Page 412 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 27 Host Defenses to Extracellular Bacteria 393

present in secretions, such as ABO blood group antigens. Cell
adhesion and extracellular matrix molecules, such as fibronectin
and proteoglycans, can also inhibit or enhance bacterial binding
to epithelial surfaces. The Tamm-Horsfall glycoprotein, found
in urine, can bind avidly to a variety of bacteria and facilitate
clearance. Proteins, such as lactoferrin (Lf), present at mucosal
surfaces, bind iron, an important requirement for bacterial growth.
This action may reduce microbial proliferation, but some mucosal
pathogens bind Lf and remove iron from the molecule for growth.
Normal Microbiota as Host Defense
The human microbiome is now recognized as a major host defense
against bacterial pathogens by providing “colonization resistance,”
maintaining a balance of commensals to pathogens, and by
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priming the immune system (Chapter 14). Altering or disrupting
the normal microbiota by antibiotics facilitates the expansion
of enteric pathogens as Clostridium difficile and Salmonella
typhimurium or selection of antibiotic-resistant members of the
microbiome. Similarly, changes in human physiology, for example,
exposure of skin to elevated temperatures and humidity, chronic
stress, host immune suppression, or active behavioral changes,
such as smoking, can cause a commensal-to-pathogen switch.
Recent studies have demonstrated that certain resident microbiota
can resist pathogen colonization and infection. For example,
FIG 27.1 Mucociliary Host Defense. Scanning electron micro- matched volunteers were inoculated with Haemophilus ducreyi
graph of human upper respiratory mucosa showing the ciliated into the arms, and the subsequent infection either resolved or
and nonciliated epithelial surface (×16000). resulted in formation of abscesses; characterization of the skin
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microbiome before, during, and after the experimental inoculation
showed that the microbiomes of those with pustule formation
are detrimental to many bacteria. The constant desquamation and of those with resolved infection were distinct and influenced
of stratified epithelial surface of skin helps in the removal of the course of the H. ducreyi infection. 6
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microorganisms. Nevertheless, a complex skin microbiome that The interaction of the microbiome with the immune system
can include bacterial pathogens has been identified, and this differs is also important for defense against extracellular pathogens.
remarkably, depending on location in the body. Disruption of Normal microbiota facilitate a high level of priming of the
these physical barriers can augment pathogen tissue colonization immune system by maintaining high levels of major histocompat-
and invasion. Infections by S. aureus and S. pyogenes, bacteria that ibility complex (MHC) class II molecule expression on macro-
can colonize skin, are often preceded by skin damage. Repeated phages and other antigen-presenting cells (APCs). PRRs (see
trauma to skin (e.g., dialysis and intravenous drug use) also below) are traditionally known to recognize microbial molecules
enhances skin colonization with pathogens, including that by during infection; however, ligands for PRRs are abundantly
S. aureus. produced by the resident microbiota during normal colonization.
Mucosal surfaces have additional nonspecific antibacterial The integrity of the intestinal epithelial layer is dependent on
defenses. The mucociliary blanket of the respiratory tract (Fig. activation of Toll-like receptors (TLRs; see below) by normal
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27.1) and the female urogenital tract (fallopian tube) move microbiota. Stimulation of TLR-5 has been shown to increase
bacteria away from epithelial surfaces, as does the flushing of resistance to E. faecium infection in a murine model. Activation
the urinary tract with urine, intestinal peristalsis, and the bathing of nucleotide oligomerization domain 1 (NOD1) receptors by
of the conjunctiva with tears. Lysozyme is found in most mucosal gut resident microbiota is necessary for priming of the innate
secretions and lyses bacterial cell walls by splitting muramic acid immune system. Additionally, resident microbiota produce such
β(1–4)-N-acetyl-glucosamine linkages. The acid pH of the factors as bacteriocins, lantibiotics, and phenol-soluble modulin
stomach, intestinal peristalsis, and the antibacterial effect of (PSM), which function in a similar manner to that of host-derived
proteolytic enzymes present in intestinal secretions are important antimicrobial proteins and peptides (APPs; see below), suggesting
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GI tract host defenses against many pathogenic bacteria. The an important host defense strategy against pathogen colonization.
GI mucosa has a layer of mucus that acts as a physical shield to Importantly, members of the resident microbiota can cause
bacteria. Mucus is rich in mucin, glycoproteins that limit pathogen disease, particularly with loss of epithelial integrity and transloca-
binding to other host molecules necessary for mucosal adhesion. tion to a different host tissue.
Additionally, the mucus layer may function more than as a physical
barrier by acting as a diffusion barrier to concentrate antimicrobial Antimicrobial Peptides and Antimicrobial Proteins
proteins at the appropriate epithelial cell surface. The glycocalyx, Pathogens colonizing or invading epithelial surfaces are confronted
an extracellular layer of the apical surface of mucosal cells with APPs, which can be produced both by the host and the
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composed of carbohydrates, also protects cells against bacterial microbiota (Table 27.2). In addition to pathogen killing, APPs
attachment. control host physiological functions, such as inflammation,
Bacterial attachment and colonization of mucosal surfaces angiogenesis, and wound healing. They also limit pathogen
can be inhibited by bacterial binding to human cellular antigens colonization and shape the composition of the host microbiome