Adherence: The Search for a Unique Niche - Attributes of Microbial Pathogenicity

Adherence: The Search for a Unique Niche

The first major interaction between a pathogenic microorganism and its host entails attachment to an eukaryotic cell surface. In its simplest form, adherence requires the par-ticipation of two factors: a receptor on the host cell and an adhesin on the invading mi-crobe. Most viruses attach specifically to sites on target cells through an envelope protein. For example, the influenza viruses attach specifically to neuraminic acid – containing glycoprotein receptors on the surface of respiratory cells before penetrating to the interior of the cell. 

Bacteria, like viruses, generally have protein structures on their surface that recognize either a protein or a carbohydrate moiety on the host cell surface. Finding the correct host cell surface in many cases appears to be a probability event related to the in-fectious dose. Because the mucosal surface is constantly bathed by a moving fluid layer, it is not surprising that many bacteria that infect the bladder or gastrointestinal tract are motile, and some (such as the typhoid bacillus) may use chemotaxis  to home in on the correct host cell surface. Some bacteria use mucolytic enzymes to reach epithelial surfaces.

Some bacterial adherence may involve hydrophobic interruptions between nonpolar groups present on the microbe and host cell. Alternatively, one can envision cationic bridging between cells. Such interactions lack the specificity seen in most host – pathogen interactions. Rather, pathogens most often employ highly specific receptor-ligand bind-ing. In the last decade, it has become clear that most pathogenic microorganisms have more than a single mechanism of host cell attachment, which is not just a redundant fea-ture. More often it reflects that pathogenic microbes require different types of adherence factors depending on their location and the types of host cells they may encounter. Thus, bacteria may employ one set of adhesins at the epithelial surface but respond with a dif-ferent set when they encounter cells of the immune system. Finally, not all adhesins are essential virulence factors; they may play a role in survival outside of a host or add to the biology of the microbe outside of its pathogenic lifestyle.

Bacterial adhesins can be divided into two major groups: pili (fimbriae) and nonpilus adhesins (afimbrial adhesins). The pili of many Gram-negative bacteria bind directly to sugar residues that are part of glycolipids or glycoproteins on host cells or act as a protein scaffold to which another more specific adhesive protein is affixed. One of the major fea-tures among diverse pili is conservation of the molecular machinery needed for pilus bio-genesis and assembly onto the bacterial surface. One of the best-studied examples of pilus assembly is P-pili (pyelonephritis-associated pili), which are encoded by pap genes. E. coli strains that express P-pili are associated with pyelonephritis, which arises fromurinary tract colonization and subsequent infection of the kidney. It is thought that P-pili are essential adhesins in this disease process. The pap operon is a useful paradigm, because it contains many conserved features found among various pilus operons. Two molecules guide newly synthesized pilus components to the bacterial surface. The major subunit of the pilus rod is PapA, which is anchored in the bacterial outer membrane by PapH. At the distal end of the pilus rod is the tip fibrillum, composed of PapE, and the actual tip adhesin, PapG, which mediates attachment to the host cell surface. Two other proteins, PapF and PapK, are involved in tip fibrillum synthesis. Although the host recep-tor varies for different bacterial pili, the general concepts provided by studying the P pilus operon are conserved in many other pilus systems, and components are often interchange-able. Homologous sequences to pap genes also have been found in genes involved in bacterial capsule and lipopolysaccharide biosynthesis.

Although many pili look alike morphologically, there are at least five general classes in various Gram-negative bacteria that recognize different entities on the host cell surface. Thus, although pap-like sequences are common throughout Gram-negative adhesins, other families of pili use alternative biogenesis and assembly machinery to form a pilus. One such group, type IV pili, is found in diverse Gram-negative organisms, including the causal agents of gonorrhea and cholera. Type IV pili subunits contain specific features, including a conserved, unusual amino-terminal sequence that lacks a classic leader se-quence and, instead, generally utilizes a specific leader peptidase that removes a short, basic peptide sequence. Several possess methylated amino termini on their pilin mole-cules and usually contain pairs of cysteines that are involved in intrachain, disulfide bond formation near their carboxyl termini; however, analogous to the P-pilus tip adhesin, a separate tip protein may function as a tip adhesin for type IV pili. The host receptor that a pathogenicity-associated adhesin recognizes probably determines the tissue specificity for that adhesin and bacterial colonization or persistence; of course, other factors also may make a contribution. The location of the adhesin at the distal tip of pili ensures adhesin exposure to potential host receptors. Alterations in the pilus subunit can also affect adherence levels, and antigenic variation in the actual structural pilin protein can be an important source of antigenic diversity for the pathogen.

The pilus model of attachment is the best-known means of bacterial attachment to a host cell surface; however, nonpilin adhesins have been demonstrated in a number of bac-terial species. These are often specific outer membrane proteins that form an intimate contact between the bacterial surface and the surface of the host cell. Several of these are intriguing because they resemble or “mimic” eukaryotic sequences that mediate cell – cell adhesion and adherence to the extracellular matrix. Similar classes of molecules thought to mediate adherence in the Gram-positive bacteria are surface fibrils composed of pro-teins and lipoteichoic acid. For example, streptococci causing pharyngitis, express an M protein – lipoteichoic acid structure believed to mediate attachment to the prevalent host cell protein, fibronectin.

Bacterial capsular polysaccharide also may mediate adherence to host cells or play an important role in binding layers of bacteria to others immediately adherent to the epithe-lial surface. These bacterial biofilms not only can coat the mucosal surface but play an important role in the bacterial colonization of the inert materials used as catheters.

Some organisms excrete an enzyme IgA protease, which cleaves human IgA1 in the hinge region to release the Fc portion from the Fab fragment. This enzyme might play an important role in establishing microbial species at the mucosal surface, as bacteria that cleave IgA can bind the antigen-binding domain of the immunoglobulin. This is one of several cases of molecular mimicry where bacteria (and probably viruses as well) can coat themselves with a secreted host cell product. This provides a microorganism with two advantages. First, microbes use these secreted products as a bridge to adhere to cell receptors that ordinarily bind these secreted products. Second, by binding a host cell product on its surface, the microbe disguises itself from the host cell immune system.

Unlike bacteria, viruses generally only have one major adhesin that they use to attach to the host cell surface and to gain entry into the cytoplasm. Otherwise, both bacteria and viruses share the same strategy: a protein structure that recognizes a specific receptor. Host cell receptors do not exist for the sole use of infectious agents; they generally are as-sociated with important cellular functions. The adhesive molecule on the microorganism has been selected to take advantage of the host cell’s biological function(s). In this way, the adhesin provides the microbe with a unique niche where the infectious agent has the greatest chance to achieve success. Presumably, a pathogen’s success can be measured by the extent of multiplication subsequent to entry. Adherence is important not only during the initial encounter between the pathogen and its host but also throughout the infection cycle.