Date Published: September 1, 2016
Publisher: Public Library of Science
Author(s): Eugenia Z. Ong, Kuan Rong Chan, Eng Eong Ooi, Vincent Racaniello.
The immune system has evolved pairs of activating and inhibitory receptors that modulate the magnitude of immune responses, enabling the maintenance of immune homeostasis. Inhibitory signaling dampens the immune response, which prevents inflammatory damage to the host. It has now become increasingly clear that viruses have evolved means of exploiting the inhibitory signaling pathways of the immune system in order to blunt the responses that would otherwise abrogate infection. Recent evidence demonstrates how viruses exploit inhibitory receptors both for host cell entry and to down-regulate antiviral responses for enhanced viral pathogenesis. Both acute and chronic viral infections also induce expression of intermediates of inhibitory signaling for improved odds of survival within the intracellular environment. This review highlights and synthesizes from recent findings how medically important viruses exploit the inhibitory pathways that maintain immune homeostasis for successful human infection.
The rapid initiation and timely termination of the immune response are coordinated by paired receptors expressed on immune cells. Paired receptors consisting of activating and inhibitory receptors recognize self and non-self ligands. They are essential for maintaining self-tolerance, mounting an immune response during infection, and modulating the intensity of the response to prevent autoimmunity and inflammatory damage to bystander cells . Activating receptors recruit adaptor molecules containing immunoreceptor tyrosine-based activation motifs (ITAMs) or bear ITAMs in their cytoplasmic tails for signaling. Upon ligation and clustering of activating receptors, ITAMs are phosphorylated by Src family kinases, which create docking sites for Src homology 2 (SH2)-domain containing kinases like spleen tyrosine kinase (Syk) and zeta chain-associated protein kinase 70 (ZAP-70) . These kinases phosphorylate downstream substrates and form receptor-proximal signaling complexes that drive phagocytosis, cellular activation, and pro-inflammatory responses. To achieve immune homeostasis, inhibitory receptors containing one or several immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic tail are employed . Ligation of inhibitory receptors leads to Src family kinase-mediated ITIM phosphorylation and recruitment of SH2-domain containing cytoplasmic phosphatases like SH2-containing phosphatase 1 (SHP-1), SHP-2, and SH2-containing inositol phosphatase 1 (SHIP-1) . Dephosphorylation of downstream signaling effector molecules results in down-regulation of immune responses and maintenance of peripheral self-tolerance.
The viral life cycle starts with host cell entry, which involves direct fusion with cell membrane or ligating an appropriate receptor to trigger endocytosis, pinocytosis, or macropinocytosis. Use of inhibitory receptors during host cell entry could thus simultaneously initiate inhibitory signaling to dampen the immune response for enhanced viral replication (Table 1).
NK cells serve as sentinels of the immune response, expressing a repertoire of paired receptors that enables discrimination of healthy cells from infected or transformed cells. During viral infections, viruses have to strike a delicate balance of limiting MHC-I presentation of viral peptides and maintaining sufficient levels of MHC-I to avoid NK cell-mediated lysis . By expressing viral proteins that serve as MHC-I mimics and modulation of MHC-I molecules, viral manipulation of inhibitory signaling on NK cells constitutes a key thrust of how viruses overcome host immunity (Table 2).
Viruses that cause chronic diseases and persistent infection in their human hosts exploit inhibitory signaling to prevent viral clearance (Table 3). NK cells are widely recognized as innate immune effector cells and also produce cytokines like IFN-γ and TNF-α to activate DCs and T cells. Thus, inhibitory signaling on NK cells could down-regulate the adaptive immune response, suppressing viral clearance to drive chronic infection. Indeed, CD94/NKG2A was up-regulated in NK cells from chronic HCV-infected patients . NK cells from these donors were deficient in activating DCs and produced IL-10 and TGF-β when cultured with hepatic cells expressing HLA-E .
A substantial body of work has now refined our mechanistic understanding of how various medically important viruses manipulate inhibitory signaling for survival within the host cell. Given that members of a virus family share many conserved structural and non-structural proteins, it is plausible that viral strategies to manipulate inhibitory signaling could be relevant to a broader range of viruses than those discussed here. Understanding how viruses exploit inhibitory signaling could lead to rationally designed interventions that interrupt these critical virus–host interactions. The potential of an anti-PD-L1 antibody in reducing viral reservoirs in HIV-1 patients was recently evaluated in a clinical trial (NCT02028403). We anticipate that a combination of therapies targeting critical steps of the viral life cycle and boosting different arms of the immune response could provide recourse for both acute and persistent viral infections.