32 Host–Pathogen Interactions

1. INTRODUCTION

In this chapter, I address the fundamental questions of what differentiates pathogens from commensal microorganisms and how pathogens succeed in causing infectious disease. I delve in more detail into host mechanisms evolved to detect the presence of invaders and to fight infections. I focus on the role of innate immunity, production of antimicrobial peptides, inflammation, and cell death in the host–pathogen battle and discuss the remarkable conservation of innate immunity between plants, invertebrates, and mammals, despite having evolved under selective pressure imposed by distinct pathogens.

2. FROM THE PATHOGEN PERSPECTIVE

2.1. Commensals versus pathogens

We live in a world laden with microbes. At birth, microorganisms populate our body, forming what is called the normal or microbial flora, which constitute 90% of the cells in our body. The composition of the flora is different among anatomical sites and varies among individuals depending on genetics, age, sex, diet, and stress. Microorganisms in our flora are called commensals. Sociologically, a commensal is defined as an “individual not competing while residing in or occupying the same area as another having independent or different values.” Literally, a commensal is a companion eating at the same table. Both definitions are indeed appropriate to describe our symbiotic relationship with commensal microorganisms. They share our nutrients and in return provide us with vitamins, aide in our digestion, and are an important component of our innate immune system,

where they compete with, and protect us from, invading pathogens.

Pathogenic and commensal bacteria share a common structure. They have a nucleoid, a cytoplasm, a plasma membrane, and a cell wall composed of proteins and carbohydrates. Some have additional features such as flagella that allow motility (Figure 32-1). Molecules that constitute the general structure of microbes are unique to them and are thus recognized by the host innate immune system as foreign or non-self. Because microbes evolve rapidly, innate immunity focuses on molecules, predominantly structural elements, which are common to broad classes of microbes. It is useful to think of them as patterns. These include, for example, lipopolysaccharide (LPS), also called endotoxin, found on the cell wall of Gram-negative bacteria; peptidoglycan, which forms approximately 90% of the dry weight of Gram-positive bacteria but only 10% of Gram-negative strains (Figure 32-2); nucleic acids; and flagellin, the main constituent of flagella. Although these patterns are common to both commensals and pathogens, they were named pathogen-associated molecular patterns (PAMPs). In theory, a host would equally recognize commensals and pathogens. However, our coexistence with commensals suggests otherwise and indicates the presence of intriguing host mechanisms that limit the recognition of commensals. PAMPs are sensed by germ-line encoded receptors in the host, called pattern-recognition receptors (PRRs). Downregulation or absence of PRR expression on the surface of epithelial cells that are in direct contact with commensals might be one such mechanism.

Commensals and pathogens differ in their ability to infect the host. Pathogens are capable of evading host defenses and breaching anatomical barriers such as

Plasma membrane

Figure 32-1. General structure of bacteria. Bacteria have a nucleoid, a cytoplasm, a plasma membrane, and a cell wall composed of proteins and carbohydrates. Some have additional features, such as a carbohydrate capsule or slime layer, which protects from phagocytosis, or flagella, which allow motility.

those of the skin or internal epithelial barriers. This permits them to reach the bloodstream and enter in otherwise sterile tissues such as the spleen or liver, from which commensals are excluded. This faculty is determined at the genomic level. Pathogens harbor genomic regions or “islands” of pathogenicity, consisting of gene clusters that encode virulence factors.1 Collectively, these factors allow pathogens to go through their life cycles successfully; they function during invasion of the host, colonization, persistence, replication, and dissemination (Figure 32-3).

2.2. Pathogen strategies to infect the host

Pathogens have acquired sophisticated mechanisms to invade the host while evading phagocytosis and immune

Gram-negative bacteria

surveillance. The first step after entry in the host is for pathogens to avoid physical expulsion and to colonize the site of infection. The best example to illustrate this is that of “attaching and effacing” bacteria, such as enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli that enter the host through the oral route and colonize the colon by attaching to the surface of colonocytes and effacing their microvilli2 (Figure 32-4a). Pathogens are then faced with the task of hiding from the immune system. Various strategies are used for this purpose. Extracellular pathogens remain in the host by evading phagocytosis. Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria meningitidis, and uropathogenic E. coli surround their cell wall with a thick carbohydrate “capsule” that allows them to resist phagocytosis and complement-mediated lysis (Figure 32-4b). Many Gram-negative bacteria evolved modifications in their molecular patterns to avoid recognition by PRRs. Structurally, LPS is composed of a lipid A moiety that anchors polysaccharide O-antigen chains to the outer leaflet of the bacterial cell wall.3 In a complex with MD-2, the pattern recognition receptor TLR4 efficiently detects lipid A,4 which consists of hexa-acylated molecules with 12 to 16 carbon–fatty acid side chains.5 Various pathogens, including Helicobacter pylori,6 acquired changes in either the number of acyl groups or length of fatty acid side chains to interfere with recognition by TLR4. Similarly, a number of bacteria, notably mucosal pathogens, modulate the structure