Paramyxovirus Infection Regulates T Cell Responses by BDCA-1+ and BDCA-3+ Myeloid Dendritic Cells (original) (raw)
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Differential Response of Dendritic Cells to Human Metapneumovirus and Respiratory Syncytial Virus
American Journal of Respiratory Cell and Molecular Biology, 2006
Dendritic cells (DCs) play a pivotal role in shaping antiviral immune responses in the respiratory tract. Human metapneumovirus (hMPV) is a recently identified pathogen and like its better known relative, respiratory syncytial virus (RSV), has been increasingly recognized as a major cause of respiratory morbidity in infants and in elderly persons. In the present study, we examined susceptibility as well as cellular responses of human DCs to hMPV compared with RSV. Monocyte-derived DCs (moDCs) were susceptible to infection by both viruses, but only RSV was able to induce a productive infection with release of viral progeny. Despite the fact that viral infection resulted in phenotypic maturation of moDCs, as shown by the upregulation of cell surface markers and antigen-presenting molecules (MHC I and II, CD80, CD83, CD86, CD38), RSV-infected moDCs showed a severely impaired capacity to stimulate CD4 ϩ T cell proliferation. Compared with hMPV, RSV was a more potent inducer of inflammatory and immunomodulatory cytokines, including TNF-␣, IL-6, IL-1, IL-10, and IL-12p70 in both moDCs and plasmacytoid dendritic cells (pDCs). On the other hand, hMPV, but not RSV, was able to trigger production of IFN-␣ by moDCs, while both viruses strongly induced IFN-␣ in pDCs. Finally, both viruses strikingly suppressed IFN-␣ production by moDCs or pDCs stimulated with synthetic dsRNA and CpG-ODN, respectively. The findings provide novel evidence that RSV and hMPV differentially activate human DCs and may use distinct mechanisms to interfere with the host innate and adaptive immune responses.
Journal of Virology, 2008
Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a leading cause of lower respiratory tract infections in children, the elderly, and immunocompromised patients. Virus-and host-specific mechanisms of pathogenesis and immune protection are not fully understood. By an intranasal inoculation model, we show that hMPV-infected BALB/c mice developed clinical disease, including airway obstruction and hyperresponsiveness (AHR), along with histopathologic evidence of lung inflammation and viral replication. hMPV infection protected mice against subsequent viral challenge, as demonstrated by undetectable viral titers, lack of body weight loss, and a significant reduction in the level of lung inflammation. No crossprotection with other paramyxoviruses, such as respiratory syncytial virus, was observed. T-lymphocyte depletion studies showed that CD4 ؉ and CD8 ؉ T cells cooperate synergistically in hMPV eradication during primary infection, but CD4 ؉ more than CD8 ؉ T cells also enhanced clinical disease and lung pathology.
Respiratory research, 2013
Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in children, elderly, and immunocompromised individuals. Severe infection is associated with short- and long-term morbidity including pneumonia, recurrent wheezing, and abnormal pulmonary function, and several lines of evidence indicate that impaired adaptive immune responses during infection are critical in the pathophysiology of RSV-mediated disease. Myeloid Dendritic cells (mDCs) play a pivotal role in shaping antiviral immune responses in the respiratory tract; however, few studies have examined the interactions between RSV and individual mDC subsets. In this study, we examined the effect of RSV on the functional response of primary mDC subsets (BDCA-1(+) and BDCA-3(+)) isolated from peripheral blood. BDCA-1(+) and BDCA-3(+) mDCs were isolated from the peripheral blood of healthy adults using FACS sorting. Donor-matched BDCA-1(+) and BDCA-3(+) mDCs were infected with RSV at a multiplicity of infecti...
