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Acute lower respiratory tract infections (ALRTI) such as pneumonia and bronchiolitis are major causes of mortality and morbidity in children under 5 years of age. The main microbial agents responsible for ALRTI are either bacterial agents (Streptococcus pneumoniae, Haemophilus influenzae type b, Mycoplasma pneumoniae) or viruses (respiratory syncytial virus (RSV, also known as human orthopneumovirus), Myxovirus influenzae, Myxovirus parainfluenzae, adenovirus) [1]. More recently, other viruses (rhinovirus, metapneumovirus, coronavirus, bocavirus) have been implicated in ALRTI; their identification has been facilitated by new molecular biology techniques such as real-time PCR. To our knowledge, these emerging viruses have never been the subject of epidemiologic studies in our country. [ABSTRACT FROM AUTHOR]

Summary: Respiratory infections, especially those of the lower respiratory tract, remain a foremost cause of mortality and morbidity of children greater than 5 years in developing countries including Pakistan. Ignoring these acute‐level infections may lead to complications. Particularly in Pakistan, respiratory infections account for 20% to 30% of all deaths of children. Even though these infections are common, insufficiency of accessible data hinders development of a comprehensive summary of the problem. The purpose of this study was to determine the prevalence rate in various regions of Pakistan and also to recognize the existing viral strains responsible for viral respiratory infections through published data. Respiratory viruses are detected more frequently among rural dwellers in Pakistan. Lower tract infections are found to be more lethal. The associated pathogens comprise respiratory syncytial virus (RSV), human metapneumovirus (HMPV), coronavirus, enterovirus/rhinovirus, influenza virus, parainfluenza virus, adenovirus, and human bocavirus. RSV is more dominant and can be subtyped as RSV‐A and RSV‐B (BA‐9, BA‐10, and BA‐13). Influenza A (H1N1, H5N1, H3N2, and H1N1pdm09) and Influenza B are common among the Pakistani population. Generally, these strains are detected in a seasonal pattern with a high incidence during spring and winter time. The data presented include pneumonia, bronchiolitis, and influenza. This paper aims to emphasise the need for standard methods to record the incidence and etiology of associated pathogens in order to provide effective treatment against viral infections of the respiratory tract and to reduce death rates. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (hMPV), a leading cause of respiratory tract infections in infants, encodes a small hydrophobic (SH) protein of unknown function. Here we show that infection of plasmacytoid dendritic cells (pDCs) with a recombinant virus lacking SH expression (rhMPV-ΔSH) enhanced the secretion of type I interferons (IFNs), which required TLR7 and MyD88 expression. HMPV SH protein inhibited TLR7/MyD88/TRAF6 signaling leading to IFN gene transcription, identifying a novel mechanism by which paramyxovirus SH proteins modulate innate immune responses. [ABSTRACT FROM AUTHOR]

The Human Respiratory Syncytial Virus (hRSV) and the Human Metapneumovirus (hMPV) are two pneumoviruses that are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide. Since these pathogens were first discovered, many approaches for the licensing of safe and effective vaccines have been explored being unsuccessful to date. We have previously described that immunization with recombinant strains of Mycobacterium bovis Bacillus Calmette-Guérin (rBCG) expressing the hRSV nucleoprotein (rBCG-N) or the hMPV phosphoprotein (rBCG-P) induced immune protection against each respective virus. These vaccines efficiently promoted viral clearance without significant lung damage, mainly through the induction of a T helper 1 cellular immunity. Here we show that upon viral challenge, rBCG-immunized mice developed a protective humoral immunity, characterized by production of antibodies specific for most hRSV and hMPV proteins. Further, isotype switching from IgG1 to IgG2a was observed in mice immunized with rBCG vaccines and correlated with an increased viral clearance, as compared to unimmunized animals. Finally, sera obtained from animals immunized with rBCG vaccines and infected with their respective viruses exhibited virus neutralizing capacity and protected naïve mice from viral replication and pulmonary disease. These results support the notion that the use of rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.

Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models.

