Download Learning Objectives Wk 13 – Chronic Respiratory Infections - Wk 1-2

Learning Objectives Wk 13 – Chronic Respiratory Infections
1. Identify the normal flora present at different levels of the respiratory tract
The respiratory system can be divided into two components; the upper and lower
respiratory tracts. Note: there are a number of disputes as to where *exactly* the upper
tract ends and the lower tract begins. According to Mettler’s Textbook, the upper tract ends
halfway down the larynx where the pharynx splits into the esophagus and the trachea. Of
course the lower respiratory tract will continue down to the trachea.
The upper respiratory tract:
The Nose
Nasal Cavity
Paranasal Sinuses
Pharynx
Larynx (1/2)
The lower respiratory system:
Larynx (1/2)
Trachea
Bronchi
Bronchioles
Alveoli
Most surfaces of the upper respiratory tract have natural microflora. The lower respiratory
tract on the other hand should remain sterile under normal conditions; this is maintained by
the muco-cilliary escalator which helps prevent any microorganisms from entering the lower
tract.
In the upper respiratory tract, most of the natural microflora lives in the nose and nasal
passages.



The most common bacteria found in the nose are staphylococci. These organisms
are found just inside the nares and include Staphylococcus aureus and S.
epidermidis.
In addition to the staphylococci, aerobic corynebacteria ("diphtheroids") can be
cultured from the nasal surfaces.
Small numbers of Streptococcus pneumoniae, Neisseria meningitidis, and
Haemophilus influenzae can also be found in the nasopharynx.
The normal flora of the oropharynx also contains a large number of regular bacterial
inhabitants.


The nose and the oropharynx contains large numbers of S. aureus and S.
epidermidis.
The most important group of microorganisms native to this body niche are the
alpha-hemolytic streptococci or viridans streptococci. This group includes S. mitis, S.
mutans, S. milleri, and S. salivarius. It is believed that these bacteria act as
antagonists against invasion by pathogenic streptococci.

Additionally, cultures from this region usually show large numbers of diphtheroids,
Moraxella (formerly Branhamella) catarrhalis, and small Gram-negative cocci related
to Neisseria species.
2. Outline with common pathogens, their usual clinical manifestations, and host and
bacterial factors which allow for selection of particular organisms in particular locations.
Rhinoviruses
The most common viral infective agents of humans, they are the cause of the common cold.
A Rhinovirus infection will cause cold-like symptoms like sore throats, nasal congestion,
runny nose and sneezing. A high temperature is a common bodily reaction as well as the
hyper secretion of mucosa throughout the upper respiratory tract. The virus prefers to grow
at a temperature around 32 degrees, which is one reason it prefers the upper respiratory
system; where cooler environmental air is brought into the body, decreasing the local
temperature from a less than ideal 37 degrees. This is also a good reason why the virus
tends to affect more people during winter. Additionally, the Rhinoviruses affect the upper
respiratory system specifically because they are well adapted to bind to ICAM-1 (InterCellular Adhesion Molecule 1) receptors found within the upper respiratory system. Binding
allows a pathogen to colonize and infect a particular area, where otherwise they would be
ejected from the body by the innate immune system; in this case, the mucocilliary escalator.
Influenza Viruses
These are RNA viruses from the Orthomyxoviridae family of viruses. There are a number of
different types of Influenza viruses spread over 5 genera (classifications). Many of them
share numerous qualities including the way they invade cells. Influenza viruses all have a
covering of viral hemagglutinin (glycoprotein) over each cell which permits it to bind to host
cells. In order for these viruses to infect, the viral hemagglutinin must be cleaved by a host
protease which breaks down the protein and converts hemagglutinin into an active form
which can bind to host cells. Virulence of a specific virus determines how pathogenic it is, or
more simply put, its ability to cause disease. Some Influenza viruses are more pathogenic
than others depending on the nature of their hemagglutinin. Virus strains such as H1N1 have
hemagglutinin which cleaves much more actively to proteases found in the upper
respiratory tract, making the URT a much more suitable environment for them. Strains such
as H5N1 however have hemagglutinin which reacts more actively to the proteases found
deep within the lungs and the rest of the body, making those areas ideal for infection. This
accounts for H5N1’s greater virulence as infections deep within the lungs can lead to
pneumonia and are much more life threatening.
Pseudomonas Aeruginosa (PA)
This bacteria is the most common cause of chronic infection of the respiratory tract as a
result of cystic fibrosis. PA is a very common microorganism that can be found in many
places in the environment. It is actually present as microflora in an estimated 24 percent of
the population. PA has pili on its cell surface which adheres to galactose or mannose or sialic
acid receptors frequently found on respiratory epithelial cells. Because of the mucosa of the
respiratory system, the bacterial will usually not be able to colonize large enough numbers
to cause an infection. If the mucosa was to be disturbed in any way (like in CF), PA infections
can occur frequently due to their widespread prevalence in the environment.
Overall, pathogens in the respiratory tract rely on several factors in order to cause infection:




