BBS3024 Infection and immunity
BC 1: Commensal microbes
In the twenty-first century, scientists proposed that the human microbiome—a vast
collection of microorganisms living in and on our bodies—could be considered a newly
discovered organ. Traditionally, an organ is defined as a group of tissues serving a
specific function. Here, by viewing genes (rather than tissues) as defining features, the
microbiome meets the criteria, given its essential role in human health and
function. Human life depends on microbial partners, and the body contains roughly
as many microbial cells as human cells, with microbial genes vastly outnumbering
human genes and fulfilling vital functions our own genome cannot.
The microbiome and microbiota are closely related but distinct concepts.
The microbiota refers specifically to the community of microorganisms (such as
bacteria, fungi, and viruses) that live in or on the human body. This microbial community
is found in various niches across the body, including the gut, skin, and mouth, with its
composition influenced by factors like diet, body location, age, sex, and environment.
In contrast, the microbiome refers to the collection of genes from all the
microorganisms in the microbiota. These genes encode a vast array of functions
that complement human physiology. With a microbial gene count far surpassing our
own human genes, the microbiome provides metabolic and immune
functions essential to our health. This genetic distinction makes the microbiome
significant because these genes interact with human biology in ways that shape
health, development, and disease resistance. Our genome consists of approximately
22.000 human genes and 80.000 archaea genes, 500.000 fungal genes and 5 to 10
million bacterial genes of which 99% of bacterial genes are beneficial and 1 %
pathogenic). About 99% of human genome is similar across individuals but
individuals are only 10-20% similar in bacterial genome.
Bacterial classification and characteristics
Bacteria can be classified based on a few characteristics:
- Cell Wall Composition (Gram Stain): A key distinction in bacterial
classification is between Gram-positive and Gram-negative bacteria,
which is determined by the structure of their cell walls. Gram-positive
bacteria have a thick peptidoglycan layer that retains the crystal violet
stain used in Gram staining, whereas Gram-negative bacteria have a
thinner peptidoglycan layer and an outer membrane. The outer
membrane of Gram-negative bacteria contains lipopolysaccharides
(LPS, composed of lipid A, oligosaccharides and O antigen), which are
crucial for stabilizing the membrane and creating a protective barrier.
However, LPS can release toxins, contributing to the pathogenicity of
Gram-negative bacteria. When LPS is released, it can also increase the
permeability of the outer membrane, triggering an immune response and
inflammation in the host.
- Shape and Morphology: Cocci, spherical bacteria, e.g., Streptococcus. Bacilli,
rod-shaped bacteria, e.g., Escherichia coli. Spirilla/Spirochetes, Spiral-shaped
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, bacteria, e.g., Helicobacter pylori. Vibrio, comma-shaped bacteria, e.g., Vibrio
cholerae.
- Oxygen Requirement: Aerobes require oxygen to grow (e.g., Mycobacterium
tuberculosis). Anaerobes grow without oxygen, and some are killed by its
presence (e.g., Clostridium difficile). Facultative anaerobes can grow with or
without oxygen (e.g., Escherichia coli). Microaerophiles require a low
concentration of oxygen (e.g., Helicobacter pylori).
- Ability to form endospores
- Functional characteristics: like containing a structural component.
Structure
Bacteria are single-celled organisms with a relatively simple
structure that includes several distinct components. The cell wall
provides structural support and protection, with differences
between Gram-positive bacteria, which have a thick peptidoglycan
layer, and Gram-negative bacteria, which have a thinner
peptidoglycan layer along with an outer membrane. Beneath the cell
wall, the cell membrane functions as a phospholipid bilayer that
controls the movement of substances into and out of the cell. Inside
the bacterial cell, the cytoplasm serves as a gel-like substance
containing water, enzymes, nutrients, and other cell components
necessary for survival. The nucleoid is the region where the bacterial chromosome, or
DNA, is located; this DNA is not enclosed by a membrane, distinguishing it from the
eukaryotic nucleus. Ribosomes in bacteria are critical for protein synthesis. They are
composed of two subunits: a large 50S subunit and a small 30S subunit, together
forming a 70S ribosome. The 16S rRNA (gene), found in the 30S subunit, is a key
component used for identifying and classifying bacteria due to its highly conserved
sequences across different species. Some bacteria possess flagella, which are tail-like
structures used for movement, while others may have pili or fimbriae, which are hair-
like structures on the surface that aid in attachment to surfaces or, in some cases, in
transferring DNA between cells. Plasmids are small, circular DNA molecules separate
from the main chromosomal DNA and often carry genes that offer additional
advantages, such as antibiotic resistance. The sex pilus is a specialized structure that
plays a vital role in genetic exchange. It facilitates the transfer of plasmids between
bacterial cells during a process called conjugation. Some bacteria have an additional
capsule (contains polysaccharides), a sticky, protective outer layer that assists in
evading the host immune system and aids in adherence to surfaces. These structures
collectively enable bacteria to survive in diverse environments and effectively interact
with their surroundings. An additional feature is the slime layer, which is similar to a
capsule but more diffuse and loosely associated with the bacterial cell surface. While a
capsule offers protection against phagocytosis, the slime layer facilitates bacterial
motility, helping bacteria glide along surfaces. Notably, some bacteria can possess both
a capsule and a slime layer simultaneously. Lastly, Bacteria can also form endospores,
a highly resistant, dormant structure produced in response to nutrient depletion or
harsh conditions. Endospores are extraordinarily resilient, withstanding extreme heat,
desiccation, and exposure to chemicals. This protective mechanism allows bacteria to
survive unfavorable conditions and reemerge when the environment becomes suitable.
