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1.
Immunology ; 172(3): 500-515, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38584001

ABSTRACT

Lifestyle factors like poor maternal diet or antibiotic exposure disrupt early life microbiome assembly in infants, increasing the risk of severe lower respiratory infections (sLRI). Our prior studies in mice indicated that a maternal low-fibre diet (LFD) exacerbates LRI severity in infants by impairing recruitment of plasmacytoid dendritic cells (pDC) and consequently attenuating expansion of lung regulatory T (Treg) cells during pneumonia virus of mice (PVM) infection. Here, we investigated whether maternal dietary fibre intake influences Treg cell phenotypes in the mediastinal lymph nodes (mLN) and lungs of PVM-infected neonatal mice. Using high dimensional flow cytometry, we identified distinct clusters of regulatory T cells (Treg cells), which differed between lungs and mLN during infection, with notably greater effector Treg cell accumulation in the lungs. Compared to high-fibre diet (HFD)-reared pups, frequencies of various effector Treg cell subsets were decreased in the lungs of LFD-reared pups. Particularly, recruitment of chemokine receptor 3 (CXCR3+) expressing Treg cells was attenuated in LFD-reared pups, correlating with lower lung expression of CXCL9 and CXCL10 chemokines. The recruitment of this subset in response to PVM infection was similarly impaired in pDC depleted mice or following anti-CXCR3 treatment, increasing immunopathology in the lungs. In summary, PVM infection leads to the sequential recruitment and expansion of distinct Treg cell subsets to the lungs and mLN. The attenuated recruitment of the CXCR3+ subset in LFD-reared pups increases LRI severity, suggesting that strategies to enhance pDCs or CXCL9/CXCL10 expression will lower immune-mediated pathogenesis.


Subject(s)
Immune Tolerance , Lung , Receptors, CXCR3 , T-Lymphocytes, Regulatory , Animals , T-Lymphocytes, Regulatory/immunology , Receptors, CXCR3/metabolism , Mice , Lung/immunology , Lung/virology , Female , Pneumovirus Infections/immunology , Mice, Inbred C57BL , Lymph Nodes/immunology , Chemokine CXCL10/metabolism , Disease Models, Animal , Animals, Newborn
2.
Emerg Microbes Infect ; 12(2): 2239938, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37470510

ABSTRACT

Respiratory disease is a significant economic issue in pig farming, with a complex aetiology that includes swine influenza A viruses (swIAV), which are common in European domestic pig populations. The most recent human influenza pandemic in 2009 showed swIAV's zoonotic potential. Monitoring pathogens and disease control are critical from a preventive standpoint, and are based on quick, sensitive, and specific diagnostic assays capable of detecting and distinguishing currently circulating swIAV in clinical samples. For passive surveillance, a set of multiplex quantitative reverse transcription real-time PCRs (mRT-qPCR) and MinION-directed sequencing was updated and deployed. Several lineages and genotypes of swIAV were shown to be dynamically developing, including novel reassortants between human pandemic H1N1 and the avian-derived H1 lineage of swIAV. Despite this, nearly 70% (842/1216) of individual samples from pigs with respiratory symptoms were swIAV-negative, hinting to different aetiologies. The complex and synergistic interactions of swIAV infections with other viral and bacterial infectious agents contribute to the aggravation of pig respiratory diseases. Using a newly developed mRT-qPCR for the combined detection of swIAV and the recently described porcine respirovirus 1 (PRV1) and swine orthopneumovirus (SOV) widespread co-circulation of PRV1 (19.6%, 238/1216 samples) and SOV (14.2%, 173/1216 samples) was evident. Because of the high incidence of PRV1 and SOV infections in pigs with respiratory disease, these viruses may emerge as new allies in the porcine respiratory disease syndrome.


Subject(s)
Orthomyxoviridae Infections , Pneumovirus Infections , Respiratory Tract Diseases , Respirovirus Infections , Swine Diseases , Germany/epidemiology , Swine Diseases/epidemiology , Swine Diseases/virology , Orthomyxoviridae Infections/epidemiology , Orthomyxoviridae Infections/veterinary , Influenza A virus/genetics , Respirovirus/genetics , Respirovirus Infections/epidemiology , Respirovirus Infections/veterinary , Respiratory Tract Diseases/veterinary , Respiratory Tract Diseases/virology , Pneumovirus Infections/epidemiology , Pneumovirus Infections/veterinary , Pneumovirus/genetics , Reverse Transcriptase Polymerase Chain Reaction , Real-Time Polymerase Chain Reaction , Phylogeny
3.
mSphere ; 7(1): e0098421, 2022 02 23.
Article in English | MEDLINE | ID: mdl-35044807