Thrombin has been demonstrated to be involved in several viral diseases including human metapneumovirus (hMPV) infections. We previously showed that immediate administration of thrombin inhibitor argatroban post-infection protected mice against hMPV disease. This current work aims at determining whether warfarin and heparin, two other anticoagulants inhibiting thrombin formation and activities, may also be used for treatment against hMPV in vivo. We found that immediate injections of argatroban, warfarin or heparin after virus challenge protected mice against hMPV infection, as evidenced by decreased or no mortality, less weight loss, reduced viral load and attenuated inflammation. However, delayed treatments starting 1 day post-infection with argatroban or warfarin almost did not impact the survival whereas delayed treatment with heparin induced an increased mortality during infection. Moreover, these treatments also did not reduce weight loss, viral replication and inflammation. In agreement with these results, thrombin generation was decreased upon immediate anticoagulant treatments but was unaltered upon delayed treatments. Thus, thrombin generation occurs at the onset of hMPV infection and thrombin inhibition may be only useful for the treatment of this disease when initiated in the early stage. In this case, heparin is not recommended because of its reduced efficacy on mortality in infected mice whereas argatroban and warfarin appear as safe and effective drugs for the treatment of hMPV disease. The antiviral and anti-inflammatory effects of argatroban occur via thrombin-dependent pathways whereas the mechanisms by which warfarin exerts its beneficial effects against hMPV infection were not elucidated and need to be further studied.

Human metapneumovirus (HMPV) is one of the leading causes of respiratory diseases in infants and children worldwide. Although this pathogen infects mainly young children, elderly and immunocompromised people can be also seriously affected. To date, there is no commercial vaccine available against it. Upon HMPV infection, the host innate arm of defense produces interferons (IFNs), which are critical for limiting HMPV replication. In this review, we offer an updated landscape of the HMPV mediated-IFN response in different models as well as some of the defense tactics employed by the virus to circumvent IFN response.

Human metapneumovirus (hMPV) is a common cause of respiratory infections in children. However, the precise mechanisms underlying the development of hMPV-induced pulmonary pathology remain unknown. Studies show that IL-17 plays an important role in some inflammatory diseases of the airways, including asthma and chronic obstructive pulmonary disease. Here, we generated an IL-17 KO murine model of hMPV infection and used it to characterize the role of IL-17 hMPV-induced pulmonary inflammation. The results demonstrated that the defect in IL-17 resulted in less neutrophil influx into the lungs, along with reduced ventilatory function. Meanwhile, viral infection in IL-17 KO mice increased regulatory T cells (Tregs) and reduced Th1 and Th2 cells in the lung, suggesting that lack of IL-17 skews the immune response in the lung toward an anti-inflammatory profile, as exhibited by a greater number of Treg cells and fewer Th1 and Th2 cells., (Copyright © 2018. Published by Elsevier Inc.)

Acute respiratory infection (ARI) is the second leading cause of death in children less than 5 years of age worldwide. Human Metapneumovirus (hMPV) is associated with around 5-7% of the total pneumonia admissions in children. The aim of this study was to determine the magnitude of hMPV associated hospitalizations among children, in Karachi, Pakistan. A 3 years prospective study was conducted at the Aga Khan University Hospital (AKUH), from August 2009 to June 2012. Children less than 5 years of age, admitted with ARIs, were enrolled. Throat swabs were collected and tested for hMPV using real-time PCR. Multivariable log binomial regression analysis was performed. Out of 1150 children enrolled, hMPV was detected among 84/1150 (7%). About 87% of the enrolled children presented with cough, followed by fever (73%), nasal congestion (69%) and shortness of breath (68%). Of the hMPV positive subjects, most (56/84, 67%) were less than 12 months of age. The most common diagnosis in hMPV positive infants was pneumonia, followed by asthma and bronchiolitis. HMPV was identified year round, with peaks during February and August. Sore throat was found to be significantly associated with the hMPV infection (Adjusted RR 2.23; 95%CI 1.42-3.52). The proportion of hMPV was higher among hospitalized infants with ARI. Pneumonia was the primary discharge diagnoses of patients who tested positive for hMPV. hMPV could be a target for future vaccine to further decrease the burden of ARI morbidity and possibly mortality in developing countries., (© 2018 Wiley Periodicals, Inc.)

The human metapneumovirus (hMPV) is the second leading cause globally of acute infection of the respiratory tract in children, infecting the upper and lower airways. The hMPV may induce an inappropriate Th2-type immune response, which causes severe pulmonary inflammation, leading to the obstruction of airways. Despite its severe epidemiological relevance, no vaccines are currently available for the prevention of hMPV-induced illness. In this investigation, we demonstrated that immunization of mice with the recombinant hMPV nucleoprotein (hMPV-N) mixed with the AbISCO-100 adjuvant reduced viral replication in lungs following challenge with the virus. We found that immunized mice had reduced weight loss, decreased granulocytes in the lung, an increased level of specific nucleoprotein antibodies of IgG1 and IgG2a-isotypes, and a local profile of Th1/Th17-type cytokines. Our results suggest that immunization with the hMPV-N and the AbISCO-100 adjuvant induces a reduction of viral infection and could be considered for the development of an hMPV vaccine.

