Respiratory viral infections and host responses; insights from genomics

Abstract

Respiratory viral infections are a leading cause of disease and mortality. The severity of these illnesses can vary markedly from mild or asymptomatic upper airway infections to severe wheezing, bronchiolitis or pneumonia. In this article, we review the viral sensing pathways and organizing principles that govern the innate immune response to infection. Then, we reconstruct the molecular networks that differentiate symptomatic from asymptomatic respiratory viral infections, and identify the underlying molecular drivers of these networks. Finally, we discuss unique aspects of the biology and pathogenesis of infections with respiratory syncytial virus, rhinovirus and influenza, drawing on insights from genomics.

CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication

“…Like all other viruses, IAV replication relies on many proteins or enzymes from the virus itself and the host cell (2). It is important to understand the mechanism of virus-host cell interaction to identify new therapeutic targets and develop antiviral drugs (3).…”

Respiratory syncytial virus–Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life

“…This study also showed that palivizumab prophylaxis was effective mainly in subjects without a family history of atopy or food allergies, suggesting that RSV infection may represent a risk factor for future respiratory morbidity, independent from a genetic predisposition to atopy . A close evaluation of the complex interactions between RSV and the host is a key step in uncovering factors that could explain the pathogenicity of RSV infections also in “not‐at‐risk” populations .…”

“…RSV is a single‐stranded RNA virus of the Paramyxoviridae family whose genome includes 10 genes encoding 11 proteins: three transmembrane surface glycoproteins (the attachment G protein, the fusion F protein, and the small hydrophobic SH protein), three proteins associate with the genomic RNA to form the nucleocapsid (the large L polymerase subunit, the N protein, and the phospho P protein), two non‐structural proteins (the NS1 and NS2 proteins), two transcription and replication factors (M2‐1 and M2‐2), and one unglycosylated matrix M protein (Fig. ) . Proteins F and G are key factors for virus attachment, fusion, and RSV nucleocapsid release into the cytoplasm, whereas viral transcription and subsequent replication require the L, N, P, M‐1, and M‐2 proteins that, together with the genomic RNA, form the ribonucleoprotein (RNP) complex.…”

“…The innate immune response is activated via recognition by pattern recognition receptors (PRRs) of the surface proteins, RSV RNA, and proteins produced during the viral lifecycle. The TLR4/CD14 complex is the main extracellular receptor recognizing RSV through binding with the F protein, while intracytoplasmic RIG‐I, MDA5, and TLR3 PPRs recognize RSV transcripts and viral replication intermediates . Activation of a variety of transcription factors occurs, including NF‐kB, AP‐1, JNK, JAK, p38 MAPK, and STAT signaling pathways, followed by the production of cytokines, chemokines, and type I and type III IFNs, all geared to mount an effective antiviral reaction .…”

“…TNF‐α, CXCL8/IL‐8, and ITAC/CXCL11 recruit and activate PMNs and NK cells that destroy the infected AECs in the first days of infection, while type I IFNs display potent antiviral activity, reducing protein synthesis and upregulating pro‐apoptotic factors. Apoptosis of the infected cell is a key protective mechanism in that it aborts viral replication, prevents both spread of infection with the release of a large numbers of progeny viruses, and further production of proinflammatory mediators . RSV infection of AECs promotes also the secretion of other chemokines, such as MIP‐1α/CCL3, MIP‐1β/CCL4, MIP‐2, IP‐10/CXCL10, and MCP‐1/CCL2, all of which induce recruitment and activation of monocytes and memory T cells .…”