or a family history of allergy (6) have been implicated. In addition, studies in animal models have reported that RSV can establish a persistent, low-level infection in the lungs (7,8), and results of several cross-sectional (9 -11) and longitudinal studies (12) suggest that RSV can persistently infect the human lung.However, the consequences of chronic intrapulmonary RSV persistence are unclear (13).We have developed a guinea pig model of experimental RSV infection in which lung function and airway inflammation have been studied in association with RSV persistence (8,14). In this model, intranasal RSV inoculation of juvenile CH results in a productive lung infection that is associated with nonspecific AHR and airway inflammation by lymphocytes and granulocytes, including T cells and eosinophils (8,15,16). After resolution of the acute infection, CH develop a persistent lung infection characterized by ongoing, low-level RSV replication, AHR, and airway eosinophilia (8,14,15). These findings in guinea pigs suggest a possible role for RSV persistence in the pathogenesis of AHR and airway inflammation that have features similar to asthma (17).Importantly, CH are a genetically outbred strain that is highly susceptible to allergic sensitization relative to inbred STR2 or STR13 (18). S...

Cough reflex sensitivity is increased in guinea pigs with parainfluenza virus infection

“…This finding suggested a possible role of RSV persistence in the pathogenesis of postbronchiolitis sequelae [22] [23]. No similar studies appear to be reported about PIV3, so referring to this criterion and to avoid causing pneumonia in guinea pigs, the dose of PIV3 that we selected was 3.3 × 10 5 PFU/mL.…”

Respiratory Syncytial Virus Persistence in Chronic Obstructive Pulmonary Disease

“…This has also been shown in a guinea pig model of RSV persistence where, although persistence was observed whether there was a T H 1 or T H 2 skew in immune response, there were lower viral loads in the T H 1 skewed animals. 69 There are other mechanisms that RSV may use to evade the host's immune response. The nonstructural proteins (NS1 and NS2) have been shown to antagonize IFN-␣, IFN-␤, and IFN-responses 70,71 -this would result in impaired antiviral immunity and possible persistence of virus.…”

Host and Viral Factors in Respiratory Syncytial Virus Infection

“…After initial work establishing that RSV protein and genome could persist in the guinea pig lung for up least 60 days after RSV inoculation [70], subsequent studies showed that outbred Cam Hartley guinea pigs could harbor replicating virus for at least 60-100 days after inoculation, in association with nonspecific airway hyperresponsiveness (AHR) and chronic airway inflammation (physiological and pathological hallmarks of asthma) [24,30]. However, in subsequent work, we noted that viral persistence on its own is not sufficient to produce asthmalike changes in the lungs, as inbred, ''allergy-resistant'' strain 2 guinea pigs can also develop persistent RSV lung infections but these animals do not get AHR or chronic airway inflammation in association with virus persistence [71].…”