Human Respiratory Syncytial Virus (hRSV), human Metapneumovirus (hMPV) and Adenovirus (ADV), are three of the most prevalent viruses responsible for pneumonia and bronchiolitis in children and elderly worldwide, accounting for a high number of hospitalizations annually. Diagnosis of these viruses is required to take clinical actions that allow an appropriate patient management. Thereby, new strategies to design fast diagnostic methods are highly required. In the present work, six monoclonal antibodies (mAbs, two for each virus) specific for conserved proteins from hRSV, hMPV and ADV were generated and evaluated through different immunological techniques, based on detection of purified protein, viral particles and human samples. In vitro evaluation of these antibodies showed higher specificity and sensitivity than commercial antibodies tested in this study. These antibodies were used to design a sandwich ELISA tests that allowed the detection of hRSV, hMPV, and ADV in human nasopharyngeal swabs. We observed that hRSV and ADV were detected with sensitivity and specificity equivalent to a current Direct Fluorescence Assay (DFA) methodology. However, hMPV was detected with more sensitivity than DFA. Our data suggest that these new mAbs can efficiently identify infected samples and discriminate from patients infected with other respiratory pathogens., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Financial and competing interests disclosure The authors had no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Background/aims: Human metapneumovirus (hMPV) is an important human respiratory pathogen and is implicated in an array of respiratory illnesses, ranging from asymptomatic infection to severe bronchiolitis. Currently, there is no reliable vaccine or specific antiviral therapy for hMPV infection and treatment is supportive. The use of ribonucleic acid interference has the potential to change that with the targeting of essential viral genes via small interfering RNAs (siRNAs) offering the ability to directly and rapidly treat viral infections., Method: The human lung carcinoma epithelial cell line, A549, was transfected with siRNAs targeting the N and P genes before infecting with hMPV A2 CAN97-83. Viral growth inhibition was then measured by the viral plaque assay and nucleoprotein (N) and phosphoprotein (P) gene knockdown was determined by real-time PCR., Results: In vitro prophylactic use of siRNAs targeting the 3'-abundantly expressed N and P genes of hMPV resulted in potent, sequence-specific viral inhibition. The viral inhibition was specific and not mediated by an anti-viral interferon-β response or cell death., Conclusion: The findings presented here confirmed the highly potent, sequence-specific antiviral effect of siRNAs targeting the N and P gene of hMPV. These results may facilitate the development of a novel therapeutic agent for hMPV control., (© 2018 S. Karger AG, Basel.)

Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s) in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF) and mitochondrial antiviral-signaling (MAVS) proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s). Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s). This provides further insight for evaluating M2-2 mutants as potent vaccine candidates., Competing Interests: The authors declare no conflict of interest.

Human metapneumovirus (HMPV) causes significant upper and lower respiratory disease in all age groups worldwide. The virus possesses a negative-sense single-stranded RNA genome of approximately 13.3 kb encapsidated by multiple copies of the nucleoprotein (N), giving rise to helical nucleocapsids. In addition, copies of the phosphoprotein (P) and the large RNA polymerase (L) decorate the viral nucleocapsids. After viral attachment, endocytosis, and fusion mediated by the viral glycoproteins, HMPV nucleocapsids are released into the cell cytoplasm. To visualize the subsequent steps of genome transcription and replication, a fluorescence in situ hybridization (FISH) protocol was established to detect different viral RNA subpopulations in infected cells. The FISH probes were specific for detection of HMPV positive-sense RNA (+RNA) and viral genomic RNA (vRNA). Time course analysis of human bronchial epithelial BEAS-2B cells infected with HMPV revealed the formation of inclusion bodies (IBs) from early times postinfection. HMPV IBs were shown to be cytoplasmic sites of active transcription and replication, with the translation of viral proteins being closely associated. Inclusion body formation was consistent with an actin-dependent coalescence of multiple early replicative sites. Time course quantitative reverse transcription-PCR analysis suggested that the coalescence of inclusion bodies is a strategy to efficiently replicate and transcribe the viral genome. These results provide a better understanding of the steps following HMPV entry and have important clinical implications. IMPORTANCE Human metapneumovirus (HMPV) is a recently discovered pathogen that affects human populations of all ages worldwide. Reinfections are common throughout life, but no vaccines or antiviral treatments are currently available. In this work, a spatiotemporal analysis of HMPV replication and transcription in bronchial epithelial cell-derived immortal cells was performed. HMPV was shown to induce the formation of large cytoplasmic granules, named inclusion bodies, for genome replication and transcription. Unlike other cytoplasmic structures, such as stress granules and processing bodies, inclusion bodies are exclusively present in infected cells and contain HMPV RNA and proteins to more efficiently transcribe and replicate the viral genome. Though inclusion body formation is nuanced, it corresponds to a more generalized strategy used by different viruses, including filoviruses and rhabdoviruses, for genome transcription and replication. Thus, an understanding of inclusion body formation is crucial for the discovery of innovative therapeutic targets., (Copyright © 2017 American Society for Microbiology.)