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, Difference between commensal, opportunistic and strict pathogens
Bacteria can be classified based on their relationships with hosts, particularly in terms
of pathogenicity. Commensal pathogens are those that live on or in the host without
causing harm; they are often part of the normal flora and typically benefit from the
relationship by gaining nutrients. In some cases, they can provide advantages to the
host, such as aiding digestion or protecting against harmful microbes. Examples include
Lactobacillus species in the gut and Staphylococcus epidermidis on the skin. In
contrast, opportunistic pathogens usually do not cause disease in healthy individuals
but can become pathogenic under certain conditions (they become opportunistic
whenever the commensal bacteria are extinct). Opportunistic pathogens can cause
disease in certain circumstances, either members of the commensal microbiota are
overgrown such as Clostridioides difficile (1), or when they enter normally sterile places,
sterile meaning places that are normally not inhibited by that specific bacterium (2), or
bacteria that only cause harm in people that are immunocompromised (3).
These bacteria exploit weaknesses in the immune system, breaks in the skin, or changes
in the host environment. They are particularly common in individuals with compromised
immunity, such as the elderly, those with HIV, or patients undergoing chemotherapy.
Examples include Candida albicans, which can cause infections in
immunocompromised individuals, and Pseudomonas aeruginosa. Strict, or true
pathogens, on the other hand, are capable of causing disease in healthy individuals and
are typically associated with specific infections. They possess virulence factors that
enable them to bypass host defenses and cause disease, and they are generally not part
of the normal flora. Notable examples include Streptococcus pneumoniae, which
causes pneumonia, and Mycobacterium tuberculosis, responsible for tuberculosis.
Bacterium infection Opportunistic or Related to
true pathogen? dysbiosis?
Clostridioides difficile Antibiotic-induced colitis Opportunistic Yes
Salmonella enterica serotype foodborne salmonellosis True No
Typhimurium
E.coli urinary tract infection Opportunistic No
Streptococcus pneumoniae Secondary bacterial Opportunistic No
pneumonia following
respiratory viral infection
Bifidobacterium (formerly Bacterial vaginoses Opportunistic Yes
Gardnerella) vaginalis
Overgrowth of commensal bacteria is a key factor in certain infections and
imbalances. For example, Clostridioides difficile can thrive when the natural
microbiome is disrupted, often due to antibiotic use. The ability of C. difficile to form
spores makes it particularly difficult to eliminate, as these spores are highly resistant to
environmental stress. Similarly, in conditions like bacterial vaginosis, the overgrowth
of Bifidobacterium vaginalis can inhibit Lactobacillus, a beneficial bacterium essential
for maintaining vaginal health and preventing infections. Escherichia coli is notorious
for its role in urinary tract infections. One of its main mechanisms of infection is
the adhesion to epithelial cells of the bladder (Mutations in the FimH gene of E.
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, coli enhance the binding of type 1 fimbriae to mannose residues on bladder epithelial
cells), which allows E. coli to anchor itself and colonize, leading to inflammation and
infection. In Streptococcus pneumoniae, the capsule serves as the primary virulence
factor, protecting the bacteria from the immune system. However, it also produces other
virulence factors like pneumolysin, a toxin that can damage host tissues and impair
immune responses. Moreover, Streptococcus species play a crucial role in the
formation of dental biofilms within the mouth, where they are the main bacteria
responsible for the development of plaque, contributing to tooth decay and gum
disease.
How is the microbiome established in neonates
The development of the human microbiome begins at
birth and stabilizes by age three, influenced by factors
such as birth method, diet, and environment. Infants
acquire their first microbes from their surroundings—
vaginally delivered babies receive bacteria from the
mother’s birth canal (bacteroid ad lactobacillus),
while cesarean-delivered babies acquire microbes
from the skin of caregivers (epidermis staphylococcus). Breast milk, especially
through complex sugars called oligosaccharides, selectively promotes the growth of
beneficial bacteria like bifidobacteria in the infant gut, which in turn aids in digestion,
pathogen resistance, and potentially even vaccine response. As infants transition to
solid food, gut microbial diversity increases, and different bacterial groups such as
proteobacteria and bacteroidetes become more prevalent. Throughout life, an
individual’s microbiome is shaped by genetics, diet, lifestyle, and significant events, like
puberty or infection. While the adult microbiota remains relatively stable, it can
experience temporary shifts due to factors like short-term infections or antibiotic use.
However, long-term changes may occur with chronic conditions or prolonged antibiotic
use. The adult microbiome is highly variable between individuals, with each person’s
microbiota adapting uniquely to their body and lifestyle. Despite variations, common
microbial phyla like Actinobacteriota, Bacteroidota, Firmicutes, and Proteobacteria
exist across individuals. This diversity supports bodily homeostasis, emphasizing the
importance of a stable, diverse microbiome in maintaining health. The "window of
opportunity" refers to a critical period between birth and three years of age when the
microbiota is especially malleable and can be shaped significantly. During this time, the
establishment and development of the gut microbiome are heavily influenced by
environmental factors such as mode of delivery (vaginal birth or C-section), diet
(breastfeeding or formula feeding), antibiotic exposure, and other early life experiences.
Microbiota Vary by Body Site
In healthy humans, internal organs and tissues (such as
the brain, blood, cerebrospinal fluid, and muscles) are
typically sterile, meaning they are free of
microorganisms. However, surface tissues like the skin
and mucous membranes are consistently exposed to
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