A Prospective Study Comparing Human Metapneumovirus with Other Respiratory Viruses in Adults with Hematologic Malignancies and Respiratory Tract Infections

Williams, John V.; Martino, Rodrigo; Rabella, N; Otegui, M.; Parody, Rocío; Heck, Joshua M.; Crowe, James E.

doi:10.1086/432732

Cited by 159 publications

(155 citation statements)

References 15 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…We evaluated whether immature mouse DCs are permissive to hMPV infection by inoculating DCs with variable amounts of infectious (MOI [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and UV-inactivated hMPV (UV-hMPV). After inoculation, DCs expressing the fusion and nucleoprotein of hMPV could be easily identified by fluorescence microscopy among other noninfected DCs (Fig.…”

Section: Hmpv Infects Mouse Dcsmentioning

confidence: 99%

“…1,2 Human metapneumovirus (hMPV) is a respiratory virus belonging to the Pneumovirinae subfamily and the Metapneumovirus genus, which has been suggested to be the cause of a significant proportion of respiratory illnesses in the paediatric and adult populations, producing considerable morbidity. 1,[3][4][5] Despite modest viral antigenic variability and the presence of anti-viral antibodies, re-infections are recurrent in all age groups.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

2013

View full text Add to dashboard Cite

SummaryHuman metapneumovirus (hMPV) is the second most common cause of acute lower respiratory tract infections in children, causing a significant public health burden worldwide. Given that hMPV can repeatedly infect the host without major antigenic changes, it has been suggested that hMPV may have evolved molecular mechanisms to impair host adaptive immunity and, more specifically, T-cell memory. Recent studies have shown that hMPV can interfere with superantigen-induced T-cell activation by infecting conventional dendritic cells (DCs). Here, we show that hMPV infects mouse DCs in a restricted manner and induces moderate maturation. Nonetheless, hMPV-infected DCs are rendered inefficient at activating naive antigen-specific CD4 + T cells (OT-II), which not only display reduced proliferation, but also show a marked reduction in surface activation markers and interleukin-2 secretion. Decreased T-cell activation was not mediated by interference with DC-T-cell immunological synapse formation as recently described for the human respiratory syncytial virus (hRSV), but rather by soluble factors secreted by hMPV-infected DCs. These data suggest that although hMPV infection is restricted within DCs, it is sufficient to interfere with their capacity to activate naive T cells. Altogether, by interfering with DC function and productive priming of antigen-inexperienced T cells, hMPV could impair the generation of long-term immunity.

show abstract

Section: Hmpv Infects Mouse Dcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

2013

View full text Add to dashboard Cite

show abstract

“…uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1)(2)(3)(4)(5)(6)(7)(8)(9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection.…”

mentioning

confidence: 99%

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

View full text Add to dashboard Cite

Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR ؊/؊ ) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8 ؉ T cell response. HMPV-infected IFNAR ؊/؊ mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR ؊/؊ mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8؉ T cells of IFNAR ؊/؊ mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8 ؉ T cells of IFNAR ؊/؊ mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1 low dendritic cells (DCs), but not PD-L1 high alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8 ؉ T cell impairment. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8 ؉ T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8؉ T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8 ؉ T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8 ؉ T cell impairment. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1-9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection. Nearly all individuals have been exposed to HMPV by the age of 5 years (10, 11). Infection with this virus results in a neutralizing antibody (n...

show abstract

“…uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract infection worldwide, with high prevalence in pediatric, elderly, and immunocompromised patients (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). There are no licensed vaccines against HMPV.…”

mentioning

confidence: 99%

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Cox

Erickson

Hastings

et al. 2014

J Virol

View full text Add to dashboard Cite

Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract infection worldwide, with high prevalence in pediatric, elderly, and immunocompromised patients (1-12). There are no licensed vaccines against HMPV. Several strategies to develop live-attenuated HMPV vaccines have been explored, including cold passage, gene deletion, and chimeric viruses (13-17). While live-virus vaccines elicit humoral and cellular responses, they also pose safety risks. Attenuated virus strains have the potential to revert to a wild-type phenotype and cause disease or be transmitted to nonimmune individuals. For these reasons, live attenuated vaccines are often contraindicated for immunocompromised patients, individuals who are at risk for severe HMPV infections. Moreover, it is often difficult to find the correct balance between attenuation and immunogenicity. Many years of research on respiratory syncytial virus (RSV) live attenuated vaccines attest to the challenges (18)(19)(20)(21)(22).GSubunit protein vaccines against HMPV targeting mainly the fusion (F) protein have been effective in rodent models by inducing B cell responses only (23,24). Experience with formalin-inactivated (FI) RSV and HMPV vaccines in humans and animals further raises concern about imbalanced immunity (25)(26)(27)(28)(29)(30). Studies demonstrate that the generation of antibodies to a denatured F protein or low-affinity nonneutralizing antibodies is associated with enhanced respiratory disease (31-36). Thus, a safe and effective vaccine should induce both potent neutralizing antibodies and cytotoxic T cell responses.A vaccination strategy combining elements of both live virus and subunit vaccines is virus-like particles (VLPs). VLPs are formed by the self-assembly of viral structural proteins but lack

show abstract

A Prospective Study Comparing Human Metapneumovirus with Other Respiratory Viruses in Adults with Hematologic Malignancies and Respiratory Tract Infections

Cited by 159 publications

References 15 publications

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

Human metapneumovirus keeps dendritic cells from priming antigen‐specific naive T cells

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Contact Info

Product

Resources

About