Critical role of TLR4 in human metapneumovirus mediated innate immune responses and disease pathogenesis.

Thangam Sudha Velayutham, Deepthi Kolli, Teodora Ivanciuc, Roberto Garofalo, Antonella Casola

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Abstract

Human metapneumovirus (hMPV) is one of the main causes of acute respiratory tract infections in children, elderly and immunocompromised patients. The mammalian Toll-like receptors (TLR) were identified as critical regulators of innate immunity to a variety of microbes, including viruses. We have recently shown that hMPV-induced cytokine, chemokine and type I interferon secretion in dendritic cells occurs via TLR4, however, its role in hMPV-induced disease is unknown. In this study, wild-type(WT) and TLR4-deficient mice (TLR4-/-) were infected with hMPV and examined for clinical disease parameters, such as body weight loss and airway obstruction, viral clearance, lung inflammation, dendritic cell maturation, T-cell proliferation and antibody production. Our results demonstrate that absence of TLR4 in hMPV-infected mice significantly reduced the inflammatory response as well as disease severity, shown by reduced body weight loss and airway obstruction and hyperresponsiveness (AHR), compared to WT mice. Levels of cytokines and chemokines were also significantly lower in the TLR4-/- mice. Accordingly, recruitment of inflammatory cells in the BAL, lungs, as well as in lymph nodes, was significantly reduced in the TLR4-/- mice, however, viral replication and clearance, as well as T-cell proliferation and neutralizing antibody production, were not affected. Our findings indicate that TLR4 is important for the activation of the innate immune response to hMPV, however it does play a role in disease pathogenesis, as lack of TLR4 expression is associated with reduced clinical manifestations of hMPV disease, without affecting viral protection.

Original languageEnglish (US)
Article numbere78849
JournalPLoS One
Volume8
Issue number10
StatePublished - 2013

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Human metapneumovirus
Metapneumovirus
Immune System Diseases
Innate Immunity
pathogenesis
mice
T-cells
Cell proliferation
Chemokines
Bridge clearances
antibody formation
Airway Obstruction
chemokines
dendritic cells
Cytokines
Dendritic Cells
Dimercaprol
Antibody Formation
Interferon Type I
Weight Loss

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Critical role of TLR4 in human metapneumovirus mediated innate immune responses and disease pathogenesis. / Velayutham, Thangam Sudha; Kolli, Deepthi; Ivanciuc, Teodora; Garofalo, Roberto; Casola, Antonella.

In: PLoS One, Vol. 8, No. 10, e78849, 2013.

Research output: Contribution to journalArticle

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