Human Metapneumovirus: Mechanisms and Molecular Targets Used by the Virus to Avoid the Immune System

Abstract

Human metapneumovirus (hMPV) is a respiratory virus, first reported the year 2001. Since then, it has been described as one of the main etiological agents that causes acute lower respiratory tract infections (ALRTIs), which is characterized by symptoms such as bronchiolitis, wheezing and coughing. Susceptible population to hMPV-infection includes newborn, children, elderly and immunocompromised individuals. This viral agent is a negative-sense, single-stranded RNA enveloped virus, that belongs to the Pneumoviridae family and Metapneumovirus genus. Early reports-previous to 2001-state several cases of respiratory illness without clear identification of the responsible pathogen, which could be related to hMPV. Despite the similarities of hMPV with several other viruses, such as the human respiratory syncytial virus or influenza virus, mechanisms used by hMPV to avoid the host immune system are still unclear. In fact, evidence indicates that hMPV induces a poor innate immune response, thereby affecting the adaptive immunity. Among these mechanisms, is the promotion of an anergic state in T cells, instead of an effective polarization or activation, which could be induced by low levels of cytokine secretion. Further, the evidences support the notion that hMPV interferes with several pattern recognition receptors (PRRs) and cell signaling pathways triggered by interferon-associated genes. However, these mechanisms reported in hMPV are not like the ones reported for hRSV, as the latter has two non-structural proteins that are able to inhibit these pathways. Several reports suggest that viral glycoproteins, such as G and SH, could play immune-modulator roles during infection. In this work, we discuss the state of the art regarding the mechanisms that underlie the poor immunity elicited by hMPV. Importantly, these mechanisms will be compared with those elicited by other common respiratory viruses.

Keywords: cytokines; evasion; human metapneumovirus; immune system; respiratory virus.

Figure 1

Molecular description of hMPV and the role of viral proteins in the evasion of the immune response. Schematics of the hMPV viral particle in the center and its genomic organization. In the left panel are depicted the viral proteins synthetized by hMPV, separated in two different groups: “surface proteins” and “internal proteins.” The right panel describes the main roles of some viral proteins involved in the evasion of the immune response. The proteins M2.1 and M2.2 are expressed only during the replicative viral cycle.

Figure 2

Toll-like receptors (TLRs) and their role in the evasion of the immune response induced by hMPV. The figure shows the effect of different TLRs in response to hMPV-infection. (1) At the surface of the host cell, TLR4 (green receptor) is associated with the inhibition of type-I IFN. (2) In the intracellular space, TLR3 (red receptor) is involved in the negative regulation of the MyD88/TRAF6/IKKα pathway. (3) The roles of TLRs 7 and 9 (purple and yellow receptor, respectively) in hMPV infection are currently unclear.

Figure 3

Effects of hMPV proteins on signaling pathways. Once the viral particle has fused with the plasmatic membrane, the viral RNA is delivered to the cytoplasm and recognized by MDA5 or RIG-I (PRRs), activating the IRF3 and NF-κB pathways through TRAF3, TRAF5, and TRAF6 after these factors are recruited by MAVS. After the viral proteins are translated from viral RNA inside the host cell, the M2-2 viral protein can inhibit MAVS and thus, the MAVS-dependent immune response. Viral particles are also detected by TLR4, initiating the signaling which ends in the translocation of both transcription factors IRF3 and NF-κB to the nucleus, promoting an antiviral state and the expression of type-I IFN. The G viral protein interferes with the TLR4-dependent signaling, negatively modulating the immune response of the host and promoting viral replication. The SH viral protein can inhibit the NF-κB signaling as well. Viral RNA detected inside endosomes by TLR3 and TLR7/9 results in the phosphorylation of both transcriptional factors IRF3 and IRF7, and their entry to the nucleus to promote the expression of type-III IFN and proinflammatory cytokines. The M2-2 viral protein inhibits the phosphorylation of IRF7, preventing its translocation to the nucleus. The SH viral protein induces the same effect on IFNAR signaling by preventing the phosphorylation of STAT1.