Penetrating Host Defenses

Penetrating Host Defenses

Although humans host many beneficial bacteria, certain pathogens can penetrate host defenses and cause illness or disease.

Learning Objectives

Recognize the ways a host can be infected by, and resist, pathogens

Key Takeaways

Key Points

  • Infections are caused by pathogens such as viruses, prions, bacteria, and viroids, and larger organisms like macroparasites and fungi.
  • Mammalian hosts react to infections with an innate response, often involving inflammation, followed by an adaptive response.
  • Pathogens can evade the body’s immune responses through means that include specialized adaptations, mutation, evolved resistance to treatments, genetic recombination, and the production of immunosuppressive molecules that impair immune function.

Key Terms

  • Human microbiome: The aggregate of microorganisms that reside on the surface and in deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts.

The human microbiome (or human microbiota) is the aggregate of microorganisms that reside on the surface and in deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts. They include bacteria, fungi, and archaea. Some of these organisms perform tasks that are useful for the human host. However, the majority have no known beneficial or harmful effect. Organisms that are expected to be present, and that under normal circumstances do not cause disease, but participate in maintaining health, are deemed members of the normal flora.

Many of the bacteria in the digestive tract, collectively referred to as the gut flora, are able to break down certain nutrients such as carbohydrates that humans otherwise could not digest. The majority of these commensal bacteria are anaerobes, meaning they survive in an environment with no oxygen. Normal flora bacteria can act as opportunistic pathogens at times of lowered immunity. Escherichia coli (E. coli) is a bacterium that lives in the colon. It is an extensively studied model organism. Certain mutated strains of these gut bacteria do cause disease. An example is E. coli O157:H7.

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Escherichia coli O157:H7: Topographical images of colonies of E. coli O157:H7 strains (A) 43895OW (curli non-producing) and (B) 43895OR (curli producing) grown on agar for 48 h at 28°C. Escherichia coli O157:H7 is an enterohemorrhagic strain of the bacterium Escherichia coli and a cause of food borne illness. Infection often leads to hemorrhagic diarrhea and occasionally to kidney failure, especially in young children and elderly persons. Transmission is via the fecal-oral route. Most illness has been associated with eating under cooked, contaminated ground beef or ground pork, swimming in or drinking contaminated water, or eating contaminated vegetables.

Infection is the invasion of a host organism’s bodily tissues by disease-causing organisms, their multiplication, and the host’s reaction to these organisms and the toxins they produce. Infections are caused by pathogens such as viruses, prions, bacteria, and viroids, and larger organisms like macroparasites and fungi.

It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example already mentioned is in Mycobactrium tuberculosis, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis. This section briefly summarizes other ways in which pathogens can “outwit” immune responses. But keep in mind, although it seems as if pathogens have a will of their own, they do not. All of these evasive “strategies” arose strictly by evolution, driven by selection.

Bacteria sometimes evade immune responses because they exist in multiple strains, such as different groups of Staphylococcus aureus. S. aureus is commonly found in minor skin infections, such as boils, and some healthy people harbor it in their nose. One small group of strains of this bacterium, however, called methicillin-resistant Staphylococcus aureus, has become resistant to multiple antibiotics and is essentially untreatable. Different bacterial strains differ in the antigens on their surfaces. The immune response against one strain (antigen) does not affect the other; thus, the species survives.

Another method of immune evasion is mutation. Because viruses’ surface molecules mutate continuously, viruses like influenza change enough each year that the flu vaccine for one year may not protect against the flu common to the next. New vaccine formulations must be derived for each flu season.

Genetic recombination—the combining of gene segments from two different pathogens—is an efficient form of immune evasion. For example, the influenza virus contains gene segments that can recombine when two different viruses infect the same cell. Recombination between human and pig influenza viruses led to the 2010 H1N1 swine flu outbreak.

Pathogens can produce immunosuppressive molecules that impair immune function, and there are several different types. Viruses are especially good at evading the immune response in this way, and many types of viruses have been shown to suppress the host immune response in ways much more subtle than the wholesale destruction caused by HIV.

Pili and Pilus Assembly

Attachment of bacteria to host surfaces often aided by pili or fimbrae is required for colonization during infection or to initiate formation of a biofilm.

Learning Objectives

Describe the function of the pili in regards to pathogenecity

Key Takeaways

Key Points

  • The process of bacterial conjugation allow for the exchange of genes via the formation of “sex pili”.
  • All pili are primarily composed of oligomeric pilin proteins.
  • Conjugative pili allow the transfer of DNA between bacteria in the process of bacterial conjugation.

