Immune response and alteration of pulmonary function after primary human metapneumovirus (hMPV) infection of BALB/c mice

Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.

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Human Metapneumovirus Establishes Persistent Infection in Lung Microvascular Endothelial Cells and Primes a Th2-Skewed Immune Response

Microorganisms ◽

10.3390/microorganisms8060824 ◽

2020 ◽

Vol 8 (6) ◽

pp. 824

Author(s):

Antonella Bugatti ◽

Stefania Marsico ◽

Manuela Fogli ◽

Sara Roversi ◽

Serena Messali ◽

...

Keyword(s):

Immune Response ◽

Endothelial Cells ◽

Human Metapneumovirus ◽

Size Exclusion ◽

Microvascular Endothelial Cells ◽

Cytopathic Effects ◽

Viral Particles ◽

Hmpv Infection ◽

Microvascular Endothelial ◽

Tract Infections

Human Metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se, could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment.

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The Immune Response to Human Metapneumovirus Is Associated with Aberrant Immunity and Impaired Virus Clearance in BALB/c Mice

Journal of Virology ◽

10.1128/jvi.79.10.5971-5978.2005 ◽

2005 ◽

Vol 79 (10) ◽

pp. 5971-5978 ◽

Cited By ~ 62

Author(s):

Rene Alvarez ◽

Ralph A. Tripp

Keyword(s):

Immune Response ◽

Cytotoxic T Lymphocyte ◽

Adaptive Immune Response ◽

Interleukin 10 ◽

Human Metapneumovirus ◽

Delayed Response ◽

Adaptive Immune ◽

Virus Clearance ◽

Hmpv Infection ◽

Syncytial Virus

ABSTRACT Human metapneumovirus (HMPV), recently identified in isolates from children hospitalized with acute respiratory tract illness, is associated with clinical diagnosis of pneumonia, asthma exacerbation, and acute bronchiolitis in young children. HMPV has been shown to cocirculate with respiratory syncytial virus (RSV) and mediate clinical disease features similarly to RSV. Little is known regarding the pathophysiology or immune response associated with HMPV infection; thus, animal models are needed to better understand the mechanisms of immunity and disease pathogenesis associated with infection. In this study, we examine features of the innate and adaptive immune response to HMPV infection in a BALB/c mouse model. Primary HMPV infection elicits weak innate and aberrant adaptive immune responses characterized by induction of a Th2-type cytokine response at later stages of infection that coincides with increased interleukin-10 expression and persistent virus replication in the lung. Examination of the cytotoxic T lymphocyte and antibody response to HMPV infection revealed a delayed response, but passive transfer of HMPV-specific antibodies provided considerable protection. These features are consistent with virus persistence and indicate that the immune response to HMPV is unique compared to the immune response to RSV.

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Human Metapneumovirus Induces Mucin 19 Which Contributes to Viral Pathogenesis

Pathogens ◽

10.3390/pathogens9090726 ◽

2020 ◽

Vol 9 (9) ◽

pp. 726

Author(s):

Kaitlin McBride ◽

Ma. del Rocio Banos-Lara ◽

Nagarjuna R. Cheemarla ◽

Antonieta Guerrero-Plata

Keyword(s):

Immune Response ◽

Respiratory Tract ◽

Viral Infections ◽

Clinical Symptoms ◽

Human Metapneumovirus ◽

Hmpv Infection ◽

Lower Lung ◽

Tract Infections ◽

Mouse Model Of Infection

Human Metapneumovirus (HMPV) remains one of the most common viral infections causing acute respiratory tract infections, especially in young children, elderly, and immunocompromised populations. Clinical symptoms can range from mild respiratory symptoms to severe bronchiolitis and pneumonia. The production of mucus is a common feature during HMPV infection, but its contribution to HMPV-induced pathogenesis and immune response is largely unknown. Mucins are a major component of mucus and they could have an impact on how the host responds to infections. Using an in vitro system and a mouse model of infection, we identified that Mucin 19 is predominantly expressed in the respiratory tract upon HMPV infection. Moreover, the lack of Muc19 led to an improved disease, lower lung viral titers and a decrease in the number of CD4+ T cells. These data indicate that mucin 19 contributes to the activation of the immune response to HMPV and to HMPV-induced pathogenesis.