ABSTRACT

Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal coinfections with respiratory syncytial virus (RSV). Here, we developed a novel infant mouse model of coinfection using pneumonia virus of mice (PVM), a murine analogue of RSV, to examine the dynamics of coinfection in the upper respiratory tract, an anatomical niche that is essential for host-to-host transmission and progression to disease. Coinfection increased damage to the nasal tissue and increased production of the chemokine CCL3. Nasopharyngeal pneumococcal density and shedding in nasal secretions were increased by coinfection. In contrast, coinfection reduced PVM loads in the nasopharynx, an effect that was independent of pneumococcal strain and the order of infection. We showed that this "antagonistic" effect was absent using either ethanol-killed pneumococci or a pneumococcal mutant deficient in capsule production and incapable of nasopharyngeal carriage. Colonization with a pneumococcal strain naturally unable to produce capsule also reduced viral loads. The pneumococcus-mediated reduction in PVM loads was caused by accelerated viral clearance from the nasopharynx. Although these synergistic and antagonistic effects occurred with both wild-type pneumococcal strains used in this study, the magnitude of the effects was strain dependent. Lastly, we showed that pneumococci can also antagonize influenza virus. Taken together, our study has uncovered multiple novel facets of bacterial-viral coinfection. Our findings have important public health implications, including for bacterial and viral vaccination strategies in young children. IMPORTANCE Respiratory bacterial-viral coinfections (such as pneumococci and influenza virus) are often synergistic, resulting in enhanced disease severity. Although colonization of the nasopharynx is the precursor to disease and transmission, little is known about bacterial-viral interactions that occur within this niche. In this study, we developed a novel mouse model to examine pneumococcal-viral interactions in the nasopharynx with pneumonia virus of mice (PVM) and influenza. We found that PVM infection benefits pneumococci by increasing their numbers in the nasopharynx and shedding of these bacteria in respiratory secretions. In contrast, we discovered that pneumococci decrease PVM numbers by accelerating viral clearance. We also report a similar effect of pneumococci on influenza. By showing that coinfections lead to both synergistic and antagonistic outcomes, our findings challenge the existing dogma in the field. Our work has important applications and implications for bacterial and viral vaccines that target these microbes.


Subject(s)
Antibiosis , Coinfection/microbiology , Coinfection/virology , Pneumococcal Infections/virology , Pneumovirus Infections/virology , Respiratory System/virology , Age Factors , Animals , Coinfection/immunology , Cytokines/analysis , Cytokines/immunology , Disease Models, Animal , Influenza A virus/genetics , Influenza A virus/immunology , Mice , Mice, Inbred C57BL , Murine pneumonia virus/genetics , Murine pneumonia virus/immunology , Nasopharynx/virology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Pneumovirus Infections/immunology , Respiratory System/immunology , Streptococcus pneumoniae/genetics , Streptococcus pneumoniae/immunology , Viral Load
4.
Viruses ; 14(1)2022 01 06.
Article in English | MEDLINE | ID: mdl-35062301

ABSTRACT

Human respiratory syncytial virus (hRSV) infection brings a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis or even acute interstitial pneumonia. Among the known factors influencing this clinical diversity, genetic background has often been mentioned. In parallel, recent evidence has also pointed out that an early infectious experience affects heterologous infections severity. Here, we analyzed the importance of these two host-related factors in shaping the immune response in pneumoviral disease. We show that a prior gammaherpesvirus infection improves, in a genetic background-dependent manner, the immune system response against a subsequent lethal dose of pneumovirus primary infection notably by inducing a systematic expansion of the CD8+ bystander cell pool and by modifying the resident alveolar macrophages (AMs) phenotype to induce immediate cyto/chemokinic responses upon pneumovirus exposure, thereby drastically attenuating the host inflammatory response without affecting viral replication. Moreover, we show that these AMs present similar rapid and increased production of neutrophil chemokines both in front of pneumoviral or bacterial challenge, confirming recent studies attributing a critical antibacterial role of primed AMs. These results corroborate other recent studies suggesting that the innate immunity cells are themselves capable of memory, a capacity hitherto reserved for acquired immunity.


Subject(s)
Genetic Background , Herpesviridae Infections/immunology , Macrophages, Alveolar/immunology , Pneumovirus Infections/immunology , Pneumovirus/immunology , Rhadinovirus/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Female , Herpesviridae Infections/genetics , Herpesviridae Infections/pathology , Herpesviridae Infections/virology , Immunity, Innate , Inflammation/immunology , Lung/immunology , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Monocytes/immunology , Pneumococcal Infections/immunology , Pneumovirus/physiology , Pneumovirus Infections/genetics , Pneumovirus Infections/pathology , Pneumovirus Infections/virology , Rhadinovirus/physiology
5.
Immunobiology ; 226(6): 152151, 2021 11.
Article in English | MEDLINE | ID: mdl-34742024

ABSTRACT

Resolvin D1 (RvD1), which is biosynthesized from essential long-chain fatty acids, is involved in anti-inflammatory activity and modulation of T cell response. Memory CD8+ T cells are important for controlling tumor growth and viral infections. Exacerbated inflammation has been described as impairing memory CD8+ T cell differentiation. This study aimed to verify the effects of RvD1 on memory CD8+ T cells in vitro and in vivo in a respiratory virus infection model. Peripheral blood mononuclear cells were treated at different time points with RvD1 and stimulated with anti-CD3/anti-CD28 antibodies. Pre-treatment with RvD1 increases the expansion of memory CD8+ T cells. The IL-12 level, a cytokine described to control memory CD8+ T cells, was reduced with RvD1 pre-treatment. When the mTOR axis was inhibited, the IL-12 levels were restored. In a respiratory virus infection model, Balb/c mice were treated with RvD1 before infection or after 7 days after infection. RvD1 treatment after infection increased the frequency of memory CD8+ T cells in the lung expressing II4, II10, and Ifng. During reinfection, RvD1-treated and RSV-infected mice present a high viral load in the lung and lower antibody response in the serum. Our results show that RvD1 modulates the expansion and phenotype of memory CD8+ T cells but contributed to a non-protective response after RSV reinfection.