Key Terms

  • pilus: A hair-like appendage found on the cell surface of many bacteria.

A pilus (Latin for “hair;” plural: pili) is a hairlike appendage found on the surface of many bacteria. The terms pilus and fimbria (Latin for “thread” or “fiber,” plural: fimbriae ) can be used interchangeably, although some researchers reserve the term pilus for the appendage required for bacterial conjugation. All pili are primarily composed of oligomeric pilin proteins.

Dozens of these structures can exist on the bacteria. Some bacterial viruses or bacteriophages attach to receptors on pili at the start of their reproductive cycle. Pili are antigenic. They are also fragile and constantly replaced, sometimes with pili of different composition, resulting in altered antigenicity. Specific host responses to old pili structure are not effective on the new structure. Recombination genes of pili code for variable (V) and constant (C) regions of the pili (similar to immunoglobulin diversity).

Conjugative pili allow the transfer of DNA between bacteria, in the process of bacterial conjugation. They are sometimes called “sex pili”, in analogy to sexual reproduction, because they allow for the exchange of genes via the formation of “mating pairs”. Perhaps the most well-studied is the F pilus of Escherichia coli, encoded by the F plasmid or fertility factor.

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Bacterial Conjugation: A schematic drawing of bacterial conjugation. Conjugation diagram 1- Donor cell produces pilus. 2- Pilus attaches to recipient cell, brings the two cells together. 3- The mobile plasmid is nicked, and a single strand of DNA is then transferred to the recipient cell. 4- Both cells recircularize their plasmids, synthesize second strands, and reproduce pili; both cells are now viable donors.

A pilus is typically 6 to 7 nm in diameter. During conjugation, a pilus emerging from donor bacterium ensnares the recipient bacterium, draws it in close, and eventually triggers the formation of a mating bridge, which establishes direct contact and the formation of a controlled pore that allows transfer of DNA from the donor to the recipient. Typically, the DNA transferred consists of the genes required to make and transfer pili (often encoded on a plasmid), and is a kind of selfish DNA; however, other pieces of DNA often are co-transferred, and this can result in dissemination of genetic traits, such as antibiotic resistance, among a bacterial population. Not all bacteria can make conjugative pili, but conjugation can occur between bacteria of different species.

Some pili, called “type IV pili,” generate motile forces. The external ends of the pili adhere to a solid substrate, either the surface to which the bacteria are attached or to other bacteria, and when the pilus contracts, it pulls the bacteria forward, like a grappling hook. Movement produced by type IV pili is typically jerky, and so it is called “twitching motility,” as distinct from other forms of bacterial motility, such as motility produced by flagella. However, some bacteria, for example Myxococcus xanthus, exhibit gliding motility. Bacterial type IV pilins are similar in structure to the component flagellins of Archaeal flagella.

Attachment of bacteria to host surfaces is required for colonization during infection or to initiate formation of a biofilm. A fimbria is a short pilus that is used to attach the bacterium to a surface. Fimbriae are either located at the poles of a cell or are evenly spread over its entire surface. Mutant bacteria that lack fimbriae cannot adhere to their usual target surfaces and, thus, cannot cause diseases. Some fimbriae can contain lectins. The lectins are necessary to adhere to target cells, because they can recognize oligosaccharide units on the surface of these target cells. Other fimbriae bind to components of the extracellular matrix. Fimbriae are found in both Gram-negative and Gram-positive bacteria. In Gram-positive bacteria, the pilin subunits are covalently linked.

Biofilms and Infections

Biofilms will form on virtually every non-shedding surface in a non-sterile aqueous (or very humid) environment.

Learning Objectives

Discuss the importance of biofilms in the biomedical community

Key Takeaways

Key Points

  • Biofilms have been found to be involved in a wide variety of microbial infections in the body.
  • Microbes form a biofilm in response to many factors, which may include cellular recognition of specific or non-specific attachment sites on a surface and nutritional cues.
  • Bacterial biofilms may impair cutaneous wound healing and reduce topical antibacterial efficiency in healing or treating infected skin wounds.

Key Terms

  • biofilm: A thin film of mucus created by and containing a colony of bacteria and other microorganisms.
  • sterile: unable to reproduce (or procreate)

A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance (EPS).

