Interferon- γ and infectious diseases: Lessons and prospects

Abstract

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these diseases would benefit not just from new medicines and vaccines but also from a better understanding of what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-γ (IFN-γ), a protein secreted by lymphocytes. Forty years ago, IFN-γ was identified as a macrophage-activating factor, and, in recent years, there has been a resurgent interest in IFN-γ biology and its role in human defense. Here we assess the current understanding of IFN-γ, revisit its designation as an "interferon," and weigh its prospects as a therapeutic against globally pervasive microbial pathogens.

Fig. 1.. Key discoveries on IFN-γ in infectious diseases.

Recognition of IFN-γ as a distinct molecular entity emerged in the period from 1957, when antiviral cytokines were discovered, to its cloning in 1982. Characterization of its biologic effects beyond weak antiviral activity began in 1983, with the identification of IFN-γ as a principal macrophage activating factor. Essential, nonredundant roles of IFN-γ in human biology emerged from the study of genetic deficiency states associated with MSMD. Clinical utility of recombinant IFN-γ has been demonstrated since 1986. KO, knockout.

Fig. 2.. Cell sources and targets of human IFN-γ during infection.

Human lymphoid cell subsets originating in the bone marrow can either directly differentiate into functional T_H1-like cells (ILC1) or emigrate to the thymus, where they undergo further selection. NK cells can differentiate in the bone marrow or other secondary lymphoid organs besides the thymus (dashed bracket). These T_H1 and T_H1-like subsets produce IFN-γ in response to antigen stimulation by antigen-presenting cells. Tissue-resident macrophage populations that become activated through the JAK-STAT1 signaling pathway to elicit ISGs (some examples shown in the box) are a major target of IFN-γ. ISG-encoded proteins generate toxic antimicrobial products (reactive oxygen intermediates or species, reactive nitrogen intermediates, acid, itaconate); lyse microbial cell walls; interfere with nutrient acquisition (deplete amino acids and metal ions); and block the entry or promote the exit of pathogenic bacteria, parasites, and fungi. Some of these activities can potentially injure host cells and are therefore tightly regulated. Nonimmune cells also have the machinery for IFN-γ signaling, and so these activities may function to protect other infected host cells. ACOD1, aconitate decarboxylase 1; IDOs, indoleamine-2,3-dioxygenases; PLAAT4, phospholipase A and acyltransferase 4.

Fig. 3.. Position of genetic lesions in the cellular production of and response to IFN-γ during infection.

Proteins for which germline genotype of the corresponding gene has been recognized to cause MSMD are depicted in blue (see Table 2). ZNFX1, NFX1-type zinc finger-containing protein 1; SPPL2A, signal peptide peptidase-like 2A; NEMO, NF-κB essential modulator. GAF, γ-activating factor; CCR2, C-C chemokine receptor type 2; DENR, density-regulated protein.