Subject(s)
Antiviral Agents/therapeutic use , Docosahexaenoic Acids/therapeutic use , Immunologic Memory/drug effects , Pneumovirus Infections/drug therapy , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Viral Load/drug effects , Adult , Animals , Antiviral Agents/pharmacology , Biomarkers , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Disease Models, Animal , Docosahexaenoic Acids/pharmacology , Female , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immunophenotyping , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Reinfection , Treatment Outcome , Young Adult
6.
mBio ; 12(6): e0262121, 2021 12 21.
Article in English | MEDLINE | ID: mdl-34724816

ABSTRACT

Multiple enveloped RNA viruses of the family Paramyxoviridae and Pneumoviridae, like measles virus (MeV), Nipah virus (NiV), canine distemper virus (CDV), or respiratory syncytial virus (RSV), are of high clinical relevance. Each year a huge number of lives are lost as a result of these viral infections. Worldwide, MeV infection alone is responsible for over a hundred thousand deaths each year despite available vaccine. Therefore, there is an urgent need for treatment options to counteract these viral infections. The development of antiviral drugs in general stands as a huge challenge due to the rapid emergence of viral escape mutants. Here, we disclose the discovery of a small-molecule antiviral, compound 1 (ZHAWOC9045), active against several pneumo-/paramyxoviruses, including MeV, NiV, CDV, RSV, and parainfluenza virus type 5 (PIV-5). A series of mechanistic characterizations revealed that compound 1 targets a host factor which is indispensable for viral genome replication. Drug resistance profiling against a paramyxovirus model (CDV) demonstrated no detectable adaptation despite prolonged time of investigation, thereby mitigating the rapid emergence of escape variants. Furthermore, a thorough structure-activity relationship analysis of compound 1 led to the invention of 100-times-more potent-derivatives, e.g., compound 2 (ZHAWOC21026). Collectively, we present in this study an attractive host-directed pneumoviral/paramyxoviral replication inhibitor with potential therapeutic application. IMPORTANCE Measles virus, respiratory syncytial virus, canine distemper virus, and Nipah virus are some of the clinically significant RNA viruses that threaten substantial number of lives each year. Limited to no availability of treatment options for these viral infections makes it arduous to handle the outbreaks. This highlights the major importance of developing antivirals to fight not only ongoing infections but also potential future epidemics. Most of the discovered antivirals, in clinical trials currently, are virus targeted, which consequently poses the challenge of rapid emergence of escape variants. Here, we present compound 1 (ZHAWOC9045), discovered to target viral replication in a host-dependent manner, thereby exhibiting broad-spectrum activity against several members of the family Pneumo-/Paramyxoviridae. The inability of viruses to mutate against the inhibitor mitigated the critical issue of generation of escape variants. Importantly, compound 1 was successfully optimized to a highly potent variant, compound 2 (ZHAWOC21026), with a promising profile for pharmacological intervention.


Subject(s)
Antiviral Agents/pharmacology , Paramyxoviridae/physiology , Pneumovirus/physiology , Virus Replication/drug effects , Antiviral Agents/chemistry , Drug Discovery , Humans , Paramyxoviridae/genetics , Paramyxoviridae Infections/drug therapy , Paramyxoviridae Infections/virology , Pneumovirus/genetics , Pneumovirus Infections/drug therapy , Pneumovirus Infections/virology
7.
mSphere ; 6(3): e0047921, 2021 06 30.
Article in English | MEDLINE | ID: mdl-34160242

ABSTRACT

Coinfection by heterologous viruses in the respiratory tract is common and can alter disease severity compared to infection by individual virus strains. We previously found that inoculation of mice with rhinovirus (RV) 2 days before inoculation with a lethal dose of influenza A virus [A/Puerto Rico/8/34 (H1N1) (PR8)] provides complete protection against mortality. Here, we extended that finding to a second lethal respiratory virus, pneumonia virus of mice (PVM), and analyzed potential mechanisms of RV-induced protection. RV completely prevented mortality and weight loss associated with PVM infection. Major changes in host gene expression upon PVM infection were delayed compared to PR8. RV induced earlier recruitment of inflammatory cells, which were reduced at later times in RV-inoculated mice. Findings common to both virus pairs included the upregulated expression of mucin-associated genes and dampening of inflammation-related genes in mice that were inoculated with RV before lethal virus infection. However, type I interferon (IFN) signaling was required for RV-mediated protection against PR8 but not PVM. IFN signaling had minor effects on PR8 replication and contributed to controlling neutrophilic inflammation and hemorrhagic lung pathology in RV/PR8-infected mice. These findings, combined with differences in virus replication levels and disease severity, suggest that the suppression of inflammation in RV/PVM-infected mice may be due to early, IFN-independent suppression of viral replication, while that in RV/PR8-infected mice may be due to IFN-dependent modulation of immune responses. Thus, a mild upper respiratory viral infection can reduce the severity of a subsequent severe viral infection in the lungs through virus-dependent mechanisms. IMPORTANCE Respiratory viruses from diverse families cocirculate in human populations and are frequently detected within the same host. Although clinical studies suggest that infection by multiple different respiratory viruses may alter disease severity, animal models in which we can control the doses, timing, and strains of coinfecting viruses are critical to understanding how coinfection affects disease severity. Here, we compared gene expression and immune cell recruitment between two pairs of viruses (RV/PR8 and RV/PVM) inoculated sequentially in mice, both of which result in reduced severity compared to lethal infection by PR8 or PVM alone. Reduced disease severity was associated with suppression of inflammatory responses in the lungs. However, differences in disease kinetics and host and viral gene expression suggest that protection by coinfection with RV may be due to distinct molecular mechanisms. Indeed, we found that antiviral cytokine signaling was required for RV-mediated protection against lethal infection by PR8 but not PVM.