Human Metapneumovirus (HMPV) is a leading respiratory pathogen that causes lower respiratory tract infections worldwide. Acute HMPV infection induces an exacerbated inflammatory neutrophilic response leading to bronchiolitis and pneumonia. However, the mechanism by which the virus regulates neutrophil infiltration into the airways still remains unexplored. In this work, we used an experimental mouse model of HMPV infection to demonstrate that the attachment (G) protein of HMPV contributes to the recruitment of neutrophils into the airways and modulate the production of neutrophil chemoattractants and Type I IFN responses, specifically IFN-α. These findings provide the first evidence that the HMPV G protein contributes to the in vivo neutrophilic response to HMPV infection and furthers our understanding on virus induced inflammatory responses in the airways., Competing Interests: The authors declare no conflict of interest.

Human Respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are the two major etiological viral agents of lower respiratory tract diseases, affecting mainly infants, young children and the elderly. Although the infection of both viruses trigger an antiviral immune response that mediate viral clearance and disease resolution in immunocompetent individuals, the promotion of long-term immunity appears to be deficient and reinfection are common throughout life. A possible explanation for this phenomenon is that hRSV and hMPV, can induce aberrant T cell responses, which leads to exacerbated lung inflammation and poor T and B cell memory immunity. The modulation of immune response exerted by both viruses include different strategies such as, impairment of immunological synapse mediated by viral proteins or soluble factors, and the induction of pro-inflammatory cytokines by epithelial cells, among others. All these viral strategies contribute to the alteration of the adaptive immunity in order to increase the susceptibility to reinfections. In this review, we discuss current research related to the mechanisms underlying the impairment of T and B cell immune responses induced by hRSV and hMPV infection. In addition, we described the role each virulence factor involved in immune modulation caused by these viruses.

Neutrophils are the most abundant leukocytes in human circulation. They are the first immune cell population recruited to the sites of infection. However, the role of neutrophils to regulate host immune responses during respiratory viral infections is largely unknown. To elucidate the role of neutrophils in respiratory antiviral defense, we used an experimental mouse model of human metapneumovirus (HMPV) infection. HMPV, a member of the Paramyxoviridae family, is a leading respiratory pathogen causing severe symptoms, such as bronchiolitis and pneumonia, in young, elderly, and immunocompromised patients. We demonstrate that neutrophils are the predominant population of immune cells recruited into the lungs after HMPV infection. This led us to hypothesize that neutrophils represent a key player of the immune response during HMPV infection, thereby regulating HMPV-induced lung pathogenesis. Specific depletion of neutrophils in vivo using a mAb and simultaneous infection with HMPV exhibited higher levels of inflammatory cytokines, pulmonary inflammation, and severe clinical disease compared with HMPV-infected, competent mice. Interestingly, the lack of neutrophils altered γδ T cell accumulation in the lung. The absence of γδ T cells during HMPV infection led to reduced pulmonary inflammation. These novel findings demonstrate that neutrophils play a critical role in controlling HMPV-induced inflammatory responses by regulating γδ T cell infiltration to the site of infection., (© Society for Leukocyte Biology.)

