Microbes can cause disease of varying severity and chronicity (Fig. 1). In many instances, an infection is asymptomatic and resolves without intervention. A typical host immune response is rapidly triggered by infection, wanes as the infection is cleared, and leaves memory cells and long-lived antibody-secreting plasma cells that provide long-term protection. Recurrent illnesses occur when the host response cannot eradicate the microbe and may even contribute to the disease. Although antimicrobial host defense reactions are numerous and varied, there are several important general features of immunity to microbes.
Fig1. The progression and outcome of infections. Most infections have an incubation period followed by disease that may be short lived if the host response is effective or progressive or chronic if the response does not adequately control the infection. Modified from Engleberg NC, DiRita V, Dermody TS, eds. Schaechter’s Mechanisms of Microbial Disease. 5th ed. Lippincott Williams & Wilkins; 2013.
Defense against microbes is mediated by the effector mechanisms of innate and adaptive immunity. The innate immune system provides early defense and the adaptive immune system provides a more sustained and stronger response as well as protection against repeat infection by the same microbe. Many pathogenic microbes have evolved to resist innate immunity, and protection against such infections is critically dependent on adaptive immune responses. Adaptive responses are effective against even virulent microbes because these responses generate large numbers of effector cells and antibody molecules that function to eliminate the microbes and memory cells that protect the individual from repeated infections. However, it typically takes several days for adaptive immune responses to develop fully (the time needed for naive lymphocyte proliferation and differentiation into effector cells), and innate immunity provides critical defense during this window.
The immune system responds in specialized ways to different types of microbes to combat various infectious agents most effectively. Different microbes require different mechanisms for elimination, and the adaptive immune system has evolved to respond in the optimal way to diverse microbes. The generation of different subsets of effector CD4+ T cells and the production of different classes of antibodies are excellent examples of the specialization of adaptive immunity.
The survival and pathogenicity of microbes in a host are critically influenced by the ability of the microbes to evade or resist the effector mechanisms of immunity. As we will see later in this chapter, microorganisms have developed a variety of mechanisms for surviving in the face of powerful immunologic defenses. Infectious microbes and the immune system have co-evolved and are engaged in a constant struggle for survival. The balance between host immune responses and microbial strategies for resisting immunity often determines the outcome of infections.
Some microbes establish latent, or persistent, infections in which the immune response controls but does not eliminate the microbe. Several viruses, especially DNA viruses of the herpes virus and poxvirus families, human immunodeficiency virus (HIV), and some intracellular bacteria are capable of establishing latent infections. In latent viral infections, the viral DNA persists in infected cells but no infectious virus is produced. In persistent bacterial infections, such as tuberculosis, the bacteria may survive within the phagocytic vesicles of macrophages that have ingested the bacteria. In all these situations, some latent microbes may on occasion become activated and start replicating, especially if the immune system is weakened for any reason.
In many infections, tissue injury and disease may be caused by the host response to the microbe rather than by the microbe itself. Immunity is necessary for host survival but also has the potential for causing injury to the host.
Inherited and acquired defects in innate and adaptive immunity are important causes of susceptibility to infections. Common acquired causes of immunodeficiency include therapeutic immunosuppression by drugs to treat inflammatory and autoimmune diseases or prevent transplant rejection, leukemias that destroy the bone marrow and impair the development of immune cells, and HIV infection. Although less common, there are a large number of inherited immunodeficiency syndromes caused by mutations in single genes whose major clinical consequence is increased infections. In addition, subtle and poorly defined defects in host defenses may under lie common infections. Aging individuals also show increased susceptibility to infection, presumably because of reduced immune responses.
Infections in the population elicit immune responses that establish herd immunity, which protects against the spread of the infection. Conversely, newly emerging infections are able to spread in part because of the absence of herd immunity, resulting in epidemics and pandemics. Most of these new infections are caused by viruses that develop novel strains because of reassortment between the genomes of existing human strains and animal strains. (This process is discussed in more detail later, when we consider how influenza viruses escape from immune defense.) The most devastating pandemic in recent history was caused by the influenza virus in 1918 to 1920, estimated to have killed 20 to 50 million people in Western Europe and other regions of the world. More recently, widespread infections have been caused by the coronavirus that caused severe acute respiratory distress syndrome (SARS) in 2002; a new influenza strain in 2009; the coronavirus that caused Middle Eastern respiratory syndrome (MERS), which emerged in 2012; the Zika virus in 2015 (which causes neurologic defects in newborns); and the coronavirus SARS-CoV-2 from 2019 onward (which causes the disease called COVID-19). The rapid spread of the COVID-19 pandemic, which has been linked to almost 7 million deaths by 2023 and caused major disruptions in societies worldwide, demonstrates the extreme danger of emerging infections in populations that lack preexisting immunity.
Analyses of immune responses provide valuable clinical assays for infections. The most useful test is measurement of serum anti bodies specific for particular microbes. This is helpful for detecting infections in which the microbe cannot be cultured, is not detect able in the blood by molecular assays, or is only present in tissues that are not readily accessible for sampling. The presence of IgM (immunoglobulin M) antibodies is indicative of recent infection, whereas the presence of only IgG suggests past infection, reflecting the sequence of antibody isotype production (IgM followed by IgG) in response to most immunizations. Other tests include assays for T-cell responses, such as tests for skin reactions to microbial antigens and cytokine (e.g., interferon-γ [IFN γ]) release after activation of peripheral blood cells with antigens, used to detect infection with Mycobacterium tuberculosis.
In this chapter, we will consider the main features of immunity to five categories of pathogenic microorganisms: extracellular bacteria, intracellular bacteria (including facultative intracellular bacteria living outside host cells), fungi, viruses, and protozoan and multicellular parasites (Table 1). This separation provides a useful context for discussing immunity because the dominant immune responses to these types of infections are different. We use the terms extracellular and intracellular bacteria to refer to where the organisms survive and replicate; even extracellular bacteria become intracellular when they are ingested into phagocytes, but they do not survive inside phagocytes, and intracellular bacteria may be extracellular when they spread from cell to cell.
Table1. Examples of Pathogenic Microbes
Table1. Examples of Pathogenic Microbes—cont’d