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Impact and Regulation of Lambda Interferon Response in Human Metapneumovirus Infection

Journal of Virology ◽

10.1128/jvi.02897-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 730-742 ◽

Cited By ~ 30

Author(s):

Ma. Del Rocío Baños-Lara ◽

Lindsey Harvey ◽

Alexander Mendoza ◽

Dawn Simms ◽

Vladimir N. Chouljenko ◽

...

Keyword(s):

Immune Response ◽

Protective Role ◽

Human Metapneumovirus ◽

Interferon Response ◽

Antiviral Immune Response ◽

Hmpv Infection ◽

Experimental Mouse ◽

Mouse Model Of Infection

ABSTRACTHuman metapneumovirus (hMPV) is a respiratory paramyxovirus that is distributed worldwide and induces significant airway morbidity. Despite the relevance of hMPV as a pathogen, many aspects of the immune response to this virus are still largely unknown. In this report, we focus on the antiviral immune response, which is critical for viral clearance and disease resolution. Usingin vitroandin vivosystems, we show that hMPV is able to induce expression of lambda interferon 1 (IFN-λ1), IFN-λ2, IFN-λ3, and IFN-λ4. The induction of IFN-λ expression by hMPV was dependent on interferon regulatory factor 7 (IRF-7) expression but not on IRF-3 expression. Treatment of hMPV-infected mice with IFN-λ reduced the disease severity, lung viral titer, and inflammatory response in the lung. Moreover, the IFN-λ response induced by the virus was regulated by the expression of the hMPV G protein. These results show that type III interferons (IFN-λs) play a critical protective role in hMPV infection.IMPORTANCEHuman metapneumovirus (hMPV) is a pathogen of worldwide importance. Despite the relevance of hMPV as a pathogen, critical aspects of the immune response induced by this virus remain unidentified. Interferons (IFNs), including IFN-λ, the newest addition to the interferon family, constitute an indispensable part of the innate immune response. Here, we demonstrated that IFN-λ exhibited a protective role in hMPV infectionin vitroand in an experimental mouse model of infection.

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Induction of Protective Immunity by a Single Low Dose of a Master Cell Bank cGMP-rBCG-P Vaccine Against the Human Metapneumovirus in Mice

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.662714 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jorge A. Soto ◽

Nicolás M. S. Gálvez ◽

Gaspar A. Pacheco ◽

Gisela Canedo-Marroquín ◽

Susan M. Bueno ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

Molecular Mechanisms ◽

Low Dose ◽

Plasma Cells ◽

The Elderly ◽

Human Metapneumovirus ◽

Cell Bank ◽

Marginal Zone B Cells ◽

Hmpv Infection

Human metapneumovirus (hMPV) is an emergent virus, which mainly infects the upper and lower respiratory tract epithelium. This pathogen is responsible for a significant portion of hospitalizations due to bronchitis and pneumonia in infants and the elderly worldwide. hMPV infection induces a pro-inflammatory immune response upon infection of the host, which is not adequate for the clearance of this pathogen. The lack of knowledge regarding the different molecular mechanisms of infection of this virus has delayed the licensing of effective treatments or vaccines. As part of this work, we evaluated whether a single and low dose of a recombinant Mycobacterium bovis Bacillus Calmette-Guérin (BCG) expressing the phosphoprotein of hMPV (rBCG-P) can induce a protective immune response in mice. Immunization with the rBCG-P significantly decreased neutrophil counts and viral loads in the lungs of infected mice at different time points. This immune response was also associated with a modulated infiltration of innate cells into the lungs, such as interstitial macrophages (IM) and alveolar macrophages (AM), activated CD4+ and CD8+ T cells, and changes in the population of differentiated subsets of B cells, such as marginal zone B cells and plasma cells. The humoral immune response induced by the rBCG-P led to an early and robust IgA response and a late and constant IgG response. Finally, we determined that the transfer of cells or sera from immunized and infected mice to naïve mice promoted an efficient viral clearance. Therefore, a single and low dose of rBCG-P can protect mice from the disease caused by hMPV, and this vaccine could be a promising candidate for future clinical trials.

