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Case Discussion
57 yo M with history of EtOH is seen for Pneumonia. Labs is as follow over the treatment course.
Gm -ve infection causes one of the worst sepsis you can ever see. Clinical question why does sepsis occur?
Some of the most frequently
isolated bacteria in sepsis are Staphylococcus aureus (S. aureus),
Streptococcus pyogenes (S. pyogenes), Klebsiella spp., Escherichia coli
(E. coli), and Pseudomonas aeruginosa (P. aureginosa)
Bacterial Toxins
Bacterial toxins are mainly divided into three types based on their
mode of action.
- Type I toxins disrupt host cells without the need
to enter the cells. These include superantigens (SAgs) produced
by S. aureus and S. progenies.
- Type II toxins, such as hemolysins
and phospholipases destroy host cell membranes to invade and
interrupt host defense processes within the cell.
- Type III toxins,
also known as A/B toxins due to their binary structure; disrupt
host cell defenses to allow dissemination to remote organs. The B
component of these toxins binds to the host cell surface, while the
A component possess the enzymatic activity to damage the cell.
- Ref
- Gram-positive and gram-negative bacterial toxins in sepsis
Endotoxins in Sepsis
- LPS macromolecules that make
up about 75% of the outer membrane of gram-negative bacte-
ria that are capable of causing lethal shock
- The structure of
LPS generally consists of a hydrophobic lipid A domain, an oligo-
saccharide core, and the outermost O-antigen polysaccharide
- Lipid A is the single region of LPS that is recognized by the
innate immune system. Picomolar concentrations of lipid A are
sufficient to trigger a macrophage to produce proinflamma-
tory cytokines like TNF-α and IL1β
- To trigger an innate
immune response, the lipid A portion of LPS alone is sufficient,
yet the adaptive immune response during infection is usually
directed toward the O-antigen
- The key pattern recognition
receptor for LPS recognition is Toll-like receptor 4 (TLR4)
- LPS induces inflammatory cells to express a number of proin-
flammatory cytokines including IL-8, IL-6, IL-1β, IL-1, IL-12,
and IFNγ; however, TNFα seems to be of critical importance
during endotoxic shock and causes tissue damage
- Despite the compelling evidence that LPS is a major factor in
the pathophysiology of septic shock, recent trial targeting lipid-A
portion of LPS with a drug called eritoran was unable to improve
outcome in a large phase 3 clinical trial
- Ref
- Gram-positive and gram-negative bacterial toxins in sepsis
 Hospital-Acquired Infections Due to Gram-Negative Bacteria NEJM 2010
Superantigen
- Superantigens (SAg) are one of the most potent toxins pro-
duced by bacteria, namely, S. aureus and S. progenies
- Unlike conventional antigens
that are processed by antigen presenting cells and presented to
T cells through the MHC-II molecules, SAgs bind directly to
the outer leaflet of MHC-II molecules71-73 specific domains of
the variable portion of β-chain (Vβ) of the T-cell receptor.
- Unlike conventional antigens that normally activate
<0.01% of T cells, SAgs activate >20% of T cells by binding
to the MHC-II and T-cell receptor directly
- This leads to a
massive induction of proinflammatory T-helper 1 (Th1) cyto-
kines including tumor necrosis factor (TNF), interferon γ (IFN
γ), and interleukin-2 (IL-2)
- Ref
- Gram-positive and gram-negative bacterial toxins in sepsis
Pseudomonas and Exotoxin- On the basis of weight, exotoxin A of this organism is the
most toxic compound it produces.91 Exotoxin A is part of an
enzyme family called mono-ADP-ribosyltransferase. The toxin
affects the protein synthesis in host cells by catalyzing the ADP
ribosylation of eukaryotic elongation factor 2, much like the
mechanism of diphtheria toxin.
- Ref
- Gram-positive and gram-negative bacterial toxins in sepsis
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