Human Metapneumovirus Disease Research Articles

IFN-λ drives distinct lung immune landscape changes and antiviral responses in human metapneumovirus infection.

Human metapneumovirus (HMPV) is a common respiratory pathogen and often contributes to severe disease, particularly in children, immunocompromised people, and the elderly. There are currently no licensed HMPV antiviral treatments or vaccines. Here, we report novel roles of host factor IFN-λ in HMPV disease that highlight therapeutic potential. We show that IFN-λ promotes lung antiviral responses by restricting lung HMPV replication and spread from upper to lower airways but does so without inducing lung immunopathology. Our data uncover recruitment of lung macrophages, regulation of ciliated epithelial cells, and modulation of inflammatory cytokines and interferon-stimulated genes as likely contributors. Moreover, we found these roles to be distinct and non-redundant, as they are not observed with knockout of, or treatment with, type I IFN. These data elucidate unique antiviral functions of IFN-λ and suggest IFN-λ augmentation as a promising therapeutic for treating HMPV disease and promoting effective vaccine responses.

Human metapneumovirus activates NOD-like receptor protein 3 inflammasome via its small hydrophobic protein which plays a detrimental role during infection in mice.

NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers caspase-1 activation-induced maturation of interleukin (IL)-1β and IL-18 and therefore is important for the development of the host defense against various RNA viral diseases. However, the implication of this protein complex in human metapneumovirus (HMPV) disease has not been fully studied. Herein, we report that NLRP3 inflammasome plays a detrimental role during HMPV infection because NLRP3 inflammasome inhibition protected mice from mortality and reduced weight loss and inflammation without impacting viral replication. We also demonstrate that NLRP3 inflammasome exerts its deleterious effect via IL-1β production since we observed reduced mortality, weight loss and inflammation in IL-1β-deficient (IL-1β-/-) mice, as compared to wild-type animals during HMPV infection. Moreover, the effect on these evaluated parameters was not different in IL-1β-/- and wild-type mice treated with an NLRP3 inflammasome inhibitor. The production of IL-1β was also abrogated in bone marrow derived macrophages deficient for NLRP3. Finally, we show that small hydrophobic protein-deleted recombinant HMPV (HMPV ΔSH) failed to activate caspase-1, which is responsible for IL-1β cleavage and maturation. Furthermore, HMPV ΔSH-infected mice had less weight loss, showed no mortality and reduced inflammation, as compared to wild-type HMPV-infected mice. Thus, NLRP3 inflammasome activation seems to be triggered by HMPV SH protein in HMPV disease. In summary, once activated by the HMPV SH protein, NLRP3 inflammasome promotes the maturation of IL-1β, which exacerbates HMPV-induced inflammation. Therefore, the blockade of IL-1β production by using NLRP3 inflammasome inhibitors might be a novel potential strategy for the therapy and prevention of HMPV infection.

Human metapneumovirus in the preterm neonate: current perspectives.

Premature birth (<37 weeks gestation) occurs in ~11% of all births in the US. These infants are at risk of chronic lung disease and respiratory conditions, including bronchopulmonary dysplasia. Respiratory viruses are important causes of acute respiratory illness (ARI) in preterm infants, leading to rehospitalization, increased health care burden, and long-term morbidity. Human metapneumovirus (HMPV) is a paramyxovirus discovered in 2001 that is related to respiratory syncytial virus. Epidemiologic studies show that HMPV is a leading cause of ARI in children and adults worldwide. Prematurity is a major risk factor for severe HMPV disease, requiring hospitalization. Moreover, limited data suggest that HMPV infection during infancy is associated with asthma and recurrent wheezing, which are common long-term pulmonary complication of prematurity. HMPV causes nosocomial outbreaks of ARI in hospitals and long-term care facilities, although there are few studies of the prevalence of HMPV in neonatal intensive care unit populations. HMPV is a common and important virus in premature infants, and caregivers for preterm infants should consider this virus in patients with acute respiratory symptoms.