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Differential Mucin Expression by Respiratory Syncytial Virus and Human Metapneumovirus Infection in Human Epithelial Cells

Mediators of Inflammation ◽

10.1155/2015/347292 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Ma. Del Rocío Baños-Lara ◽

Boyang Piao ◽

Antonieta Guerrero-Plata

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Epithelial Cells ◽

Viral Infections ◽

Human Metapneumovirus ◽

Human Epithelial Cells ◽

Mucin Expression ◽

Rsv Infection ◽

Syncytial Virus ◽

Tract Disease

Mucins (MUC) constitute an important component of the inflammatory and innate immune response. However, the expression of these molecules by respiratory viral infections is still largely unknown. Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two close-related paramyxoviruses that can cause severe low respiratory tract disease in infants and young children worldwide. Currently, there is not vaccine available for neither virus. In this work, we explored the differential expression of MUC by RSV and hMPV in human epithelial cells. Our data indicate that the MUC expression by RSV and hMPV differs significantly, as we observed a stronger induction of MUC8, MUC15, MUC20, MUC21, and MUC22 by RSV infection while the expression of MUC1, MUC2, and MUC5B was dominated by the infection with hMPV. These results may contribute to the different immune response induced by these two respiratory viruses.

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Molecular typing and epidemiologic profiles of human metapneumovirus infection among children with severe acute respiratory infection in Huzhou, China

Molecular Biology Reports ◽

10.1007/s11033-021-06776-1 ◽

2021 ◽

Author(s):

Lei Ji ◽

Liping Chen ◽

Deshun Xu ◽

Xiaofang Wu

Keyword(s):

Respiratory Infection ◽

Acute Respiratory Infection ◽

Epidemiological Data ◽

Human Metapneumovirus ◽

Respiratory Pathogen ◽

Nasopharyngeal Swab ◽

F Gene ◽

Severe Acute Respiratory Infection ◽

Hmpv Infection ◽

High Incidence

Abstract Background Human metapneumovirus (hMPV) is one of the important pathogens in infant respiratory tract infection. However, the molecular epidemiology of hMPV among children < 14 years of age hospitalized with severe acute respiratory infection (SARI) is unclear. We investigated the hMPV infection status and genotypes of children hospitalized with SARI from January 2016 to December 2020 in Huzhou, China. Methods A nasopharyngeal flocked swab, nasal wash, or nasopharyngeal swab/or opharyngeal swab combination sample was collected from children with SARI in Huzhou from January 2016 to December 2020. Quantitative reverse transcription-polymerase chain reaction was performed to detect hMPV RNA. The hMPV F gene was amplified and sequenced, followed by analysis using MEGA software (ver. 7.0). Epidemiological data were analyzed using Microsoft Excel 2010 and SPSS (ver. 22.0) software. Results A total of 1133 children with SARI were recruited from 2016 to 2020. Among them, 56 (4.94%) were positive for hMPV-RNA. Children < 5 years of age accounted for 85.71% of the positive cases. The hMPV incidence was high in spring and winter, especially in December and January to March. Phylogenetic analysis of the F-gene sequences of 28 hMPV strains showed that the A1, B1, and B2 genotypes were prevalent in Huzhou, and the dominant hMPV genotype varied according to surveillance year. Conclusions HMPV is an important respiratory pathogen in children in Huzhou, with a high incidence in winter and spring in children < 5 years of age. In this study, genotypes A1, B1, and B2 were the most prevalent.

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Immunofluorescence Assay for Detection of Human Metapneumovirus-Specific Antibodies by Use of Baculovirus-Expressed Fusion Protein

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.12.1.202-205.2005 ◽

2005 ◽

Vol 12 (1) ◽

pp. 202-205 ◽

Cited By ~ 16

Author(s):

Nobuhisa Ishiguro ◽

Takashi Ebihara ◽

Rika Endo ◽

Xiaoming Ma ◽

Ryo Shirotsuki ◽

...