Subject(s)
Coinfection/immunology , Host-Pathogen Interactions , Interferon Type I/immunology , Picornaviridae Infections/immunology , Rhinovirus/immunology , Rhinovirus/pathogenicity , Animals , Coinfection/virology , Female , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Influenza A virus/immunology , Influenza A virus/pathogenicity , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Murine pneumonia virus/immunology , Murine pneumonia virus/pathogenicity , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Pneumovirus Infections/immunology , Pneumovirus Infections/prevention & control , Severity of Illness Index , Transcriptome , Virus Replication
8.
Viruses ; 13(5)2021 04 22.
Article in English | MEDLINE | ID: mdl-33922096

ABSTRACT

Respiratory virus infections can have long-term effects on lung function that persist even after the acute responses have resolved. Numerous studies have linked severe early childhood infection with respiratory syncytial virus (RSV) to the development of wheezing and asthma, although the underlying mechanisms connecting these observations remain unclear. Here, we examine airway hyperresponsiveness (AHR) that develops in wild-type mice after recovery from symptomatic but sublethal infection with the natural rodent pathogen, pneumonia virus of mice (PVM). We found that BALB/c mice respond to a limited inoculum of PVM with significant but reversible weight loss accompanied by virus replication, acute inflammation, and neutrophil recruitment to the airways. At day 21 post-inoculation, virus was no longer detected in the airways and the acute inflammatory response had largely resolved. However, and in contrast to most earlier studies using the PVM infection model, all mice survived the initial infection and all went on to develop serum anti-PVM IgG antibodies. Furthermore, using both invasive plethysmography and precision-cut lung slices, we found that these mice exhibited significant airway hyperresponsiveness at day 21 post-inoculation that persisted through day 45. Taken together, our findings extend an important and versatile respiratory virus infection model that can now be used to explore the role of virions and virion clearance as well as virus-induced inflammatory mediators and their signaling pathways in the development and persistence of post-viral AHR and lung dysfunction.


Subject(s)
Murine pneumonia virus/immunology , Pneumovirus Infections/complications , Pneumovirus Infections/veterinary , Respiratory Hypersensitivity/etiology , Animals , Antibodies, Viral/immunology , Humans , Lung/immunology , Lung/virology , Mice , Mice, Inbred BALB C , Murine pneumonia virus/physiology , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/virology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/immunology , Respiratory Syncytial Virus, Human/physiology
9.
Viruses ; 12(12)2020 12 02.
Article in English | MEDLINE | ID: mdl-33276587

ABSTRACT

The paramyxo- and pneumovirus family includes a wide range of viruses that can cause respiratory and/or systemic infections in humans and animals. The significant disease burden of these viruses is further exacerbated by the limited therapeutics that are currently available. Host cellular proteins that can antagonize or limit virus replication are therefore a promising area of research to identify candidate molecules with the potential for host-targeted therapies. Host proteins known as host cell restriction factors are constitutively expressed and/or induced in response to virus infection and include proteins from interferon-stimulated genes (ISGs). Many ISG proteins have been identified but relatively few have been characterized in detail and most studies have focused on studying their antiviral activities against particular viruses, such as influenza A viruses and human immunodeficiency virus (HIV)-1. This review summarizes current literature regarding host cell restriction factors against paramyxo- and pneumoviruses, on which there is more limited data. Alongside discussion of known restriction factors, this review also considers viral countermeasures in overcoming host restriction, the strengths and limitations in different experimental approaches in studies reported to date, and the challenges in reconciling differences between in vitro and in vivo data. Furthermore, this review provides an outlook regarding the landscape of emerging technologies and tools available to study host cell restriction factors, as well as the suitability of these proteins as targets for broad-spectrum antiviral therapeutics.


Subject(s)
Host-Pathogen Interactions , Paramyxoviridae Infections/virology , Paramyxovirinae/physiology , Pneumovirus Infections/virology , Pneumovirus/physiology , Animals , Biomarkers , Gene Expression Regulation, Viral , Host Specificity , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Paramyxoviridae Infections/genetics , Paramyxoviridae Infections/metabolism , Pneumovirus Infections/genetics , Pneumovirus Infections/metabolism , Viral Tropism , Virus Replication
10.
Gac Med Mex ; 156(4): 265-272, 2020.
Article in English | MEDLINE | ID: mdl-32831337

ABSTRACT

INTRODUCTION: Acute respiratory infections are the second cause of mortality in children younger than five years, with 150.7 million episodes per year. Human orthopneumovirus (hOPV) and metapneumovirus (hMPV) are the first and second causes of bronchiolitis; type 2 human orthorubulavirus (hORUV) has been associated with pneumonia in immunocompromised patients. OBJECTIVE: To define hOPV, hMPV and hORUV geographical distribution and circulation patterns. METHOD: An observational, prospective cross-sectional pilot study was carried out. Two-hundred viral strains obtained from pediatric patients were genotyped by endpoint reverse transcription polymerase chain reaction (RT-PCR). RESULTS: One-hundred and eighty-six positive samples were typed: 84 hOPV, 43 hMPV, two hORUV and 57 co-infection specimens. Geographical distribution was plotted. hMPV, hOPV, and hORUV cumulative incidences were 0.215, 0.42, and 0.01, respectively. Cumulative incidence of hMPV-hORUV and hMPV-hOPV coinfection was 0.015 and 0.23; for hOPV-hMPV-hORUV, 0.035; and for hORUV-hOPV, 0.005. The largest number of positive cases of circulating or co-circulating viruses occurred between January and March. CONCLUSIONS: This study successfully identified circulation and geographical distribution patterns of the different viruses, as well as of viral co-infections.