Human Metapneumovirus Infection is Associated with Severe Respiratory Disease in Preschool Children with History of Prematurity

Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen of the family Paramyxoviridae, the same family as that of respiratory syncytial virus (RSV). Premature children are at high risk of severe RSV infections, however, it is unclear whether HMPV infection is more severe in hospitalized children with a history of severe prematurity. We conducted a retrospective analysis of the clinical respiratory presentation of all polymerase chain reaction-confirmed HMPV infections in preschool-age children (≤5 years) with and without history of severe prematurity (<32 weeks gestation). Respiratory distress scores were developed to examine the clinical severity of HMPV infections. Demographic and clinical variables were obtained from reviewing electronic medical records. A total of 571 preschool children were identified using polymerase chain reaction-confirmed viral respiratory tract infection during the study period. HMPV was identified as a causative organism in 63 cases (11%). Fifty-eight (n=58) preschool-age children with HMPV infection were included in this study after excluding those with significant comorbidities. Our data demonstrated that 32.7% of children admitted with HMPV had a history of severe prematurity. Preschool children with a history of prematurity had more severe HMPV disease as illustrated by longer hospitalizations, new or increased need for supplemental O2, and higher severity scores independently of age, ethnicity, and history of asthma. Our study suggests that HMPV infection causes significant disease burden among preschool children with a history of prematurity leading to severe respiratory infections and increasing health care resource utilization due to prolonged hospitalizations.

Effect of in vitro syncytium formation on the severity of human metapneumovirus disease in a murine model.

Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infections (ARTI) in children, elderly individuals and immunocompromised patients. In vitro, different HMPV strains can induce variable cytopathic effects ranging from large multinucleated syncytia to focal cell rounding. In this study, we investigated the impact of different in vitro phenotypes of two HMPV strains on viral replication and disease severity in a BALB/c mouse model. We first generated two recombinant GFP-expressing HMPV viruses: C-85473, a syncytium-inducing strain (rC-85473) belonging to the A1 subtype and CAN98-75, a focal cell rounding-inducing strain (rCAN98-75) of the B2 subtype. We subsequently exchanged the F genes of both strains to create the chimeric viruses rC-85473_F and rCAN98-75_F. We demonstrated that the F protein was the sole protein responsible for the syncytium phenotype and that viruses carrying a syncytium-inducing F protein replicated to significantly higher titers in vitro. In vivo, however, the virulence and replicative capacity of the different HMPV strains did not appear to be solely dependent on the F gene but also on the viral background, with the strains containing the C-85473 background inducing more weight loss as well as increased lung viral titers, pro-inflammatory cytokines and inflammation than strains containing the CAN98-75 background. In conclusion, the F protein is the main determinant of syncytium formation and replication kinetics in vitro, although it is not the only factor implicated in HMPV disease severity in mice.

Human metapneumovirus viral load is an important risk factor for disease severity in young children

BackgroundThe role of viral load in human metapneumovirus (HMPV) disease severity has not yet been clearly determined. ObjectiveWe evaluated the importance of viral load along with other factors in HMPV disease severity among children aged <3 years old. Study designHMPV-positive cases were selected from a cohort of outpatients and hospitalized children with lower respiratory tract infections. HMPV groups (A or B) and viral loads were determined in their nasopharyngeal aspirates. Disease severity was defined by assessing risk for hospitalization and by using two validated clinical severity scores. ResultsOf the 118 HMPV cases detected over 4 years for which viral load could be determined, 60 belonged to genotype A and 58 to genotype B. Baseline characteristics were similar in HMPV-A and HMPV-B mono-infected patients. In multivariate analysis, HMPV hospitalization was associated with viral load ≥1000copies/104cells (OR, 3.2; 95%CI, 1.4–7.4), age <6 months (OR, 3.1; 95%CI, 1.2–8.6) and presence of ≥3 children in the household (OR, 2.7; 95%CI, 1.04–6.9). A high HMPV viral load was also associated with pulmonary rales (p=.03), use of bronchodilators (p=.02) and inhaled corticosteroids (p=.01). ConclusionHMPV viral load is associated with disease severity in young children along with young age and household crowding.

