Cell-Type-Specific Transcription of Innate Immune Regulators in response to HMPV Infection

Abstract

Human metapneumovirus (HMPV) may cause severe respiratory disease. The early innate immune response to viruses like HMPV is characterized by induction of antiviral interferons (IFNs) and proinflammatory immune mediators that are essential in shaping adaptive immune responses. Although innate immune responses to HMPV have been comprehensively studied in mice and murine immune cells, there is less information on these responses in human cells, comparing different cell types infected with the same HMPV strain. The aim of this study was to characterize the HMPV-induced mRNA expression of critical innate immune mediators in human primary cells relevant for airway disease. In particular, we determined type I versus type III IFN expression in human epithelial cells and monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). In epithelial cells, HMPV induced only low levels of IFN-β mRNA, while a robust mRNA expression of IFN-λs was found in epithelial cells, MDMs, and MDDCs. In addition, we determined induction of the interferon regulatory factors (IRFs) IRF1, IRF3, and IRF7 and critical inflammatory cytokines (IL-6, IP-10, and IL-1β). Interestingly, IRF1 mRNA was predominantly induced in MDMs and MDDCs. Overall, our results suggest that for HMPV infection of MDDCs, MDMs, NECs, and A549 cells (the cell types examined), cell type is a strong determinator of the ability of HMPV to induce different innate immune mediators. HMPV induces the transcription of IFN-β and IRF1 to higher extents in MDMs and MDDCs than in A549s and NECs, whereas the induction of type III IFN-λ and IRF7 is considerable in MDMs, MDDCs, and A549 epithelial cells.

Host Components That Modulate the Disease Caused by hMPV

“…The response elicited by the innate immune system upon hMPV infection plays an essential role in the primary control of the disease and the subsequent activation of the adaptive immune response [ 47 , 48 , 49 , 50 , 51 , 52 ]. In the following section, the innate immune response elicited during infections with hMPV will be discussed as well as how the innate immune cells activate the interferon pathways.…”

“…Recent reports have focused on understanding the mechanisms that different human cell types have for facing hMPV infections. Remarkably, the antiviral immune response associated with the IFN signaling pathways is dependent on the cell type (epithelial or immune) that elicits it [ 49 , 50 ]. The effect of hMPV infections in alveolar epithelial cells (A549), nasal epithelial cells (NEC), monocyte-derived macrophages (MDM), and monocyte-derived dendritic cells (MDDC) has been studied [ 49 , 50 ].…”

“…Remarkably, the antiviral immune response associated with the IFN signaling pathways is dependent on the cell type (epithelial or immune) that elicits it [ 49 , 50 ]. The effect of hMPV infections in alveolar epithelial cells (A549), nasal epithelial cells (NEC), monocyte-derived macrophages (MDM), and monocyte-derived dendritic cells (MDDC) has been studied [ 49 , 50 ]. A differential expression profile of IFN molecules and IRFs was correlated with the different cells studied [ 49 , 50 ].…”

Cell-Mediated Responses to Human Metapneumovirus Infection

“…IFNs can amplify the antiviral response and limit viral replication by inducing the expression of ISGs. Several in vitro studies have shown that different strains of hMPV induce the production of IFNs (type I, II, and III) in A549 cells and that this response relies on viral replication [57][58][59]63,64]. Schoggins et al have catalogued several ISGs that might have an inhibitory effect on different DNA and RNA viruses [65].…”

“…One may expect that viral infection of AECs will result in a gene expression profile with an innate immune signature. Indeed, several transcriptomic studies focused on the many upregulated genes that are involved in the initiation of pro-inflammatory and antiviral immune responses, including chemokines, cytokines, type I IFN, and interferon-inducible proteins [59,64,80]. However, other and more recent transcriptomic studies also show that metabolic genes and several mucins are upregulated, and cilium-associated genes are downregulated [63,81].…”