INTRODUCCIÓN: Las infecciones respiratorias agudas constituyen la segunda causa de mortalidad en los niños menores de cinco años, con 150.7 millones de episodios anuales. Entre los principales agentes etiológicos están Orthopneumovirus (hOPV) y metapneumovirus (hMPV) humanos como primera y segunda causa de bronquiolitis, respectivamente; Orthorubulavirus humano tipo 2 (hORUV) se ha asociado a neumonía en pacientes inmunocomprometidos. OBJETIVO: Definir patrones de distribución geográfica y de circulación de hOPV, hMPV y hORUV. MÉTODO: Se llevó a cabo un estudio piloto transversal prospectivo observacional. Se genotipificaron 200 aislamientos virales de pacientes pediátricos mediante transcripción inversa seguida de reacción en cadena de la polimerasa en punto final (RT-PCR). RESULTADOS: Se tipificaron 186 muestras positivas: 84 de hOPV, 43 de hMPV, dos de hORUV y 57 de coinfecciones. Se trazó la distribución geográfica. Las incidencias acumuladas de hMPV, hOPV y hORUV fueron de 0.215, 0.42 y 0.01, respectivamente. Las incidencias acumuladas de la coinfección de hMPV-hORUV y hMPV-hOPV fueron de 0.015 y 0.23; de hOPV-hMPV-hORUV, de 0.035; y de hORUV-hOPV, de 0.005. El mayor número de casos positivos de virus circulantes o cocirculantes se presentó entre enero y marzo. CONCLUSIONES: Fue posible identificar patrones de circulación y distribución geográfica de los diferentes virus, así como de las coinfecciones virales.


Subject(s)
Paramyxoviridae Infections/epidemiology , Pneumovirus Infections/epidemiology , Respiratory Tract Infections/epidemiology , Rubulavirus Infections/epidemiology , Adolescent , Child , Child, Preschool , Coinfection/epidemiology , Coinfection/virology , Cross-Sectional Studies , Genotype , Humans , Incidence , Infant , Infant, Newborn , Paramyxoviridae Infections/virology , Pilot Projects , Pneumovirus Infections/virology , Prospective Studies , Respiratory Tract Infections/virology , Reverse Transcriptase Polymerase Chain Reaction , Rubulavirus Infections/virology
11.
Gac. méd. Méx ; 156(4): 263-269, Jul.-Aug. 2020. tab, graf
Article in English | LILACS | ID: biblio-1249909

ABSTRACT

Abstract Introduction: Acute respiratory infections are the second cause of mortality in children younger than five years, with 150.7 million episodes per year. Human orthopneumovirus (hOPV) and metapneumovirus (hMPV) are the first and second causes of bronchiolitis; type 2 human orthorubulavirus (hORUV) has been associated with pneumonia in immunocompromised patients. Objective: To define hOPV, hMPV and hORUV geographical distribution and circulation patterns. Method: An observational, prospective cross-sectional pilot study was carried out. Two-hundred viral strains obtained from pediatric patients were genotyped by endpoint reverse transcription polymerase chain reaction (RT-PCR). Results: One-hundred and eighty-six positive samples were typed: 84 hOPV, 43 hMPV, two hORUV and 57 co-infection specimens. Geographical distribution was plotted. hMPV, hOPV, and hORUV cumulative incidences were 0.215, 0.42, and 0.01, respectively. Cumulative incidence of hMPV-hORUV and hMPV-hOPV coinfection was 0.015 and 0.23; for hOPV-hMPV-hORUV, 0.035; and for hORUV-hOPV, 0.005. The largest number of positive cases of circulating or co-circulating viruses occurred between January and March. Conclusions: This study successfully identified circulation and geographical distribution patterns of the different viruses, as well as of viral co-infections.


Resumen Introducción: Las infecciones respiratorias agudas constituyen la segunda causa de mortalidad en los niños menores de cinco años, con 150.7 millones de episodios anuales. Entre los principales agentes etiológicos están Orthopneumovirus (hOPV) y metapneumovirus (hMPV) humanos como primera y segunda causa de bronquiolitis, respectivamente; Orthorubulavirus humano tipo 2 (hORUV) se ha asociado a neumonía en pacientes inmunocomprometidos. Objetivo: Definir patrones de distribución geográfica y de circulación de hOPV, hMPV y hORUV. Método: Se llevó a cabo un estudio piloto transversal prospectivo observacional. Se genotipificaron 200 aislamientos virales de pacientes pediátricos mediante transcripción inversa seguida de reacción en cadena de la polimerasa en punto final (RT-PCR). Resultados: Se tipificaron 186 muestras positivas: 84 de hOPV, 43 de hMPV, dos de hORUV y 57 de coinfecciones. Se trazó la distribución geográfica. Las incidencias acumuladas de hMPV, hOPV y hORUV fueron de 0.215, 0.42 y 0.01, respectivamente. Las incidencias acumuladas de la coinfección de hMPV-hORUV y hMPV-hOPV fueron de 0.015 y 0.23; de hOPV-hMPV-hORUV, de 0.035; y de hORUV-hOPV, de 0.005. El mayor número de casos positivos de virus circulantes o cocirculantes se presentó entre enero y marzo. Conclusiones: Fue posible identificar patrones de circulación y distribución geográfica de los diferentes virus, así como de las coinfecciones virales.