A Comparison of Characteristics and Outcomes in Severe Human Metapneumovirus and Respiratory Syncytial Virus Infections in Children Treated in an Intensive Care Unit

Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are among the leading causes of respiratory tract infections requiring admission to the pediatric intensive care unit (PICU). We evaluated the risk factors, clinical courses and outcomes of severe HMPV disease relative to severe RSV in children admitted to the PICU. Retrospective chart review of children ≤18 years old admitted to a tertiary PICU between October 2008 through July 2010 with acute respiratory tract infection and positive direct antigen stain or polymerase chain reaction for RSV or HMPV. One hundred thirty-three patients met inclusion criteria: 107 (80.5%) with RSV and 26 (19.5%) with HMPV. HMPV-infected patients were older than RSV children (3.4 vs. 1.5 years, P = 0.002) and more likely to have congenital heart disease (34.6% vs. 10.3%, P = 0.002). Although HMPV children required longer duration of mechanical ventilation (11 vs. 7 days, P = 0.01), there were no other differences in hospital course. HMPV patients were more likely to be discharged receiving inhaled steroids (53.8% vs. 30.8%, P = 0.03), but there were no differences in other outcome assessments. Children admitted to the PICU with HMPV are significantly older and more likely to have congenital heart disease than those with RSV. The course of illness was similar between the 2 groups, but HMPV-infected children were more likely to be discharged with inhaled steroid therapy.

Human metapneumovirus infections are associated with severe morbidity in hospitalized children of all ages

The impact of human metapneumovirus (HMPV) in children aged >5 years and the risk factors associated with disease severity for all ages have not been well characterized. A retrospective cohort study of 238 children aged 0–15 years hospitalized over a 3-year period was performed. Medical records were reviewed for demographic information, clinical parameters and outcomes. Multivariable analyses were performed to identify independent factors associated with worse disease severity assessed by length of hospital stay (LOS), need for ICU care, respiratory support, and a disease severity score. Pulmonary diseases were associated with all outcomes of care, while congenital heart disease (CHD) and neuromuscular disorders were associated with longer LOS, and CHD and trisomy 21 were associated with worse severity scores independent of other covariables. Fever, retractions, use of steroids and albuterol were also associated with enhanced disease severity. Understanding the determinants of HMPV disease in children may help design targeted preventive strategies.

Human Metapneumovirus: Lessons Learned over the First Decade

It has been 10 years since human metapneumovirus (HMPV) was identified as a causative agent of respiratory illness in humans. Since then, numerous studies have contributed to a substantial body of knowledge on many aspects of HMPV. This review summarizes our current knowledge on HMPV, HMPV disease pathogenesis, and disease intervention strategies and identifies a number of areas with key questions to be addressed in the future.

Immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed SCT recipients

Immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed SCT recipients

Human metapneumovirus as a causative agent of lower respiratory tract infection in four patients: The first report of human metapneumovirus infection confirmed by RNA sequences in Taiwan

Human metapneumovirus (HMPV) has been described as a human pathogen associated with respiratory disease in most parts of the world from all age groups. This report presents the first 4 cases of HMPV disease confirmed by the sequences of PCR products in Taiwan.

Perspective on the host response to human metapneumovirus infection: what can we learn from respiratory syncytial virus infections?

Human metapneumovirus (HMPV) is a recently discovered pathogen first identified in respiratory specimens from young children suffering from clinical respiratory syndromes ranging from mild to severe lower respiratory tract illness. HMPV has worldwide prevalence, and is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to respiratory syncytial virus (RSV). The disease burden associated with HMPV infection has not been fully elucidated; however, studies indicate that HMPV may cause upper or lower respiratory tract illness in patients between ages 2 months and 87 years, may co-circulate with RSV, and HMPV infection may be associated with asthma exacerbation. The mechanisms and effector pathways contributing to immunity or disease pathogenesis following infection are not fully understood; however, given the clinical significance of HMPV, there is a need for a fundamental understanding of the immune and pathophysiological processes that occur following infection to provide the foundation necessary for the development of effective vaccine or therapeutic intervention strategies. This review provides a current perspective on the processes associated with HMPV infection, immunity, and disease pathogenesis.