First and foremost, in order for a pathogen to establish an infection in a susceptible host, it must breach physical and chemical barriers. One of the first and most important of these barriers consists of the epithelial surfaces of the skin and the lining of the gut. The difficulty of penetrating these surfaces ensures that most pathogens never gain productive entry into the host. In addition, the epithelia produce chemicals that are useful in preventing infection. The secretion of gastric enzymes by specialized epithelial cells lowers the pH of the stomach and upper gastrointestinal tract, and other specialized cells in the gut produce antibacterial peptides. In addition, normal commensal flora present at mucosal surfaces (the gastrointestinal, urogenital, and respiratory tracts) can competitively inhibit the binding of pathogens to host cells. When the host is otherwise healthy, and pathogen dose and virulence are minimal, these barriers can often block productive infection altogether.
Sometimes infectious agents get help from other organisms to circumvent host barriers. In these cases a third party, called a vector, helps to carry the infection from one organism to another. These vectors, or intermediate hosts, can transmit a pathogen between one infected human and another, or from an infected animal to a human. Infectious disease vectors are most often blood-sucking arthropods (e.g., ticks, fleas, flies, or mosquitoes), which breach natural barriers like the skin with their bite and introduce the pathogens they carry directly into a susceptible host. These vector-borne infections account for approximately one out of every six instances of human infectious disease and are typically restricted to areas in which the intermediate host is found. Examples include malaria and Zika fever, both discussed later in this chapter.
Interventions that introduce barriers to infection in these intermediate hosts can be used as an indirect strategy to disrupt the cycle of infectious disease in humans. Recent studies in dengue virus, transmitted by the bite of an infected mosquito and the cause of an often fatal hemorrhagic fever in humans, suggest that it may be possible to engineer mosquitoes that are resistant to infection with the virus. When these engineered mosquitoes were released into the wild, they began to supplant the wild-type, virus-susceptible mosquito population, potentially breaking the cycle of transmission. This and other exciting new avenues of research that target animal disease vectors could advance infectious disease eradication without the requirement to intervene with the human immune response. Of course, this strategy is not a possibility with most infectious diseases, for which there is no arthropod vector.
Of course, even infectious agents that penetrate these barriers will need to face the first responders of innate immunity, which in many instances take care of them without the need for a full-scale adaptive response. These early responses are often tailored to the type of pathogen, using molecular pattern recognition receptors (see Chapter 4). Some bacteria produce endotoxins such as lipopolysaccharide (LPS), which stimulate macrophages or endothelial cells to produce cytokines, including IL-1, IL-6, and tumor necrosis factor-α (TNF-α). These cytokines can activate nearby innate cells, encouraging phagocytosis of the bacteria. The cell walls of many gram-positive bacteria contain a peptidoglycan that activates the alternative complement pathway, leading to opsonization and phagocytosis or lysis (see Chapter 5). Viruses commonly induce the production of interferons, which can inhibit viral replication by inducing an antiviral response in neighboring cells. Viruses are also controlled by natural killer (NK) cells, which frequently form the first line of defense in these infections (see Chapter 4). In many cases, these innate responses can lead to the resolution of infection. If these innate measures are not sufficient to eradicate the pathogen, the more specific adaptive immune response will come into play.
During this later, very pathogen-specific stage of the immune response, final eradication of the foreign invader often occurs, typically leaving a memory response capable of halting secondary infections. However, just as adaptive immunity in vertebrates has evolved over many millennia, pathogens have evolved a variety of strategies to escape destruction by the immune system. Some pathogens reduce their own antigenicity either by growing within host cells, where they are sequestered from immune attack, or by shedding their membrane antigens. Other pathogen strategies include camouflage (expressing molecules with amino acid sequences similar to those of host cell membrane molecules or acquiring a covering of host membrane molecules); suppressing the immune response selectively or directing it toward a pathway that is ineffective at fighting the infection; and continual variation in microbial surface antigens. Examples of these evasion strategies will be highlighted throughout the chapter as we discuss the four different classes of pathogen—viral, bacterial, fungal, and parasitic—and the various adaptive responses that are most effective against them.