Subject(s)
Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Respiratory Tract Infections/epidemiology , Pneumovirus Infections/epidemiology , Paramyxoviridae Infections/epidemiology , Reverse Transcriptase Polymerase Chain Reaction , Respiratory Tract Infections/virology , Pilot Projects , Incidence , Cross-Sectional Studies , Prospective Studies , Pneumovirus Infections/virology , Paramyxoviridae Infections/virology , Rubulavirus Infections/virology , Coinfection/epidemiology , Coinfection/virology , Genotype
12.
Mucosal Immunol ; 13(5): 799-813, 2020 09.
Article in English | MEDLINE | ID: mdl-32424182

ABSTRACT

Human respiratory syncytial virus (RSV) is a pneumovirus that causes severe infections in infants worldwide. Despite intensive research, safe and effective vaccines against RSV have remained elusive. The main reason is that RSV infection of children previously immunized with formalin-inactivated-RSV vaccines has been associated with exacerbated pathology, a phenomenon called RSV vaccine-enhanced respiratory disease. In parallel, despite the high RSV prevalence, only a minor proportion of children develop severe diseases. Interestingly, variation in the immune responses against RSV or following RSV vaccination could be linked with differences of exposure to microbes during childhood. Gammaherpesviruses (γHVs), such as the Epstein-Barr virus, are persistent viruses that deeply influence the immune system of their host and could therefore affect the development of pneumovirus-induced immunopathologies for the long term. Here, we showed that a previous ɣHV infection protects against both pneumovirus vaccine-enhanced disease and pneumovirus primary infection and that CD8 T cells are essential for this protection. These observations shed a new light on the understanding of pneumovirus-induced diseases and open new perspectives for the development of vaccine strategies.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Disease Susceptibility , Gammaherpesvirinae/immunology , Host-Pathogen Interactions/immunology , Pneumovirus Infections/etiology , Pneumovirus Infections/metabolism , Pneumovirus/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Disease Models, Animal , Humans , Immunophenotyping , Leukocytes/immunology , Leukocytes/metabolism , Leukocytes/pathology , Lung/immunology , Lung/metabolism , Lung/pathology , Mice , Microbial Interactions , Pneumovirus Infections/pathology , Respiratory Syncytial Virus Infections/etiology , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus, Human/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Vaccination , Viral Vaccines/immunology
13.
Viruses ; 12(3)2020 03 20.
Article in English | MEDLINE | ID: mdl-32245118

ABSTRACT

Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Paramyxovirinae/physiology , Pneumovirus/physiology , Virus Internalization/drug effects , Animals , Binding Sites , Drug Discovery/methods , Humans , Models, Molecular , Paramyxoviridae Infections/drug therapy , Paramyxoviridae Infections/virology , Paramyxovirinae/drug effects , Pneumovirus/drug effects , Pneumovirus Infections/drug therapy , Pneumovirus Infections/virology , Protein Binding , Structure-Activity Relationship
14.
Front Immunol ; 10: 2778, 2019.
Article in English | MEDLINE | ID: mdl-31849961

ABSTRACT

The pneumoviruses respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two widespread human pathogens that can cause severe disease in the young, the elderly, and the immunocompromised. Despite the discovery of RSV over 60 years ago, and hMPV nearly 20 years ago, there are no approved vaccines for either virus. Antibody-mediated immunity is critical for protection from RSV and hMPV, and, until recently, knowledge of the antibody epitopes on the surface glycoproteins of RSV and hMPV was very limited. However, recent breakthroughs in the recombinant expression and stabilization of pneumovirus fusion proteins have facilitated in-depth characterization of antibody responses and structural epitopes, and have provided an enormous diversity of new monoclonal antibody candidates for therapeutic development. These new data have primarily focused on the RSV F protein, and have led to a wealth of new vaccine candidates in preclinical and clinical trials. In contrast, the major structural antibody epitopes remain unclear for the hMPV F protein. Overall, this review will cover recent advances in characterizing the antigenic sites on the RSV and hMPV F proteins.


Subject(s)
Antibodies, Viral/immunology , Epitopes/immunology , Pneumovirus Infections/epidemiology , Pneumovirus Infections/immunology , Pneumovirus/immunology , Viral Fusion Proteins/immunology , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Viral/chemistry , Antigens, Viral/chemistry , Antigens, Viral/immunology , Cost of Illness , Epitopes/chemistry , Global Health , Humans , Pneumovirus Infections/virology , Protein Binding/immunology , Public Health Surveillance , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/immunology , Structure-Activity Relationship , Viral Fusion Proteins/chemistry
15.
Antiviral Res ; 171: 104594, 2019 11.
Article in English | MEDLINE | ID: mdl-31470041

