Host Immune Defenses Against Viral Infections, Part II: Adaptive Immunity

Elene Tsopurashvili (elenet@princeton.edu) and Katelyn C. Cook (katelync@princeton.edu)

July 25th, 2020

 

While the innate immune system (discussed in our previous post) yields swift action upon pathogenic invasion, its long-term scope is limited by lack of specificity. Only general microbe features can activate innate responses, which is often insufficient for a host living within a rapidly evolving world of viruses. Therefore, innate pathways work in concert with the adaptive immune system, altogether providing sensitive and robust immune memory.

The primary goal of adaptive immunity is to impede repeated infections by the same pathogen. By synthesizing and secreting specialized proteins known as “antibodies”, adaptive immune cells can recognize, bind, and remember unique molecular signatures on microbes. This system is incredibly complex and dynamic, capable of producing nearly 1016-1018distinct antibodies – that’s a quintillion antibodies per person. To put this in perspective, the estimated number of insects currently alive on our planet is approximately one quintillion.

Altogether, antibodies enable the rapid detection and elimination of a vast repertoire of pathogens. Each antibody is initially developed following the innate immune signaling events that flag invading microbes. This information is communicated to adaptive immune cells in the lymph nodes called “B lymphocytes” via the action of dendritic cells (e.g., macrophages). These specialized cells detect, engulf, and digest pathogens, preventing the spread of infection. As part of this, dendritic cells will utilize digested pieces of the invading microbes – such as a viral protein or bacterial carbohydrate – as “antigens”, which are displayed on the cell surface. Dendrites then travel to the lymph nodes and present antigens to the lymphocytes, triggering lymphocyte differentiation. Activated B cells produce antigen-specific antibodies, which can be released into the bloodstream and used to both neutralize and target the invading pathogen en masse. For example, antibodies attach to viruses and hamper them from accessing other cells. The antibody-antigen complex also predisposes these intracellular microbes to detection and engulfment by dendritic cells.

In addition to the antibody response, the adaptive system includes a cell-mediated immune response that is executed by two types of T lymphocytes: cytotoxic T cells and helper T cells. Instead of directly targeting the microbes, T lymphocytes prey on host cells that exhibit pathologies resulting from infection. Upon detection of antigens on the cell surface, cytotoxic T lymphocytes stimulate the infected cell to trigger cell death pathways, thus stopping an infection at its source. Helper T lymphocytes serve as master activators of the greater immune system, assisting B cells, cytotoxic T cells, and macrophages in their specific roles.

Altogether, adaptive immune processes require multiple days to develop after the initial infection but provide dynamic and rapid responses during subsequent encounters with the same pathogen. Antibodies, in particular, will be present for weeks, years, or even decades – giving rise to what is known as “immune memory”. This enables the success of vaccines, whereby individuals can receive one dose of an avirulent pathogen (e.g., one lacking in infection potency yet presenting antigens common to the parent pathogen) and develop immunity to last a lifetime.

Yet, considering the ongoing arms race between pathogens and their hosts, immune memory is not always as robust as desired. Just as viruses have co-evolved ways to circumvent innate detection processes, they also possess numerous strategies to bypass recognition by B and T lymphocytes. One of the best characterized – and most well-known – examples of this is in Influenza A (Infl. A) virus infections. Infl. A undergoes frequent genetic mutations and exchanges with other influenza strains, gradually resulting in alterations to viral surface proteins. This co-evolution makes new virions unrecognizable to the antibodies created for neutralizing the original viral antigens, thus evading the host anti-viral response. Therefore, the host must regenerate influenza-specific immune memory, necessitating the production of new vaccines to combat its seasonal emergence nearly every year. Alternatively, viruses can hijack cell-mediated adaptive responses, interfering with pathways that process viral proteins into antigens. For example, cytomegalovirus (CMV) directly targets and degrades the major histocompatibility complex (MHC) class I proteins, which are responsible for presenting antigens to the immune system. Other viruses infect immune cells directly, including human immunodeficiency virus (HIV) that replicates within CD4+ T cells, repurposing a major branch of adaptive immune response.

Pathogen invasions can also broadly paralyze adaptive immunity’s defense against other microbes by severely diminishing immune memory. Measles virus (MV) had long been suspected to reduce the body’s antibody repertoire, making patients susceptible to re-infection with various pathogens. Just last year, a study in children found evidence of MV immunosuppression, with infected individuals showing significantly curtailed diversity and abundance of antibodies after measles infection. Similarly, HIV compromises host immunity by inducing the dysfunction and diminishment of T cells, eliminating their ability to exert anti-microbial roles. Such immunopathology underlies the acquired immunodeficiency syndrome (AIDS), giving rise to opportunistic infections – infections that are usually defeated by a healthy individual’s immune system. The impact of measles-induced antibody degeneration and HIV-promoted polymicrobial infections emphasize the importance of a robust adaptive immune response in a world dominated by viruses and other pathogens.