Pathogenesis of acute respiratory illness caused by human parainfluenza viruses
Highlights
► HPIVs evade the innate immune response and replicate efficiently in respiratory epithelium. ► Cellular pathology in ex vivo epithelium is limited. ► Previous homotypic HPIV infections protect against severe disease, not against infection. ► There are no licensed vaccines or specific antiviral drugs for the HPIVs.
Introduction
Human parainfluenza viruses (HPIVs) are a common cause of acute respiratory infections (ARIs) in infants and young children, with 80% of children testing seropositive for HPIV1, 2, and 3 by age five [1•]. Re-infection with HPIV of the same serotype can occur throughout life but secondary infections are typically limited to the upper respiratory tract (URT). The majority of HPIV patients are treated in outpatient settings, yet HPIVs are a major cause of hospitalization for lower respiratory illness (LRI) in children under five years of age, second only to respiratory syncytial virus (RSV) [2, 3, 4, 5••]. In this age group, HPIVs are a more common cause of hospitalization for ARI or fever than influenza viruses, with a hospitalization rate of 1/1000/year, or approximately 23 000 hospitalizations per year in the United States alone [4, 5••, 6]. Of the HPIVs, HPIV3 is the most frequent cause of hospitalization, followed by HPIV1 and 2 [5••]. HPIV4 has been reported to be a much less frequent cause of clinically significant respiratory illness [7, 8], although a more recent study found HPIV4 in 10% of all HPIV positive samples in a daycare setting [9]. Although significant progress has been made in the past decade toward the development of vaccines for HPIV1, 2, and 3, a licensed vaccine is not yet available and neither are specific antiviral drugs [3, 4, 10, 11, 12, 13••, 14].
Section snippets
The nature of HPIV disease
HPIV infection usually initiates at the epithelium of the URT following exposure by contact or inhalation. Infection frequently spreads to the paranasal sinuses, larynx and bronchi, and obstruction of the Eustachian tubes can lead to otitis media. Each of the HPIVs has been associated with a similar broad spectrum of respiratory tract disease including the common cold, croup, bronchitis, bronchiolitis, and pneumonia, but certain serotypes are more frequently associated with certain illnesses [3
Viral genome and proteins
The HPIVs are enveloped, non-segmented, negative-strand RNA viruses of subfamily Paramyxovirinae, family Paramyxoviridae [15, 21]. HPIV1 and 3 belong to genus Respirovirus, while HPIV2 and 4 belong to genus Rubulavirus [21]. The genomes of HPIV1, 2, and 3 are similar in size (15.5–15.7 kb), whereas that of HPIV4 is somewhat larger (17.4 kb) [8]. They share the same order of 6 genes: 3′-N-P-M-F-HN-L, which are transcribed sequentially into separate mRNAs. There are two viral surface proteins: the
Contributions of the HPIV C and V accessory proteins to pathogenesis
For cytoplasmic RNA viruses such as the HPIVs, the most potent stimulus for innate immunity is viral RNA synthesis, which can strongly activate host cytoplasmic sensors such as MDA5, RIG-I, and PKR. Downstream effects include: signal transduction that activates transcription factors IRF3 and NF-κB and induces IFN-β and pro-inflammatory cytokines; suppression of cellular translation by PKR; and IFN-induced signaling to induce an antiviral state [25, 26, 27, 28, 29]. These responses can strongly
Tissue tropism and cytopathology
HPIVs replicate to high titer in the epithelial cells that line the respiratory tract [53••, 54, 55]. In an in vitro model of well-differentiated mucociliary human airway epithelium (HAE) [56, 57], HPIV1, 2, and 3 infected only the superficial ciliated cells on the apical (lumenal) face and did not spread to the underlying basal cells or goblet cells [53••, 54, 55]. The release of progeny HPIV1, 2, and 3 occurred solely at the apical surface. This selective tropism is consistent with the
Factors contributing to HPIV pathogenesis
Young age and lack of prior exposure to the infecting HPIV serotype are two major factors associated with HPIV LRI. Young infants are at greater risk partly because their smaller airways are more susceptible to obstruction, and their immune responses are reduced owing to immunological immaturity and the presence of HPIV-specific maternal antibodies that suppress antibody responses (reviewed in [15, 66]). Host genetic factors, particularly those affecting innate and inflammatory responses,
Immune responses
HPIV infection induces innate immune responses, serum and mucosal antibody responses, and CD8+ and CD4+ T-cell responses that restrict replication and clear HPIV infection. Neutralizing antibodies that target the HN and F glycoproteins are the most important determinants of long-term protection from HPIV disease [70•, 71, 72]. Serum IgG antibodies provide the most durable protection against re-infection, but transport to the respiratory lumen is mostly non-specific and inefficient, and
Inflammatory responses
HPIV infection of the airway epithelium causes extensive changes in cellular gene expression and stimulates increased production of numerous cytokines and chemokines that either have antiviral functions themselves or attract and activate cells that mediate an immune response ([38•] and Schaap-Nutt et al., unpublished data). Microarray analysis of epithelial cells infected with HPIV1 has indicated that the NF-κB, IRF3 and type 1 IFN pathways play a major role in regulating the cellular antiviral
Conclusions
HPIV infections are common throughout life, and disease severity is greatest in the immunologically naïve and the immunocompromised. The magnitude of HPIV replication is a major factor determining severity of illness [80]. The viral C and V accessory proteins are key players in suppression of the innate immune response to HPIV infection, thus enabling efficient virus replication. The response of the airway epithelium to infection is crucial for initiating an inflammatory and innate immune
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors are funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
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