ABSTRACT

Respiratory syncytial virus (RSV) is responsible for a large proportion of acute lower respiratory tract infections, specifically in children. Pneumonia virus of mice (PVM) causes similar lung pathology and clinical disease in rodents, and is therefore an appropriate model of RSV infection. Previously, we demonstrated that a single intranasal dose of P-I-P, a novel immunomodulator composed of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene, confers protection in Balb/c mice for up to 3 days from lethal PVM-15 infection. In the present study a dual intranasal treatment with P-I-P was shown to extend the duration of the protection conferred by P-I-P from PVM-15 challenge. Balb/c mice treated twice with P-I-P showed higher survival rates and milder clinical signs when compared to animals that received a single P-I-P dose. While the mice treated with two consecutive doses of P-I-P experienced some weight loss, they all recovered. The dual P-I-P treatment mediated infiltration of several innate immune cells into the BALF and lung, including alveolar macrophages, neutrophils, and γδ T cells. Partial depletion of alveolar macrophages decreased survival rates and exacerbated clinical signs of mice subjected to the P-I-P dual treatment regime followed by PVM-15 challenge. This suggests that the alveolar macrophage is at least partially responsible for the protection elicited by this novel prophylactic treatment strategy.


Subject(s)
Immunity, Innate , Immunologic Factors/pharmacology , Macrophages/drug effects , Macrophages/immunology , Murine pneumonia virus/drug effects , Murine pneumonia virus/immunology , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Animals , Cell Line , Cytokines/biosynthesis , Cytokines/blood , Female , Host-Pathogen Interactions , Immunologic Factors/administration & dosage , Macrophages/metabolism , Macrophages/virology , Mice , Pneumovirus Infections/drug therapy , Pneumovirus Infections/mortality
16.
BMC Vet Res ; 15(1): 300, 2019 Aug 19.
Article in English | MEDLINE | ID: mdl-31426794

ABSTRACT

BACKGROUND: Canine pneumovirus (CPV) is a pathogen that causes respiratory disease in dogs, and recent outbreaks in shelters in America and Europe have been reported. However, based on published data and documents, the identification of CPV and its variant in clinically symptomatic individual dogs in Thailand through Asia is limited. Therefore, the aims of this study were to determine the emergence of CPV and to consequently establish the genetic characterization and phylogenetic analysis of the CPV strains from 209 dogs showing respiratory distress in Thailand. RESULTS: This study identified and described the full-length CPV genome from three strains, designated herein as CPV_CP13 TH/2015, CPV_CP82 TH/2016 and CPV_SR1 TH/2016, that were isolated from six dogs out of 209 dogs (2.9%) with respiratory illness in Thailand. Phylogenetic analysis suggested that these three Thai CPV strains (CPV TH strains) belong to the CPV subgroup A and form a novel lineage; proposed as the Asian prototype. Specific mutations in the deduced amino acids of these CPV TH strains were found in the G/glycoprotein sequence, suggesting potential substitution sites for subtype classification. Results of intragenic recombination analysis revealed that CPV_CP82 TH/2016 is a recombinant strain, where the recombination event occurred in the L gene with the Italian prototype CPV Bari/100-12 as the putative major parent. Selective pressure analysis demonstrated that the majority of the nucleotides in the G/glycoprotein were under purifying selection with evidence of positive selection sites. CONCLUSIONS: This collective information on the CPV TH strains is the first evidence of CPV emergence with genetic characterization in Thailand and as first report in Asia, where homologous recombination acts as a potential force driving the genetic diversity and shaping the evolution of canine pneumovirus.


Subject(s)
Dog Diseases/virology , Phylogeny , Pneumovirus Infections/veterinary , Pneumovirus/classification , Reassortant Viruses/genetics , Respiratory Tract Infections/veterinary , Amino Acid Sequence , Animals , Dog Diseases/epidemiology , Dogs , Genome, Viral , Mutation , Pneumovirus/genetics , Pneumovirus Infections/epidemiology , Pneumovirus Infections/virology , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Thailand/epidemiology , Viral Proteins/genetics , Viral Proteins/metabolism
17.
Acta Clin Belg ; 74(4): 229-235, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30029583

ABSTRACT

Objectives: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are important respiratory pathogens. Both viral pathogens have similar clinical manifestations. The epidemiology of RSV is well known, that of hMPV is less clear. We reviewed the results of 10 consecutive years of molecular testing for RSV and hMPV in respiratory samples of Flemish patients. Methods: In the laboratory of the OLV hospital Aalst, Belgium, multiplex RT-PCR assays are used for the detection of RSV and hMPV. The lab receives invasive and noninvasive respiratory samples of patients from all over Flanders. Results: Between September 2006 and August 2016, 16,826 respiratory samples were analyzed for RSV and hMPV. Of these samples, 18% tested positive for RSV and 7.3% for hMPV. RSV consistently peaked in November/December each year within a very narrow time frame. The occurrence of hMPV was less predictable and spreaded more widely throughout the winter and spring. Both viruses were mainly found in samples from young children. RSV was most frequently detected in samples from infants <3 months, while hMPV peaked between 6 and 9 months. After the age of 1 year, RSV rapidly dropped. hMPV dropped a little later and slower. Both viruses slightly increased again at older age (>50 years). Conclusions: Despite their similarities, some of the epidemiologic characteristics of hMPV and RSV differ. The most striking difference is the annual distribution of RSV and hMPV infections.