Characterization of human metapneumovirus infection of myeloid dendritic cells
Virology, 2007
Recent in vivo studies suggest that hMPV is a poor inducer of inflammatory cytokines and that clinical symptoms may not be related to immune-mediated pathogenesis as it has been proposed for respiratory syncytial virus (RSV) and human parainfluenza 3 (HPF3). Dendritic cells (DCs) are specialized antigen presenting cells, and very effective at inducing specific CTLs after encountering invading viruses. Interactions of hMPV with DCs have not been characterized. We hypothesized that the relatively mild inflammatory responses observed in vivo after hMPV infection might be at least in part due to hMPV's poor ability to stimulate and activate DCs. hMPV actively infected immature monocyte-derived CD11c+/HLA-DR+ DCs. However, in contrast to RSV or HPF3, hMPV caused no gross cytopathic effects such as syncytia, lytic infection, or massive apoptosis. DCs exposed to hMPV show no cytopathic effects under tissue culture conditions permissive for viral replication. The surface maturation markers CD83 and CD86 were not significantly up-regulated in infected DCs as compared to uninfected controls, while expression of CD80 appeared increased. Stimulation of hMPV-infected DCs with LPS resulted in the enhanced expression of all these surface markers indicating that hMPV is not generally suppressing DC maturation. Overall, cytokine expression remained low. These results indicate that hMPV does not induce effective DC maturation in vitro and suggest that the weak stimulation of DCs may account for the overall low immunogenicity of this virus observed in vivo.
2010
Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a leading cause of lower respiratory tract infections in children, the elderly, and immunocompromised patients. Virus-and host-specific mechanisms of pathogenesis and immune protection are not fully understood. By an intranasal inoculation model, we show that hMPV-infected BALB/c mice developed clinical disease, including airway obstruction and hyperresponsiveness (AHR), along with histopathologic evidence of lung inflammation and viral replication. hMPV infection protected mice against subsequent viral challenge, as demonstrated by undetectable viral titers, lack of body weight loss, and a significant reduction in the level of lung inflammation. No crossprotection with other paramyxoviruses, such as respiratory syncytial virus, was observed. T-lymphocyte depletion studies showed that CD4 ؉ and CD8 ؉ T cells cooperate synergistically in hMPV eradication during primary infection, but CD4 ؉ more than CD8 ؉ T cells also enhanced clinical disease and lung pathology.
Virulence, 2016
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.
Host immunity during RSV pathogenesis
International Immunopharmacology, 2008
Infection by respiratory syncytial virus (RSV) is the leading cause of childhood hospitalization as well as a major health and economic burden worldwide. Unfortunately, RSV infection provides only limited immune protection to reinfection, mostly due to inadequate immunological memory, which leads to an exacerbated inflammatory response in the respiratory tract promoting airway damage during virus clearance. This exacerbated and inefficient immuneinflammatory response triggered by RSV, has often been attributed to the induction of a Th2biased immunity specific for some of the RSV antigens. These features of RSV infection suggest that the virus might possess molecular mechanisms to enhance allergic-type immunity in the host in order to prevent clearance by cytotoxic T cells and ensure survival and dissemination to other hosts. In this review, we discuss recent findings that contribute to explain the components of the innate and adaptive immune response that are involved in RSV-mediated disease exacerbation. Further, the virulence mechanisms used by RSV to avoid activation of protective immune responses are described.
The Human Metapneumovirus Matrix Protein Stimulates the Inflammatory Immune Response In Vitro
Plos One, 2011
Each year, during winter months, human Metapneumovirus (hMPV) is associated with epidemics of bronchiolitis resulting in the hospitalization of many infants. Bronchiolitis is an acute illness of the lower respiratory tract with a consequent inflammation of the bronchioles. The rapid onset of inflammation suggests the innate immune response may have a role to play in the pathogenesis of this hMPV infection. Since, the matrix protein is one of the most abundant proteins in the Paramyxoviridae family virion, we hypothesized that the inflammatory modulation observed in hMPV infected patients may be partly associated with the matrix protein (M-hMPV) response. By western blot analysis, we detected a soluble form of M-hMPV released from hMPV infected cell as well as from M-hMPV transfected HEK 293T cells suggesting that M-hMPV may be directly in contact with antigen presenting cells (APCs) during the course of infection. Moreover, flow cytometry and confocal microscopy allowed determining that M-hMPV was taken up by dendritic cells (moDCs) and macrophages inducing their activation. Furthermore, these moDCs enter into a maturation process inducing the secretion of a broad range of inflammatory cytokines when exposed to M-hMPV. Additionally, M-hMPV activated DCs were shown to stimulate IL-2 and IFN-c production by allogeneic T lymphocytes. This M-hMPV-mediated activation and antigen presentation of APCs may in part explain the marked inflammatory immune response observed in pathology induced by hMPV in patients.