Natural killer (NK) cells are capable of killing various pathogens upon stimulation of activating receptors. Human metapneumovirus (HMPV) is a respiratory virus, which was discovered in 2001 and is responsible for acute respiratory tract infection in infants and children worldwide. HMPV infection is very common, infecting around 70% of all children under the age of five. Under immune suppressive conditions, HMPV infection can be fatal. Not much is known on how NK cells respond to HMPV. In this study, using reporter assays and NK-cell cytotoxicity assays performed with human and mouse NK cells, we demonstrated that the NKp46-activating receptor and its mouse orthologue Ncr1, both members of the natural cytotoxicity receptor (NCR) family, recognized an unknown ligand expressed by HMPV-infected human cells. We demonstrated that MHC class I is upregulated and MICA is downregulated upon HMPV infection. We also characterized mouse NK-cell phenotype in the blood and the lungs of HMPV-infected mice and found that lung NK cells are more activated and expressing NKG2D, CD43, CD27, KLRG1, and CD69 compared to blood NK cells regardless of HMPV infection. Finally, we demonstrated, using Ncr1-deficient mice, that NCR1 plays a critical role in controlling HMPV infection., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Both respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are important viral pathogens causing respiratory tract infection (RTI) in the pediatric population. However, the clinical manifestations of RSV and hMPV infections are similar. Therefore, a reliable and rapid diagnostic tool is needed for diagnostic performance., Methods: In order to optimize diagnosis efficiency of RTI, the aim of this study is to establish a rapid and advanced method for simultaneous detecting RSV and hMPV in nasopharyngeal aspirates specimens from patients. We designed a one-step triplex real-time RT-PCR (qRT-PCR) protocol using TaqMan probes for detecting RSV and hMPV. The plasmid clones containing RSV nucleoprotein gene and hMPV fusion gene were established as reference standards. We used virus culture supernatants from 86 known pediatric RTI patient to test the specificity and sensitivity of our assay. Then we used total 222 nasopharyngeal aspirates specimens from pediatric patients hospitalized with respiratory symptoms to evaluate our assay., Results: Our one-step triplex qRT-PCR assay showed 100% sensitivity and specificity in testing RSV and hMPV in 86 known virus culture supernatants, with excellent linearity (R 2  > 0.99) and reliable reproducibility (CV lower than 1.04%). This assay has a wide dynamic range 10 2 -10 9 copies/reaction (limit of detection; LOD = 100 copies/reaction). A total of 222 patients hospitalized with respiratory symptoms were enrolled for clinical evaluation. In these samples, our qRT-PCR assay detected 68 RSV positive and 18 hMPV positive cases. However, standard virus culture only detected 8 RSV positive cases and 0 hMPV cases. Based on this improved triplex qRT-PCR assay, we found that RSV infection was associated with severe inflammation by chest X-ray and occurrence of pneumonia which were not observed previously., Conclusions: In summary, we have developed a highly specific and sensitive one-step triplex qRT-PCR assay to detect hMPV and RSV simultaneously. This assay offers a valuable tool for routine diagnosis.

Human metapneumovirus (HMPV), a single-stranded negative-sense RNA virus belonging to the family Paramyxoviridae, is associated with respiratory tract illness, primarily in young children and persons with underlying disease. Based on genetic and antigenic variation, HMPV strains are classified into two serotypes, with isolates NL/1/00 and NL/1/99 as prototypes for serotypes A and B, respectively. The development of plasmid-based reverse genetics systems for both serotypes has resulted in developments of a wide range of vaccine candidates against HMPV infection. The approach to virus rescue of HMPV is similar to that used for other paramyxoviruses, starting with mini-replicon assays for optimizations of the rescue protocols and subsequent replacement of the mini genome with a plasmid expressing the cDNA of the full-length viral RNA genome. Here, we provide detailed information on the reverse genetics systems for HMPV.

Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The innate sensing system is equipped with PRRs specialized in recognizing molecular structures (PAMPs) of various pathogens. This leads to the induction of anti-viral genes and inhibition of virus growth. Human Metapneumovirus (HMPV) is a major respiratory virus that causes an upper and lower respiratory tract infection in children. In this study we show that upon HMPV infection, the innate sensing system detects the viral RNA through the RIG-I sensor leading to induction of CEACAM1 expression. We further show that CEACAM1 is induced via binding of IRF3 to the CEACAM1 promoter. We demonstrate that induction of CEACAM1 suppresses the viral loads via inhibition of the translation machinery in the infected cells in an SHP2-dependent manner. In summary, we show here that HMPV-infected cells upregulates CEACAM1 to restrict HMPV infection.