Keyword(s):

Trichoplusia Ni ◽

Respiratory Infections ◽

Recombinant Baculovirus ◽

Immunofluorescence Assay ◽

Human Metapneumovirus ◽

Specific Method ◽

Serum Samples ◽

F Protein ◽

Hmpv Infection ◽

Well Correlation

ABSTRACT Human metapneumovirus (hMPV) has recently been identified as an etiological agent of acute respiratory infections. The hMPV fusion (F) protein has been indicated to be a major antigenic determinant that mediates effective neutralization and protection against hMPV infection. We developed a new immunofluorescence assay (IFA) using Trichoplusia ni (Tn5) insect cells infected with a recombinant baculovirus-expressing hMPV F protein (Bac-F IFA). A total of 200 serum samples from Japanese people 1 month to 41 years old were tested for immunoglobulin G antibodies to hMPV F protein by Bac-F IFA. The results were compared with those of the conventional IFA based on hMPV-infected LLC-MK2 cells (hMPV IFA). The titers obtained by the two IFAs correlated well (correlation coefficient of 0.88), and the concordance of seroreactivities between the two IFAs was 91% (κ = 0.76). For 192 of the 200 serum samples, the titers obtained by the Bac-F IFA were equal to or higher than those obtained by the hMPV IFA. These results indicated that the Bac-F IFA was more sensitive than the hMPV IFA and that the majority of the antibodies detected by the hMPV IFA reacted with the hMPV F protein. The Bac-F IFA is a more reliable, sensitive, and specific method for the detection of hMPV antibodies than is the hMPV IFA.

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DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans

Journal of Virology ◽

10.1128/jvi.00537-16 ◽

2016 ◽

Vol 90 (17) ◽

pp. 7848-7863 ◽

Cited By ~ 1

Author(s):

Leah Gillespie ◽

Kathleen Gerstenberg ◽

Fernanda Ana-Sosa-Batiz ◽

Matthew S. Parsons ◽

Rubaiyea Farrukee ◽

...

Keyword(s):

Cell Surface ◽

Cho Cells ◽

Experimental System ◽

Human Metapneumovirus ◽

Host Cells ◽

Cell Surface Receptor ◽

Target Cells ◽

Transmembrane Receptors ◽

Hmpv Infection ◽

Attachment Factor

ABSTRACTIt is well established that glycosaminoglycans (GAGs) function as attachment factors for human metapneumovirus (HMPV), concentrating virions at the cell surface to promote interaction with other receptors for virus entry and infection. There is increasing evidence to suggest that multiple receptors may exhibit the capacity to promote infectious entry of HMPV into host cells; however, definitive identification of specific transmembrane receptors for HMPV attachment and entry is complicated by the widespread expression of cell surface GAGs. pgsA745 Chinese hamster ovary (CHO) cells are deficient in the expression of cell surface GAGs and resistant to HMPV infection. Here, we demonstrate that the expression of the Ca2+-dependent C-type lectin receptor (CLR) DC-SIGN (CD209L) or L-SIGN (CD209L) rendered pgsA745 cells permissive to HMPV infection. Unlike infection of parental CHO cells, HMPV infection of pgsA745 cells expressing DC-SIGN or L-SIGN was dynamin dependent and inhibited by mannan but not by pretreatment with bacterial heparinase. Parental CHO cells expressing DC-SIGN/L-SIGN also showed enhanced susceptibility to dynamin-dependent HMPV infection, confirming that CLRs can promote HMPV infection in the presence or absence of GAGs. Comparison of pgsA745 cells expressing wild-type and endocytosis-defective mutants of DC-SIGN/L-SIGN indicated that the endocytic function of CLRs was not essential but could contribute to HMPV infection of GAG-deficient cells. Together, these studies confirm a role for CLRs as attachment factors and entry receptors for HMPV infection. Moreover, they define an experimental system that can be exploited to identify transmembrane receptors and entry pathways where permissivity to HMPV infection can be rescued following the expression of a single cell surface receptor.IMPORTANCEOn the surface of CHO cells, glycosaminoglycans (GAGs) function as the major attachment factor for human metapneumoviruses (HMPV), promoting dynamin-independent infection. Consistent with this, GAG-deficient pgaA745 CHO cells are resistant to HMPV. However, expression of DC-SIGN or L-SIGN rendered pgsA745 cells permissive to dynamin-dependent infection by HMPV, although the endocytic function of DC-SIGN/L-SIGN was not essential for, but could contribute to, enhanced infection. These studies provide direct evidence implicating DC-SIGN/L-SIGN as an alternate attachment factor for HMPV attachment, promoting dynamin-dependent infection via other unknown receptors in the absence of GAGs. Moreover, we describe a unique experimental system for the assessment of putative attachment and entry receptors for HMPV.

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