3.
Adherence factors that allow them to establish themselves in host cells such as
specific receptor sites.
Agents they produce that breaks down protective barriers and reduces the
effectiveness of immune responses.
Conditions which they grow most favourably in.
The immune response of the host (or lack of one).
Distinguish planktonic from sessile organisms, and relate this distinction to the
implications for antimicrobial therapy.
The distinguishing feature between the two is that planktonic organisms are suspended
within an aqueous solution (such as blood) while sessile organisms remain static and often
anchored onto one spot. When bacteria become sessile and anchor to one spot, they may
begin secreting a glue-like substance called biofilm. Bacteria, fungi, algae and protozoa are
all capable of forming a biofilm though it only takes a cluster of one species of
microorganism to form a biofilm, many different organisms can form them together.
Adhesion to surfaces provides considerable advantage for the biofilm forming bacteria, such
as protection from anti-microbial agents, exchange of nutrients, metabolites or genetic
material from close proximity to other micro organisms resulting in possible mutations. Such
symbiotic relationships although benefit the participating bacterial growth the physical
presence of biofilm either damages surfaces or causes obstruction so that the efficiency of
the surface is reduced. Biofilm infections such as pneumonia and meningitis are considered
very serious and can be extremely difficult to treat.
Appendix:
More about Pseudomonas Aeruginosa –
Pathogenesis
For an opportunistic pathogen such as Pseudomonas aeruginosa, the disease process
begins with some alteration or circumvention of normal host defenses. The pathogenesis of
Pseudomonass infections is multifactorial, as suggested by the number and wide array of
virulence determinants possessed by the bacterium. Multiple and diverse determinants of
virulence are expected in the wide range of diseases caused, which include septicemia,
urinary tract infections, pneumonia, chronic lung infections, endocarditis, dermatitis, and
osteochondritis.
Most Pseudomonas infections are both invasive and toxinogenic. The ultimate
Pseudomonas infection may be seen as composed of three distinct stages: (1) bacterial
attachment and colonization; (2) local invasion; (3) disseminated systemic disease.
However, the disease process may stop at any stage. Particular bacterial determinants of
virulence mediate each of these stages and are ultimately responsible for the characteristic
syndromes that accompany the disease.
Colonization
Although colonization usually precedes infections by Pseudomonas aeruginosa, the exact
source and mode of transmission of the pathogen are often unclear because of its
ubiquitous presence in the environment. It is sometimes present as part of the normal
flora of humans, although the prevalence of colonization of healthy individuals outside the
hospital is relatively low (estimates range from 0 to 24 percent depending on the
anatomical locale).
The pili of Pseudomonas aeruginosa will adhere to the epithelial cells of the upper
respiratory tract and, by inference, to other epithelial cells as well. These adhesins appear
to bind to specific galactose or mannose or sialic acid receptors on epithelial cells.
Colonization of the respiratory tract by Pseudomonas requires pili adherence and may be
aided by production of a protease enzyme that degrades fibronectin in order to expose the
underlying pilus receptors on the epithelial cell surface. Tissue injury may also play a role
in colonization of the respiratory tract, since P. aeruginosa will adhere to tracheal epithelial
cells of mice infected with influenza virus but not to normal tracheal epithelium. This has
