Extracellular bacteria are capable of replicating outside host cells, for example, in tissue spaces such as the lumens of the airways and gastrointestinal tract, in connective tissues, and even in the blood. Many different species of extracellular bacteria are pathogenic, and disease is caused by two principal mechanisms. First, these bacteria induce inflammation, which results in tissue injury at the site of infection. Second, bacteria produce toxins, which have diverse pathologic effects. The toxins include an endotoxin, which, in gram-negative bacteria, is the lipopolysaccharide (LPS) complex in the cell wall, and exotoxins, which are secreted by many types of bacteria. Endotoxin activates macrophages, endothelial cells and other cell types and stimulates the production of cytokines that mediate host defense and also can cause disease. Many exotoxins are cytotoxic and kill host cells by various mechanisms. For instance, diphtheria toxin shuts down protein syn thesis in infected cells, and anthrax toxin disrupts several critical biochemical signaling pathways in infected cells. Other toxins are not cytotoxic but cause disease by various other mechanisms. For example, cholera toxin interferes with ion and water transport in intestinal epithelium, causing diarrhea, and tetanus toxin inhibits neuromuscular transmission, causing paralysis.
Innate Immunity to Extracellular Bacteria
The principal mechanisms of innate immunity to extracellular bacteria are phagocytosis, complement activation, and the inflammatory response.
• Activation of phagocytes and inflammation. Extracellular bacteria are efficiently killed by phagocytes (neutrophils and macrophages) because these microbes have not adapted to surviving inside these cells. Therefore, recruitment and activation of phagocytes to the site of infection, which is part of the inflammatory response, is the major defense mechanism against these microbes. Phagocytes are recruited and activated in response to bacterial products, which act directly on the phagocytes and also induce secretion of cytokines that activate the cells. Tissue-resident dendritic cells (DCs) and macrophages that are activated by the microbes secrete cytokines that promote leukocyte infiltration into sites of infection. Recruited neutrophils and blood monocyte–derived macrophages, as well as tissue-resident macrophages, use surface receptors, including mannose receptors and scavenger receptors, to recognize extracellular bacteria, and they use Fc receptors and complement receptors to recognize bacteria opsonized with antibodies and complement proteins, respectively. Microbial products activate Toll-like receptors (TLRs) and other pattern recognition receptors in phagocytes and other cells. Some of these receptors function mainly to promote the phagocytosis of the microbes (e.g., mannose receptors); others stimulate the microbicidal activities of the phagocytes (mainly TLRs); and yet others promote both phagocytosis and activation of the phagocytes (Fc receptors). The activated phagocytes ingest microbes and destroy them mainly in phagolysosomes.
• Complement activation. Bacteria provide a surface for complement activation by the alternative pathway. Bacteria express terminal mannose residues on cell surface carbohydrates that binds to mannose-binding lectin, or N-acetylated carbohydrates and some other N-acetylated compounds that bind to ficolins, both of which activate complement by the lectin pathway. One result of complement activation is opsonization and enhanced phagocytosis of the bacteria. In addition, the membrane attack complex (MAC) generated by complement activation lyses bacteria, especially Neisseria species, which are particularly susceptible to lysis because of their thin cell walls, and complement by-products stimulate inflammatory responses by recruiting and activating leukocytes.
• Innate lymphoid cells (ILCs), γδ T cells, and NKT cells have all been described in infections, mostly in experimental models, but their role in host defense, especially in humans, is not established.
Adaptive Immunity to Extracellular Bacteria
Humoral immunity is a major protective immune response against extracellular bacteria, and it functions to block infection, eliminate the microbes, and neutralize their toxins (Fig. 1A). Antibody responses against extracellular bacteria are directed against cell wall antigens and toxins, which may be polysaccharides or proteins. The polysaccharides are T-independent antigens that elicit antibody responses but do not activate T cells. Therefore, humoral immunity is the principal mechanism of defense against bacteria with polysaccharide-rich capsules, often called encapsulated bacteria, including Streptococcus pneumoniae, Neisseria species, and others. In these infections, the spleen plays a major role in both production of the antibodies and phagocytic clearance of the opsonized bacteria. People whose spleens are either surgically removed because of trauma or other reasons or are damaged in hematologic disorders are at increased risk for severe infections by these encapsulated bacteria. Protein antigens, which are present in or secreted by most bacteria, elicit more potent class-switched, high-affinity antibodies, as well as cell-mediated immunity. The effector mechanisms used by antibodies to combat infections include neutralization, opsonization, and phagocytosis, and activation of complement by the classical pathway. Neutralization is mediated by high-affinity IgG, which binds microbes in the circulation and tissues, and IgA, which neutralizes microbes in the lumens of mucosal organs. Opsonization is best mediated by the IgG1 and IgG3 subclasses of IgG, and complement activation is most efficiently initiated by IgM, IgG1, and IgG3.
Fig1. Adaptive immune responses to extracellular microbes. Adaptive immune responses to extracellular microbes such as bacteria and their toxins consist of antibody production (A) and the activation of CD4+ helper T cells, which work by secreted cytokines (B) and CD40 ligand (not shown). Antibodies neutralize and eliminate microbes and toxins by several mechanisms. Helper T cells produce cytokines that stimulate inflammation, macrophage activation, and B-cell responses. DC, Dendritic cell; IFN-γ, interferon-gamma; IL, interleukin; TNF, tumor necrosis factor.
The protein antigens of extracellular bacteria also activate CD4+ helper T cells, which produce cytokines and express cell surface molecules that induce local inflammation, enhance the phagocytic and microbicidal activities of macrophages and neutrophils, and stimulate antibody production (see Fig. 1B). Th17 responses induced by these microbes recruit neutrophils and monocytes and thus promote local inflammation at sites of bacterial infection. Patients with genetic defects in Th17 development and those who make neutralizing autoantibodies specific for IL-17 have increased susceptibility to extracellular bacterial and fungal infections and develop multiple skin abscesses.
