General Considerations of Bacterial Diseases: Introduction
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The microbes that live on or in the human body are collectively referred to as the human microbiome. Some microbes of the human microbiome cause disease and others do not (commensals). The skin microbiome is a complex and diverse population of organisms that includes many bacteria, both commensals and pathogenic. The Human Microbiome Project includes recent work using metagenomic sequencing that describes the skin microbiome in previously inconceivable detail. The effects of multiple factors, including sebum secretion, body location, lipid content, pH, and sweat production significantly influence the growth of bacteria on the skin.1 The effects of skin diseases such as psoriasis also dictate the composition of the skin microbiome.2 It is clear there are many more bacteria normally living on our skin than previously imagined. Understanding the factors that contribute to healthy skin and skin disease will lead to improved treatment and prevention of skin infections and perhaps many noninfectious skin diseases.
The relationship of bacteria and the skin may be considered in four major categories1: (1) primary skin infections,2 (2) secondary infection of a primary skin disease (e.g., infected atopic dermatitis),3 (3) the skin lesions as manifestations of primary infection in some other organ system, usually the blood, and4 (4) reactive skin conditions resulting from bacterial infection elsewhere (e.g., erythema nodosum due to streptococcal pharyngitis). Thus, the balance of host immunity and the growth of the skin bacteria determine the disease state of the skin. Controlling a disease state, like atopic dermatitis, clearly reduces the number of skin infections that arise in the broken skin barrier. Conversely, controlling skin infections with dilute bleach baths and mupirocin ointment can lead to decreased atopic dermatitis flare as well.3
When considering the patient, it is important to remember that not all skin infections are suppurative but may present as reactive responses (e.g., erythema nodosum). Equally important, not all suppurative skin problems are primary skin infections (e.g., hidradenitis suppurativa). Notably, many erythematous skin lesions are not infectious at all (e.g., stasis dermatitis). The importance of the skin as a mirror of systemic infection cannot be overemphasized, especially when classic clinical findings are distorted as in immunocompromised patients. The timely recognition of the cutaneous clues of bacteremia may prevent the rapid spread of life-threatening infections due to organisms such as Pseudomonas aeruginosa, Vibrio vulnificus, Salmonella typhi, Staphylococcus aureus, and Neisseria meningitidis.
Pathogenesis of Bacterial Infection of the Skin
The development and evolution of bacterial infection involve three major factors1: (1) the portal of entry and skin barrier function,2 (2) the host defenses and inflammatory response to microbial invasion, and3 (3) the pathogenic properties of the organism.
Normal intact pediatric and adult skin is relatively resistant to infection and most skin infections occur when there is disruption of the skin barrier. Maceration, shaving, chronic wounds, excoriation of pruritic insect bites, and disruption of the epidermal barrier by other pathogens are some of the ways bacteria can breach the skin barrier. For example, skin trauma, interdigital maceration, or tinea pedis can be predisposing factors for lower leg cellulitis in an otherwise healthy person without venous incompetence or a leg ulcer.4
The character of the cutaneous inflammatory response to bacteria will be influenced by how the organisms reach the involved area. Local inflammation and suppuration commonly accompany direct bacterial infection of the skin. In septicemia, the vascular wall is often the primary site of skin involvement; hemorrhage, or thrombosis with infarction is the initial manifestation leading to ulceration or eschar. Certain bacteria can produce bacteremia or distant lesions without evoking an obvious inflammatory response at the portal of entry [e.g., Yersinia pestis, Streptobacillus moniliformis (rat-bite fever)], even in a healthy host. Occasionally, a devastating Streptococcus pyogenes septicemia has followed closely on an innocuous pinprick or abrasion that has not induced a significant local lesion.