Subject(s)
Metapneumovirus/isolation & purification , Pneumovirus Infections , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human/isolation & purification , Respiratory Tract Infections , Adult , Age Factors , Aged , Belgium/epidemiology , Child , Female , Humans , Infant , Male , Pneumovirus Infections/epidemiology , Pneumovirus Infections/virology , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/virology , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Seasons
18.
J Immunol ; 202(3): 871-882, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30578308

ABSTRACT

Severe respiratory virus infections feature robust local host responses that contribute to disease severity. Immunomodulatory strategies that limit virus-induced inflammation may be of critical importance, notably in the absence of antiviral vaccines. In this study, we examined the role of the pleiotropic cytokine IL-6 in acute infection with pneumonia virus of mice (PVM), a natural rodent pathogen that is related to respiratory syncytial virus and that generates local inflammation as a feature of severe infection. In contrast to Influenza A, PVM is substantially less lethal in IL-6 -/- mice than it is in wild-type, a finding associated with diminished neutrophil recruitment and reduced fluid accumulation in lung tissue. Ly6Chi proinflammatory monocytes are recruited in response to PVM via a CCR2-dependent mechanism, but they are not a major source of IL-6 nor do they contribute to lethal sequelae of infection. By contrast, alveolar macrophages are readily infected with PVM in vivo; ablation of alveolar macrophages results in prolonged survival in association with a reduction in virus-induced IL-6. Finally, as shown previously, administration of immunobiotic Lactobacillus plantarum to the respiratory tracts of PVM-infected mice promoted survival in association with diminished levels of IL-6. We demonstrated in this study that IL-6 suppression is a critical feature of the protective mechanism; PVM-infected IL-6 -/- mice responded to low doses of L. plantarum, and administration of IL-6 overcame L. plantarum-mediated protection in PVM-infected wild-type mice. Taken together, these results connect the actions of IL-6 to PVM pathogenesis and suggest cytokine blockade as a potential therapeutic modality in severe infection.


Subject(s)
Interleukin-6/immunology , Murine pneumonia virus/immunology , Pneumovirus Infections/immunology , Animals , Inflammation , Interleukin-6/pharmacology , Lactobacillus plantarum/immunology , Lung/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Probiotics/administration & dosage , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , Respiratory System/immunology , Respiratory System/virology
19.
Vet Res ; 49(1): 118, 2018 Dec 05.
Article in English | MEDLINE | ID: mdl-30518406

ABSTRACT

The presence of pneumoviruses in pigs is poorly documented. In this study, we used the published sequence of the nucleoprotein (N) of the recently identified Swine Orthopneumovirus (SOV) to express and purify SOV N as a recombinant protein in Escherichia coli. This protein was purified as nanorings and used to set up an enzyme-linked immunosorbent assay, which was used to analyse the presence of anti-pneumovirus N antibodies in swine sera. Sera collected from different pig farms in the West of France and from specific pathogen free piglets before colostrum uptake showed indirectly that a pneumovirus is circulating in pig populations with some variations between animals. Piglets before colostrum uptake were sero-negative for anti-pneumovirus antibodies while most of the other pigs showed positivity. Interestingly, in two farms presenting respiratory clinical signs and negative or under control for some common respiratory pathogens, pigs were detected positive for anti-pneumovirus antibodies. Globally, anti-pneumovirus N antibody concentrations were variable between and within farms. Further studies will aim to isolate the circulating virus and determine its potential pathogenicity. SOV could potentially become a new member of the porcine respiratory complex, important on its own or in association with other viral and bacterial micro-organisms.


Subject(s)
Antibodies, Viral/blood , Nucleocapsid Proteins/blood , Pneumovirus Infections/veterinary , Pneumovirus/isolation & purification , Swine Diseases/virology , Animals , Colostrum , Enzyme-Linked Immunosorbent Assay/veterinary , Escherichia coli/genetics , France , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Recombinant Proteins/analysis , Sequence Analysis, RNA/veterinary , Specific Pathogen-Free Organisms , Swine , Swine Diseases/immunology
20.
J Immunol ; 200(2): 632-642, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29212906

ABSTRACT

A link between inflammatory disease and bone loss is now recognized. However, limited data exist on the impact of virus infection on bone loss and regeneration. Bone loss results from an imbalance in remodeling, the physiological process whereby the skeleton undergoes continual cycles of formation and resorption. The specific molecular and cellular mechanisms linking virus-induced inflammation to bone loss remain unclear. In the current study, we provide evidence that infection of mice with either lymphocytic choriomeningitis virus (LCMV) or pneumonia virus of mice (PVM) resulted in rapid and substantial loss of osteoblasts from the bone surface. Osteoblast ablation was associated with elevated levels of circulating inflammatory cytokines, including TNF-α, IFN-γ, IL-6, and CCL2. Both LCMV and PVM infections resulted in reduced osteoblast-specific gene expression in bone, loss of osteoblasts, and reduced serum markers of bone formation, including osteocalcin and procollagen type 1 N propeptide. Infection of Rag-1-deficient mice (which lack adaptive immune cells) or specific depletion of CD8+ T lymphocytes limited osteoblast loss associated with LCMV infection. By contrast, CD8+ T cell depletion had no apparent impact on osteoblast ablation in association with PVM infection. In summary, our data demonstrate dramatic loss of osteoblasts in response to virus infection and associated systemic inflammation. Further, the inflammatory mechanisms mediating viral infection-induced bone loss depend on the specific inflammatory condition.


Subject(s)
Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Murine pneumonia virus/immunology , Osteoblasts/virology , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Animals , Biomarkers , Bone Marrow/pathology , Bone and Bones/metabolism , Bone and Bones/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Homeodomain Proteins/genetics , Lymphocyte Depletion , Mice , Mice, Knockout , Osteoblasts/immunology , Osteogenesis
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