Microbes form a biofilm in response to many factors, which may include cellular recognition of specific or non-specific attachment sites on a surface, nutritional cues, or in some cases, by exposure of planktonic cells to sub-inhibitory concentrations of antibiotics. When a cell switches to the biofilm mode of growth, it undergoes a phenotypic shift in behavior in which large suites of genes are differentially regulated.

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Biofilm development: 5 stages of biofilm development. Stage 1, initial attachment; stage 2, irreversible attachment; stage 3, maturation I; stage 4, maturation II; stage 5, dispersion. Each stage of development in the diagram is paired with a photomicrograph of a developing Pseudomonas aeruginosa biofilm. All photomicrographs are shown to same scale.

Biofilms are ubiquitous. Nearly every species of microorganism, not only bacteria and archaea, have mechanisms by which they can adhere to surfaces and to each other. Biofilms will form on virtually every non-shedding surface in a non-sterile aqueous (or very humid) environment.

Biofilms have been found to be involved in a wide variety of microbial infections in the body, by one estimate in 80% of all infections. Infectious processes in which biofilms have been implicated include common problems such as urinary tract infections, catheter infections, middle-ear infections, formation of dental plaque, gingivitis, and coating contact lenses. Biofilms have also been implicated in less common but more lethal processes such as endocarditis, infections in cystic fibrosis, and infections of permanent indwelling devices such as joint prostheses and heart valves.

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Staphylococcus aureus biofilm: Staphylococcus aureus forming a biofilm on a catheter.

More recently it has been noted that bacterial biofilms may impair cutaneous wound healing and reduce topical antibacterial efficiency in healing or treating infected skin wounds. It has recently been shown that biofilms are present on the removed tissue of 80% of patients undergoing surgery for chronic sinusitis. The patients with biofilms were shown to have been denuded of cilia and goblet cells, unlike the controls without biofilms who had normal cilia and goblet cell morphology. Biofilms were also found on samples from two of 10 healthy controls mentioned. The species of bacteria from interoperative cultures did not correspond to the bacteria species in the biofilm on the respective patient’s tissue. In other words, the cultures were negative though the bacteria were present.

Biofilms can also be formed on the inert surfaces of implanted devices such as catheters, prosthetic cardiac valves, and intrauterine devices. New staining techniques are being developed to differentiate bacterial cells growing in living animals, e.g. from tissues with allergy-inflammations.

Pseudomonas aeruginosa biofilms

The achievements of medical care in industrialized societies are markedly impaired due to chronic opportunistic infections that have become increasingly apparent in immunocompromised patients and the aging population. Chronic infections remain a major challenge for the medical profession and are of great economic relevance because traditional antibiotic therapy is usually not sufficient to eradicate these infections.

Pseudomonas aeruginosa is not only an important opportunistic pathogen and causative agent of emerging nosocomial infections but can also be considered a model organism for the study of diverse bacterial mechanisms that contribute to bacterial persistence. In this context the elucidation of the molecular mechanisms responsible for the switch from planktonic growth to a biofilm phenotype and the role of inter-bacterial communication in persistent disease should provide new insights. It should help researchers learn about the pathogenicity of P. aeruginosa, contribute to a better clinical management of chronically infected patients, and lead to the identification of new drug targets for the development of alternative anti-infective treatment strategies.

Dental plaque

Dental plaque is a biofilm that adheres to teeth surfaces and consists of bacterial cells, salivary polymers, and bacterial extracellular products. This accumulation of microorganisms subject the teeth and gingival tissues to high concentrations of bacterial metabolites which results in dental disease. The biofilms attached to the surfaces of some dental alloys, impression materials, dental implants, restorative and cement materials play an essential role concerning the biofilms establishment dynamics toward the physical-chemical properties of the materials which biofilms are attached to.

Legionellosis

Legionella bacteria are known to grow under certain conditions in biofilms, in which they are protected against disinfectants. Workers in cooling towers, persons working in air conditioned rooms, and people taking a shower are exposed to Legionella by inhalation when the systems are not well designed, constructed, or maintained. Neisseria gonorrhoeae is an exclusive human pathogen. Recent studies have demonstrated that it utilizes two distinct mechanisms for entry into human urethral and cervical epithelial cells involving different bacterial surface ligands and host receptors. In addition, it has been demonstrated that the gonococcus can form biofilms on glass surfaces and over human cells. There is evidence for the formation of gonococcal biofilms on human cervical epithelial cells during natural disease. Evidence also suggests that the outer membrane blebbing by the gonococcus is crucial in biofilm formation over human cervical epithelial cells.