The normal skin of healthy individuals is highly resistant to invasion by the wide variety of bacteria to which it is constantly exposed. It is difficult to produce localized infections such as impetigo, furunculosis, or cellulitis, if the integument is intact.5 Pathogenic organisms such as S. pyogenes (group A streptococcus, GAS) and S. aureus produce characteristic lesions of cellulitis and furunculosis in hosts with normal defenses usually because there is a disruption of the normal skin barrier. The presence of a silk suture reduces by a factor of 10,000, in the case of S. aureus, the number of organisms needed to produce an abscess in the human skin.6
Bacteria are unable to penetrate the keratinized layers of normal skin and, when applied to the surface, rapidly decrease in number. Maceration and occlusion, which result in increased pH, higher carbon dioxide content, and higher epidermal water content, result in dramatic increases in bacterial flora.7 Some bacteria, such as those that are Gram negative, can only be found in such sites, suggesting that normal skin conditions prevent them from colonizing the skin. The relative dryness of normal skin specifically contributes to the marked limitation of growth of bacteria, especially Gram-negative bacilli.
Lipids found on the skin surface also may have antibacterial properties.8,9 Reduction of skin surface lipids with topical solvents prolongs the survival time of S. aureus on the skin. The free fatty acids, and linoleic and linolenic acids, are more inhibitory for S. aureus than for coagulase-negative staphylococci, a component of the normal skin flora. Sphingosine, glucosylceramides, and cis-6-hexadeconic acid have been demonstrated to have antimicrobial activity against S. aureus. Bacterial interference (the suppressive effect of one bacterial species on colonization by another) exerts a major influence on the overall composition of the skin flora.
The organisms that characteristically survive and multiply in various ecologic niches of the skin constitute the “normal cutaneous flora.” As an example, the distribution of different species of coagulase-negative staphylococci varies among different anatomic areas, and their relative numbers can depend on age. In adults, Staphylococcus epidermidis is the principal staphylococcal species isolated from the scalp, face, chest, and axilla. In a study of the skin microbiome of healthy adults, over 98% of skin bacteria belonged to four phyla: (1) Actinobacteria (51.8%), (2) Firmicutes (24.4%), (3) Proteobacteria (16.5%), and (4) Bacteroidetes (6.3%). Although 205 genera were identified on only 20 individuals, three were associated with more than 62% of the sequences: (1) Corynebacteria (22.8%; Actinobacteria), (2) Propionibacteria (23.0%; Actinobacteria), and (3) Staphylococci (16.8%; Firmicutes).10
Human skin contains a wide range of proteins with inherent antimicrobial properties. These antimicrobial peptides (AMPs) are expressed on the skin surface as well as in eccrine sweat and saliva.11 Activated keratinocytes produce AMPs. The AMPs produced in keratinocytes are delivered to the skin surface in the lamellar bodies, and their appearance on the skin surface is closely tied to the production of normal skin stratum corneum lipids (see Chapter 47). These small proteins have as a characteristic physical property: the presence of an amphipathic organization, with one portion being cationic and capable of binding to microbial membranes, and another being hydrophobic allowing for insertion into the bacterial lipid membrane. The insertion into the membrane results in membrane disruption and microbial death. The second principle of AMPs is that they are processed after release by enzymes on the skin surface, resulting in multiple peptides each with different activities and different targets. The third principle of AMPs is that they not only kill microbes directly, but they are also potent activators of the host immune response. There are dozens of AMPs with activity on the human skin.12 The two major AMPs studied to date on the skin are (1) the cathelicidins (LL-37) and (2) the defensins. The marked decrease of these molecules on the inflamed skin of patients with atopic dermatitis may be related to the susceptibility of atopic patients to infections with S. aureus, herpes simplex virus, and vaccinia virus.13 T-helper 2 cytokines specifically suppress the production of these AMPs, a possible explanation for why psoriatic skin has normal or elevated AMP content and is less susceptible to bacterial and viral infections.14
The adaptive immune system, which requires the development of targeted cells and antibodies, is highly effective in protecting humans from infection once the effector cells and antibodies have been produced. However, this takes days, and bacteria replicate and invade in hours. The discovery of the “innate” immune system explains the ability of organisms to mount an effective and targeted immune response to microbes before the adaptive immune system comes into play (see Chapter 10). The innate immune system is present in plants, invertebrates, and vertebrates. This system relies on a series of pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPS) that are not present on “self”.15 Binding of the PRRs to the PAMPs results in opsonization and activation of the complement system as well as induction of inflammatory signaling pathways. This process involves at least three PRRs1: (1) the AMPs discussed in Antimicrobial Peptides,2 (2) Toll-like receptors (TLRs), and3 (3) the complement system. These three systems engage bacteria once they enter the skin and, by intercommunication and by signaling neutrophils and other immune cells, are vital in bringing to the site of infection the cells required to destroy the pathogen.
