Chapter 16 : Immune Responses to Viral Infection

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The concept of “immunity” dates back to ancient Greece, where as early as the fifth century BC, documented cases of “immune” individuals were described who were related to individuals who recovered from the plague (1). However, it was not until the 10th century that specific “interventions” were described that could induce immunity. In both China and the Middle East, a process known as “variolation,” consisting of purposefully exposing healthy individuals to the contents of dried variola lesions, was actively practiced to prevent severe infection with smallpox. In the early 18 century, the practice of variolation was brought to Great Britain, where the development of the first vaccine by Jenner catalyzed the creation of the field of immunology. Beginning in the late 19 century, major breakthroughs, including the establishment of the “germ theory” by Koch and Pasteur, which held that disease was caused by bacteria or pathogens; the discovery of phagocytic cells by Metchnikoff; the identification of immune proteins in serum by von Behring and Kitasato; the identification of B cells and their regulation by Ehrlich; the discovery of lymphocytes by Gowan; the identification of pattern recognition receptors and innate immune activity by Janeway; and the discovery of dendritic cells, which link the innate and adaptive immune system, by Steinman, collectively gave rise to modern immunology and our current appreciation for the host immune response. This response has evolved to contain, eliminate, and remember virtually any pathogen to which it is exposed. This chapter reviews the components of the immune system, focusing on the innate and adaptive immune response to viral infection and how these arms of the immune system collaborate to prevent and control viral disease.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 1

Three layers of immunity: physical barrier immunity, innate immunity, and adaptive immunity. 1) Physical barriers, including the skin and mucosal membranes, represent the first level of protection against foreign invaders. Damage to this layer can lead to pathogen access to the underlying cells. Many viruses utilize vectors to breach this barrier. 2) Innate immunity represents the nonspecific rapid response arm of the immune system, and the first white blood cell responders help control, clear, and arm the immune response. C) Adaptive immunity consists of the antigen-specific response that evolves to specifically clear the pathogen and to confer long-lived immunity against the pathogen upon re-exposure.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 2

The two arms of the immune system. All immune cells develop from a common hematopoietic stem-cell progenitor that can differentiate into a myeloid or common lymphoid progenitor (CLP). The adaptive arm of the immune system is composed of four immune cell types, called lymphocytes, that share a CLP origin. The innate arm consists of an array of distinct cell types, most of which are derived from the myeloid progenitor, except NK cells and plasmacytoid dendritic cells that differentiate from a CLP.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 3

Innate immune receptors. Four types of pattern recognition receptors exist that drive a rapid response to foreign pathogens including 1) extracellular secreted receptors such as mannose-binding lectin, 2) cell surface toll-like receptors or c-type lectin receptors, 3) endosomal TLRs, and 4) cytosolic pattern recognition receptors such as RigI. The secreted and surface-bound PRRs recognize extracellular pathogens whereas the endosomal and cytosolic PRRs recognize pathogens that have entered into different cellular compartments within the cell.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 4

Comparison of the structure of the major histocompatibility complexes (MHC) I and II. While class I molecules are composed of a polymorphic α chain noncovalently attached to the nonpolymorphic β2 microglobulin, class II are composed of a polymorphic α chain noncovalently attached to a polymorphic β2 microglobulin. While the peptide binding cleft of MHC I is closed, allowing only little sequence variation, the binding groove of MHC class II is open, even allowing tertiary structures.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 5

CD4 T-cell subsets. The various functional CD4 T-cell subsets are depicted, their associated main transcription factors, the cytokines they secrete, and their main effector functions.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 6

The IgH locus. The human immunoglobulin locus consists of two regions that give rise to either 1) the variable domain (Fab) or the 2) the crystallizable/constant domain (Fc). The Fab is generated following the rearrangement and selection of a V, a D, and a J segment that are assembled and tethered to the Fc region, which is also selected following gene rearrangement and selection of a single constant gene segment. Gene rearrangement requires the cutting out of excess DNA and religation of DNA ends, generating irreversible changes in the IgH locus.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 7

The germinal center reaction. The germinal center reaction begins with an initial contact between B cells and cognate Tfh cells through an array of different receptors such as PD1-PDL1, CD40-CD40L, ICOS-ICOS-L, and TCR-MHCII. This promotes extensive proliferation of antigen-primed B cells. The GC cycle is thought to form two microanatomically distinct regions: the T-cell zone-proximal dark zone (which contains proliferating centroblasts) and the T-cell zone-distal light zone (which contains centrocytes, follicular dendritic cell [DC] networks and antigen-specific gcTFH cells). The expansion of antigen-specific B cells in the dark zone is accompanied by B-cell receptor (BCR) diversification through somatic hypermutation and class switch recombination. Loss of binding through this process leads to apoptosis, and only the best “binders” receive positive signals and enter the cycle again until they leave the GC as plasmablasts or memory B cells.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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Image of FIGURE 8

Distinct Fc-receptor expression profiles on distinct innate immune cells. Differences in Fc receptor expression profiles on distinct innate immune cell subsets enable these cells to respond to antibody-opsonized material differently to promote control and clearance of pathogens. Specifically, while NK cells and neutrophils largely express a single Fcγ-receptor, FcγR3a, on NK cells and FcγR3b on neutrophils, macrophages express nearly all Fc receptors including the two activating FcγR2a and FcγR3a receptors, as well as the sole inhibitory FcγR2b receptor.

Citation: Streeck H, Suscovich T, Alter G. 2017. Immune Responses to Viral Infection, p 321-350. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch16
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