Injurious Effects of Immune Responses to Extracellular Bacteria
The principal injurious consequence of host responses to extra cellular bacteria is inflammation. Neutrophils and macro phages that function to eradicate the infection can also cause tissue damage by local production of reactive oxygen species (ROS) and lysosomal enzymes. These inflammatory reactions are usually self-limited and controlled. Cytokines secreted by leukocytes in response to bacterial products also stimulate the production of acute-phase proteins and cause the systemic manifestations of the infection. Sepsis is a pathologic consequence of severe, local, or disseminated infection by some gram-negative and gram-positive bacteria, as well as some fungi. Sepsis typically manifests clinically with abnormalities in blood perfusion of many tissues, coagulation, metabolism, and organ function. Septic shock is the most severe and frequently fatal form of sepsis, characterized by circulatory collapse (shock) and disseminated intravascular coagulation. The early phase of bacterial sepsis is caused by cytokines produced by macrophages that are activated by bacterial cell wall components, including LPS and peptidoglycans. Tumor necro sis factor (TNF), IL-6, and IL-1 are the principal cytokine mediators of sepsis, but interferons and IL-12 may also contribute. This early burst of large amounts of cytokines is sometimes called a cytokine storm. There is some evidence that in LPS-induced sepsis, activation of a noncanonical inflammasome pathway causes cell death and release of inflammatory mediators (the process is called pyroptosis), and this contributes to the pathology of the infectious disease.
Certain bacterial toxins stimulate all T cells that express members of a particular T-cell receptor (TCR) Vβ gene family. Such toxins are called superantigens because, like the typical antigens T cells recognize, they bind to TCRs and to major histocompatibility complex (MHC) class II molecules (although not to the peptide-binding clefts), but they activate many more clones of T cells than do conventional peptide antigens (Fig. 2). Their importance lies in their ability to activate many T cells, with the subsequent production of large amounts of cytokines that can also cause a sepsis-like systemic inflammatory response syndrome.
Fig2. Polyclonal activation of T cells by bacterial superantigens. (A) Conventional microbial T-cell anti gens, composed of a peptide bound to the peptide-binding groove of a major histocompatibility complex (MHC) molecule (peptide X, for example), are recognized by a very small fraction of T cells in any one individual, and only these T cells are activated to become effector T cells that protect against the microbe. (B) In contrast, a superantigen binds to MHC class II molecules outside the peptide-binding groove, in an allele-nonspecfic manner, and simultaneously binds to the variable region of many different T-cell receptor (TCR) β chains, regardless of the peptide specificity of the TCR. Different superantigens bind to TCRs of different Vβ families. Because many T cells express a TCR β chain from a particular Vβ family, superantigens can activate a large number of T cells. In the example shown, the superantigen staphylococcal enterotoxin B (SEB) binds to the MHC class II molecule HLA-DR and the V regions of TCRs belonging to the Vβ3 family. Other superantigens may bind different MHC class II molecules and TCRs of different Vβ families. APC, Antigen-presenting cell.
A late complication of the humoral immune response to bacterial infection may be the generation of disease-producing antibodies. Two examples are rare sequelae of streptococcal infections of the throat or skin that are manifested weeks or even months after the infections are controlled. Rheumatic fever is a sequel of pharyngeal infection with group A β-hemolytic streptococci. Infection leads to the production of antibodies and activation of T cells specific for bacterial cell wall proteins. Some of these antibodies and T cells cross-react with myocardial proteins and cause inflammation affecting the heart muscle (myocarditis) and valves (endocarditis). Poststreptococcal glomerulonephritis is a sequel of infection of the skin or throat with nephritogenic strains of group A β-hemolytic streptococci. Antibodies produced against these bacteria form complexes with bacterial antigen, which may be deposited in kidney glomeruli and cause inflammation (glomerulonephritis) leading to renal failure.
Immune Evasion by Extracellular Bacteria
The virulence of extracellular bacteria has been linked to a number of mechanisms that enable the microbes to resist innate immunity (Table 1 and Fig. 3). Bacteria with poly saccharide-rich capsules resist phagocytosis and are therefore more virulent than homologous strains lacking a capsule. The capsules of many pathogenic gram-positive and gram-negative bacteria contain sialic acid residues that inhibit complement activation by the alternative pathway.
Table1. Mechanisms of Immune Evasion by Bacteria
Fig3. Mechanisms of immune evasion in bacteria. Shown are the multiple mechanisms used by one bacterial species, Neisseria gonorrhoeae, to evade humoral immunity. Ig, Immunoglobulin.
A mechanism used by bacteria to evade humoral immunity is variation of surface antigens (see Fig. 3). Some surface antigens of bacteria, such as gonococci and Escherichia coli, are contained in their pili, which are the structures responsible for bacterial adhesion to host cells. The major antigen of the pili is a protein called pilin. The pilin genes of gonococci undergo extensive gene conversion, because of which the progeny of one organ ism can produce up to 106 antigenically distinct pilin molecules. This ability to alter antigens helps the bacteria to evade attack by pilin-specific antibodies, although its principal significance for the bacteria may be to select for pili that are more adherent to host cells so that the bacteria are more virulent. Changes in the production of glycosidases lead to chemical alterations in surface oligosaccharides, which enable the bacteria to evade humoral immune responses against these antigens. Bacteria also release surface antigens in membrane blebs, which may divert antibodies away from the microbes themselves. Several species of bacteria secrete a protease that cleaves IgA1, thus disabling a major mechanism of mucosal immunity.