TLRs are a repertoire of pattern recognition receptors (see Chapter 10).16 They occur on cell membranes and recognize certain exogenous ligands that are unique to invading microorganisms and not found in the host. They play a prominent role as primary sensors for invading pathogens. For instance, TLR2 recognizes the peptidoglycan on the surface of Gram-positive bacteria, TLR4 recognizes the lipopolysaccharide on Gram-negative bacteria, and TLR5 recognizes flagellin, unique to flagellated bacteria. These structural elements of the invading organism are essential for its pathogenicity and therefore are hard to eliminate on an evolutionary basis. The TLRs not only engage the invader, but they also orchestrate what type of immune response is generated for that specific pathogen. TLRs do this by instructing antigen-presenting cells that have engaged the organism to secrete appropriate cytokines to generate the desired immunologic milieu and eventual adaptive immune response (see Chapter 10). Alternative downstream signaling pathways can result in different immune responses from engagement of the identical TLRs.
Complement (see Chapter 37) is activated when mannin-binding lectin binds to carbohydrate patterns on bacteria and activates C2 and C4.17 Activation of C3 liberates C3a and C3b. C3b on membranes leads to opsonization and enhanced phagocytosis. In addition, the cleavage of C5 leads to C5a, a potent activator of neutrophils and a stimulator of proinflammatory cytokines, including interleukin 1 (IL-1) and IL-8. The “membrane attack complex” is formed by completion of the complement cascade and kills invading microbes. Not surprisingly, complement components also modulate the immune system, and alter TLR stimulation of some activation pathways. Through an extensive repertoire of outcome options, the human host has the ability to develop an organism-specific response to a wide variety of infectious agents that the host has not previously encountered. In addition, the innate immune system through complement and TLR orchestrates the adaptive immune system to appropriately respond to the invading microbe. This elaborate innate immune response explains the variety of rather distinctive clinical responses to various bacterial infections that have been described. The infectious agent, the anatomic site of the infection, and the attendant inflammatory response pattern create the clinical lesion.
To effectively invade a host, the microbe must initially gain access. S. aureus uses teichoic acid and other surface proteins that promote adherence to the nasal mucosa. The bacteria are then available to contaminate any breaches in the skin, binding to fibronectin in wounds. The disease-producing capacity of bacteria is termed virulence. The genetic material encoding virulence factors and toxins are carried on mobile genetic elements called pathogenicity islands. Bacteriophages carry genetic elements from one bacterium to the next (Panton–Valentine leukocidin for example). Panton–Valentine leukocidin is a cytotoxin directed against human immune cells. It is associated with deep-seated and more inflammatory furunculosis, and now has been correlated with methicillin resistant S. aureus (MRSA). Importantly, up to 37% of patients with purulent CA-MRSA infections are colonized at another anatomical location with the organism.18 In addition, many bacterial species contain DNA elements within their own genome that specifically are designed to escape, inactivate, or suppress the host’s innate immune response, especially by resisting killing by neutrophils and excreted products. These gene products that respond to the host’s immune attack are usually composed of a two-protein interaction cascade involving a sensor and a response protein. This is called a two-component gene regulatory system
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