Learning from the Messengers: Innate Sensing of Viruses and Cytokine Regulation of Immunity — Clues for Treatments and Vaccines

Abstract

Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs), recognizing distinct conserved pathogen-associated molecular patterns (PAMPs). The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs) and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus–host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs) and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.

Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy

“…This could be related to the ability of anthracyclines to stimulate the rapid production of Type 1 IFNs, 19 which in turn upregulates a large number of IFN-stimulated genes ( ISGs ) 54 with antiviral activities, including Myxovirus resistance ( MX ) genes (reviewed in ref. 55 ). Therefore, the current findings suggest that ordering of OVV/DOX combination treatments may be specific to the selected virus, the chemosensitivity profile, and/or phenotype of the targeted tumor cells.…”

Adenovirus VA RNA: An essential pro-viral non-coding RNA

“…Such proteins are responsible for the general detection of viruses and thus represent a potential target for influencing the outcome of infection. The ability to modulate and selectively activate these proteins is of particular interest for developing general antiviral therapies effective against viruses that rely upon manipulation of dsRNA-detecting innate immune proteins but for which there are no vaccines or treatments (Fei et al, 2011;Melchjorsen, 2013). For example, selective activation of PKR or the OAS/RNase L pathway in infected cells has already been demonstrated as a viable way to inhibit replication of a range of viruses including respiratory syncytial virus, encephalomyocarditis virus, and human parainfluenza virus 3 (Cirino et al, 1997;Rider et al, 2011;Thakur et al, 2007).…”

Cellular and viral determinants of retroviral nuclear entry

“…Moreover, integration of the viral genome into CD4+ memory cells and macrophages establishes a latent or chronic infection. To detect invaders, cells express several pattern-recognition receptors and other "sensor" proteins that can detect the pathogenassociated molecular patterns of viral components, which in turn activate antiviral interferon and other responses (Iwasaki and Medzhitov 2010;Melchjorsen 2013). After overcoming obstacles from the cell membrane to the nucleus (Melchjorsen 2013), viral cDNA associated pre-integration complexes (PICs) enter the nucleus.…”