In response to viral infection, many organisms mount a remarkable defense known as the immune response. This response to viral infection consists of an innate, or nonspecific component, and an adaptive, or specific defense. The innate response is considered the first line of immune defense because it is active even before infection begins. In fact, many viral infections are halted by the innate immune system, which responds very quickly – within minutes to hours after infection.
A key property of the innate immune system is the ability to recognize viruses as ‘foreign’. Viral proteins and nucleic acids are distinguished from cellular counterparts by cellular proteins called pattern recognition receptors (illustrated). These are proteins present either in the cell cytoplasm or on cellular membranes, where they detect viral components. For example, the cytoplasmic protein RIG-I detects double-stranded RNA (dsRNA) or single-stranded RNA (ssRNA) with a 5′-triphosphate. These types of RNAs are usually not found in the cytoplasm of unifected cells; rather they are typically products of viral replication. When RIG-I binds these viral RNAs, a series of reactions occur which lead to the synthesis of cytokines, the primary output of the innate defense system. Other detectors of viruses are the membrane-bound toll-like receptors (TLRs), which sense viral glycoproteins, dsRNA, ssRNA, and the sequence CpG in viral DNA. Engagement of TLRs by these virus-specific ligands also leads to the synthesis of cytokines, albeit by different pathways.
The presence of cytokines in the blood is typically one of the earliest indications that the host has been infected with a virus. Over 80 known cytokines are secreted by infected cells. The first that are produced after viral infection include interferon-α and -β (IFN-α, IFN-β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-12, and IFN-γ.
Cytokines function locally by binding receptors on other cells. For example, IFN produced by infected cells engages receptors on neighboring cells. Those cells then produce hundreds of cellular proteins which have antiviral activities. When cytokines enter the circulation, they elicit symptoms typical of many viral infections, including fever, sleepiness, lethargy, muscle pain, loss of appetite, and nausea.
Another key component of the innate response are the so-called sentinel cells: dendritic cells and macrophages present in peripheral compartments such as skin and mucosal surfaces. Sentinel cells patrol the body, seeking signs of infection. Dendritic cells bind cytokines produced by virus-infected cells, and also take up viral proteins released from dying virus-infected cells. They respond by producing more cytokines to amplify the original response.
In many viral infections, the early action of cytokines produced by infected cells and dendritic cells is sufficient to eliminate the pathogen. If innate defenses are overwhelmed and virus replication continues unabated, then the second-line defenses are mobilized to ensure host survival. These comprise the adaptive immune response – antibodies and immune cells. Days to weeks are required to mount an adaptive immune response that is specifically tailored to the infecting virus. The innate response therefore serves as a crucial rapid response that provides sufficient time for the activation of the adaptive immune system.