Severe viral infections and primary immunodeficiencies

Abstract

Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor-interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens.

Figures

Figure 1.

Toll-like receptor (TLR) and type I interferon (IFN) signaling pathways. A, Induction of type I IFN production in cells. Viral nucleic acids are detected by TLRs 3, 7, 8, and 9. TLR3 activation results in signaling through the Toll–interleukin (IL)–1R domain–containing adapter-inducing IFN-β (TRIF)–dependent or nuclear factor (NF)–κβ essential modulator (NEMO)–dependent pathway. Activation of TLRs 7, 8, and 9 results in signaling through the myeloid differentiation factor 88 (MyD88)–dependent pathway. Transcription factors, IFN regulatory factor (IRF) 3, IRF7, or NF-κβ, initiate transcription of IFN genes in the nucleus. IKK, inhibitor of NF-kB kinase subunit alpha or beta; IkB, inhibitor of kB; IRAK-4, IL-1R–associated kinase; RIG-1, retinoic acid–inducible gene 1; TRAF3, tumor necrosis factor receptor–associated factor 3.; TBK1, TANK-binding kinase 1. RIG 1 is a cytosolic virus sensor. B, Response of cells to IFN. IFNs bind to the IFN receptor and initiate signaling through the signal transducer and activator of transcription (STAT) pathway to induce transcription of IFN-stimulated genes that inhibit viral replication. Mutations in shaded genes have been associated with severe HSV infections, including herpes simplex encephalitis (HSE). Mutations in TYK-2, tyrosine kinase 2, have not been associated with HSE.

Figure 2.

Killing of virus-infected target cells by cytotoxic T cells. Cytotoxic T cells recognize virus-infected target cells via engagement of their T-cell receptor (TCR) with viral peptides in the context of major histocompatibility complex (MHC) class I molecules on the surface of virus-infected cells. Cytolytic granules are released from cytotoxic T cells, enter target cells through perforin pores, and release granzymes and granulysin that induce apoptosis. Alternatively, Fas ligand expressed on cytotoxic T cells can bind to the Fas on virus-infected cells and induce apoptosis. mRNA, messenger RNA.

Figure 3.

A, Disseminated molluscum contagiosum in a patient with dedicator of cytokinesis 8 deficiency. B, Cutaneous warts in a patient with idiopathic CD4+ lymphocytopenia.

Figure 4.

Algorithm for the clinical evaluation of patients with suspected primary immunodeficiency associated with severe viral infections. Abbreviations: CBC, complete blood cell count; HIV, human immunodeficiency virus; Ig, immunoglobulin; NK, natural killer; NKT, natural killer T; PCR, polymerase chain reaction; TLR, Toll-like receptor.