Background: Human metapneumovirus (HMPV) causes acute respiratory tract infections in infants and children. We sought to measure the clinical and economic burden of HMPV infection in hospitalized children., Methods: We conducted a retrospective cohort study from 2007 to 2013 at Primary Children's Hospital in Salt Lake City, Utah. Children <18 years of age with laboratory-confirmed HMPV infection were included. Demographic, clinical, and financial data were abstracted from the electronic medical record., Results: During the study period, 815 children were hospitalized with laboratory-confirmed HMPV infection: 16% <6 months, 50% 6-23 months, 23% 2-4 years, and 11% 5-17 years of age. A complex chronic condition was identified in 453 (56%) children hospitalized with HMPV infection; this proportion increased with increasing age (P < .001). There was marked variation in annual HMPV hospitalization rates, ranging from 9 of 100 000 person-years in 2012-2013 to 79 of 100 000 in 2009-2010. Hospitalization rates were highest among children <2 years (200 of 100 000 person-years) and lowest among children 5-17 years of age (5 of 100 000). Of hospitalized children, 18% were treated in the intensive care unit and 6% required mechanical ventilation. The median length of stay was 2.8 days (interquartile range [IQR], 1.8-4.6) and did not vary by age. The median total hospital cost per patient was $5513 (IQR, $3850-$9946) with significantly higher costs for patients with chronic medical conditions (P < .001)., Conclusions: Human metapneumovirus infection results in a large number of hospitalizations with substantial morbidity, resource utilization, and costs. The development of a safe and effective vaccine could reduce the clinical and economic burden of HMPV., (© The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The comparative yield of respiratory virus detection from nasopharyngeal aspirate (NPA) versus bronchoalveolar lavage (BAL) is uncertain. Furthermore, the significance of virus detection and its relationship to lower airway neutrophilic inflammation is poorly studied., Objectives: To evaluate the sensitivity, specificity and predictive values of NPA for detecting respiratory viruses in BAL; and to determine the relationship between viruses and lower airway neutrophilia in children with non-acute respiratory illness., Study Design: 150 paired NPA and BAL samples were obtained from 75 children aged <18 years undergoing flexible bronchoscopy for investigation of chronic respiratory symptoms. Viral studies were performed using polymerase chain reaction (PCR). Cellularity studies were performed on BALs. Diagnostic parameters of NPA compared to BAL and associations between viruses and lower airway %neutrophils were evaluated., Results: NPA had a higher yield than BAL for detection of any respiratory virus (52 versus 38, respectively). NPA had a high sensitivity (92%) and low specificity (57%) for detecting HRV in BAL with poor kappa agreement value of 0.398 (95% CI 0.218-0.578, p<0.001). NPA had a fair sensitivity (69%) and good specificity (90.3%) for detecting HAdV on BAL, kappa agreement was 0.561 (95% CI 0.321-0.801, p<0.001). HAdV positivity on NPA, compared to negativity, was independently associated with heightened airway neutrophilia [mean difference (95% CI): 18 (1,35); p=0.042]., Conclusions: NPA has a higher yield for respiratory virus detection than BAL, however its diagnostic accuracy is dependent on viral species. Adenovirus positivity is associated with significantly heightened lower airway neutrophilia in children with chronic respiratory symptoms., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Background: Human metapneumovirus (HMPV) is a recently discovered paramyxovirus that is a major cause of respiratory infections worldwide., Objectives: We aim to describe the molecular evolution of the HMPV F (fusion) and G (attachment) surface glycoproteins because they are targets for vaccines, monoclonal antibodies and antivirals currently in development., Study Setting: Nasopharyngeal aspirates were collected in children <3 years old with acute respiratory infection in Quebec City during 2001-2010. HMPV-positive samples (n = 163) underwent HMPV-F and -G gene sequencing. Furthermore, HMPV-F (n = 124) and -G (n = 217) sequences were obtained from GenBank and other studies. Evolutionary analyses (phylogenetic reconstruction, sequence identity, detection of recombination and adaptive evolution) were computed., Results: Sequences clustered into 5 genetic lineages (A1, A2a, A2b, B1 and B2). Multiple lineages circulated each year in Quebec City. With the exception of B1, each of the 5 subgroups was the predominant lineage during ≥1 season. The A1 lineage was not detected since 2002-2003 in our local cohort. There was no evidence of inter- or intragenic recombination. HMPV-F was highly conserved, whereas HMPV-G exhibited greater diversity. HMPV-F demonstrated strong evidence of purifying selection, both overall and in an abundance of negatively selected amino acid sites. In contrast, sites under diversifying selection were detected in all HMPV-G lineages (range, 4-15), all of which were located in the ectodomain., Conclusions: Predominant circulating HMPV lineages vary by year. HMPV-F is highly constrained and undergoes significant purifying selection. Given its high genetic variability, we found a modest number of positively selected sites in HMPV-G., (Copyright © 2013 Elsevier B.V. All rights reserved.)