been called opportunistic adherence, and it may be an important step in Pseudomonas
keratitis and urinary tract infections, as well as infections of the respiratory tract.
The receptor on tracheal epithelial cells for Pseudomonas pili is probably sialic acid (Nacetylneuraminic acid). Mucoid strains, which produce an exopolysaccharide (alginate),
have an additional or alternative adhesin which attaches to the tracheobronchial mucin (Nacetylglucosamine). Besides pili and the mucoid polysaccharide, there are possibly other
cell surface adhesins utilized by Pseudomonas to colonize the respiratory epithelium or
mucin. Also, it is possible that surface-bound exoenzyme S could serve as an adhesin for
glycolipids on respiratory cells.
The mucoid exopolysaccharide produced by P. aeruginosa is a repeating polymer of
mannuronic and glucuronic acid referred to as alginate. Alginate slime forms the matrix of
the Pseudomonas biofilm which anchors the cells to their environment and in medical
situations, it protects the bacteria from the host defenses such as lymphocytes,
phagocytes, the ciliary action of the respiratory tract, antibodies and complement. Biofilm
mucoid strains of Pseudomonas are also less susceptible to antibiotics than their planktonic
counterparts. Mucoid strains of P. aeruginosa are most often isolated from patients with
cystic fibrosis and they are usually found in lung tissues from such individuals.
Invasion
The ability of Pseudomonas aeruginosa to invade tissues depends upon production of
extracellular enzymes and toxins that break down physical barriers and damage host cells,
as well as resistance to phagocytosis and the host immune defenses. As mentioned above,
the bacterial capsule or slime layer effectively protects cells from opsonization by
antibodies, complement deposition, and phagocyte engulfment.
Two extracellular proteases have been associated with virulence that exert their activity at
the invasive stage: elastase and alkaline protease. Elastase has several activities that
relate to virulence. The enzyme cleaves collagen, IgG, IgA, and complement. It also lyses
fibronectin to expose receptors for bacterial attachment on the mucosa of the lung.
Elastase disrupts the respiratory epithelium and interferes with ciliary function. Alkaline
protease interferes with fibrin formation and will lyse fibrin. Together, elastase and alkaline
protease destroy the ground substance of the cornea and other supporting structures
composed of fibrin and elastin. Elastase and alkaline protease together are also reported to
cause the inactivation of gamma interferon (IFN) and tumor necrosis factor (TNF).
Pseudomonas aeruginosa produces three other soluble proteins involved in invasion: a
cytotoxin (mw 25 kDa) and two hemolysins. The cytotoxin is a pore-forming protein. It
was originally named leukocidin because of its effect on neutrophils, but it appears to be
cytotoxic for most eucaryotic cells. Of the two hemolysins, one is a phospholipase and the
other is a lecithinase. They appear to act synergistically to break down lipids and lecithin.
The cytotoxin and hemolysins contribute to invasion through their cytotoxic effects on
neutrophils, lymphocytes and other eucaryotic cells.
One Pseudomonas pigment is probably a determinant of virulence for the pathogen. The
blue pigment, pyocyanin, impairs the normal function of human nasal cilia, disrupts the
respiratory epithelium, and exerts a proinflammatory effect on phagocytes. A derivative of
pyocyanin, pyochelin, is a siderophore that is produced under low-iron conditions to
sequester iron from the environment for growth of the pathogen. It could play a role in
invasion if it extracts iron from the host to permit bacterial growth in a relatively ironlimited environment. No role in virulence is known for the fluorescent pigments.