Interferon-Mediated Response to Human Metapneumovirus Infection

Abstract

Human metapneumovirus (HMPV) is one of the leading causes of respiratory diseases in infants and children worldwide. Although this pathogen infects mainly young children, elderly and immunocompromised people can be also seriously affected. To date, there is no commercial vaccine available against it. Upon HMPV infection, the host innate arm of defense produces interferons (IFNs), which are critical for limiting HMPV replication. In this review, we offer an updated landscape of the HMPV mediated-IFN response in different models as well as some of the defense tactics employed by the virus to circumvent IFN response.

Keywords: HMPV; IFN; human metapneumovirus; interferon; pneumovirus; respiratory.

Figure 1

HMPV and RSV genomic configuration and the proteins they encode. (A) HMPV and RSV are negative sense single stranded RNA viruses and are members of the family Pneumoviridae. HMPV belongs to the genus Metapneumovirus, while RSV belongs to Orthopneumovirus genus; (B) Both viruses differ in the organization of the genomic proteins. Besides, the M2 and L proteins of RSV overlap by 68 nucleotides [16]. Another important difference between the viruses is that RSV genome encodes additional two proteins, non-structural proteins NS1 and NS2.

Figure 2

Induction of the interferon response by HMPV. During HMPV infection, its viral PAMPs are detected by toll-like receptors (TLRs) in the endosome and RIG-I-like receptors (RLRs) in the cytoplasm. Activation of TLR7/8 by ssRNA results in the recruitment of the adaptor molecule myeloid differentiation primary response protein 88 (MyD88). MyD88 further recruits and activates the interleukin 1 receptor associated kinases (IRAK1 and IRAK4) and the tumor necrosis factor receptor associated factor 6 (TRAF6) which in turn mediate the phosphorylation and activation of IRF7. Translocation of IRF7 into the nucleus triggers the expression of IFNs. In addition, dsRNA can be detected by TLR3 also in the endosome, which leads to the activation of TRAF3 and subsequent activation of the tank binding kinase-1 (TBK1)/I kappa B kinase epsilon (IKKɛ) kinases that eventually induce the phosphorylation of interferon regulatory factor 3 (IRF3) and IRF7. On the other hand, retinoic acid-inducible gene I (RIG-I) or melanoma differentiation associated factor 5 (MDA5) can be activated in the cytoplasm by 5′ppp-dsRNA, 5′ppp-ssRNA or long dsRNA, respectively. Activation of RIG-I or MDA5 subsequently activates the mitochondrial antiviral signaling protein (MAVS). MAVS recruits additional adaptor proteins that trigger the activation of TBK1/IKKε kinases. TBK1/IKKε phosphorylate IRF3/7 which then translocate to the nucleus to induce the expression of interferons.

Figure 3

Inhibition of interferon response by HMPV. Evasion mechanisms used by HMPV include: impairment of RIG-I and MDA5 signaling by its G protein; attenuation of MAV or MyD88 signaling by its M2-2 protein; and obstruction of TLR7/MyD88 signaling by its SH protein.