Infectious Disease
Pharmacogenomics and infectious diseases:
Impact on drug response and applications
to disease management
MARY S. HAYNEY
T
he application of pharmacogenomics
to infectious diseases is
in its infancy. The mapping of
the human genome was completed in
June 2000.1-3 The complete genomes of
at least 88 microorganisms, most of
which are important human pathogens,
have also been sequenced.4
The
availability of this genomic information
is allowing researchers to identify
new drug targets.
One key aspect of the application of
the pharmacogenomics to infectious
diseases is the need to contend with—
and the opportunity to manipulate—
the genomes of both the host and the
pathogen. The genomes of both are
important in determining the outcomes
of treatment. This article discusses
the impact of pharmacogenomics
on the prevention, diagnosis,
and treatment of infectious diseases.
The genome of the pathogen
The complete genomic sequencing
of a number of pathogens has
presented scientists with a tremendous
opportunity and a challenge.
The information that can be obtained
from these sequences is phenomenal.
The availability of entire
genomic sequences will result in new
drug targets and antigenic determiMARY
S. HAYNEY, PHARM.D., BCPS, is Assistant Professor of Pharmacy,
School of Pharmacy, University of Wisconsin, 777 Highland Avenue,
Madison, WI 53705 (mshayney@pharmacy.wisc.edu).
Copyright © 2002, American Society of Health-System Pharmacists,
Inc. All rights reserved. 1079-2082/02/0901-1626$06.00.
Abstract: The impact of pharmacogenomics
on the prevention, diagnosis, and treatment
of infectious diseases is discussed.
The application of pharmacogenomics
to infectious diseases requires consideration
of the genomes of both the pathogen
and the host. The pathogen’s genome may
be used for antigen identification, to identify
infecting organisms, and to determine
antimicrobial resistance. Diagnostic tool
development and vaccine design can be
aided by knowing which portions of a
pathogen are important antigenic determinants.
The unique genetic makeup of a
pathogen can facilitate its identification as
an augmentation to the traditional culture.
Important genes conferring resistance to
antibiotics can be detected, and this information
can be used to choose appropriate
antibiotic therapy. The genome of the host
may reveal susceptibility genes and new
drug targets that may be used in the treatment
of infectious diseases.
Thus far, polymorphisms in genes of the
host immune system have been associated
with susceptibility to infections and response
to treatment.
Examples of these findings will be
described.
Pharmacogenomics has the potential to
revolutionize the prevention, diagnosis,
and treatment of infectious diseases.
Index terms: Disease management; Gene
therapy; Infections; Pharmacogenetics
Am J Health-Syst Pharm. 2002; 59:1626-31
nants for vaccine development, and
the identification of unique sequences
could improve diagnostics. However,
much must be learned before
this information can be translated
into prophylactic and therapeutic
interventions.
Use of the pathogen’s genome for
antigen identification. The recent
genomic sequencing of Neisseria
meningitidis serogroup B is a good
example of the use of a pathogen’s
genome to explore vaccine development.5
Although this serotype causes
approximately one third of all cases
of invasive N. meningitidis infections,
the meningococcal vaccine in clinical
use contains capsular polysaccharides
for serogroups A, C, Y, and
W135 only. The serogroup B
polysaccharide resembles the human
carbohydrate polysialic acid and is
therefore poorly immunogenic or
may even induce autoantibodies.6
To
overcome these obstacles, the entire
N. meningitidis serogroup B genome
was sequenced to identify vaccine
candidates. Three-hundred fifty po-
Am J Health-Syst Pharm—Vol 59 Sep 1, 2002 1627
CLINICAL FRONTIERS Pharmacogenomics and infectious diseases
tential antigens were expressed in Escherichia
coli and injected into mice.
Antigens that induced a bactericidal
antibody response were chosen for
further study with the goal of developing
a vaccine to protect against infection
by N. meningitidis serogroup
B, other serogroups, and possibly
other pathogenic strains of Neisseria
species.
Another strategy for translating
the pathogen’s genome into a therapeutic
intervention is to identify immunologically
important peptides
for cytotoxic T lymphocytes (CTLs)
known as CTL epitopes. The response
of CTLs is often critical to the
immune response to a viral pathogen.
The role of CTLs is to seek out virally
infected cells by recognizing the peptides
presented by human leukocyte
antigen (HLA) glycoproteins on the
cell surface and killing the infected
cells. The viral peptide presented by
the HLA complex that is recognized by
a CTL is the CTL epitope.
The identification of these peptides
has been greatly facilitated by
knowing the entire genome of a
pathogen. Since each of the potentially
antigenic peptides is about 10
amino acids long, simple translation
of the genome into protein sequences
yields little information. The amino
acid sequence is divided into peptides
10 amino acids in length, each
overlapping the previous peptide by
9 amino acids. All possible peptides
of 10 amino acids are represented in
Figure 1 for a hypothetical pathogen.
For example, the West Nile virus genome
translates into 3433 amino acids:
There are 3424 peptides that are
10 amino acids in length.
Many researchers have spent years
synthesizing peptides and measuring
CTL responses to them. Bioinformatics
is speeding up the selection of
CTL epitopes. A computer-based algorithm
that matches the viral peptide
with HLA glycoproteins on the
basis of the likelihood of binding is
being developed and tested.7
Recently,
20 peptides from the West Nile
virus were selected for such testing.
The algorithm eliminated more than
99% of the peptides that needed to be
screened because of their low probability
of binding to the HLA glycoprotein.
Indeed, the relatively few
peptides screened yielded peptides
that vigorously stimulated CTL responses
when tested in biological
systems. This approach dramatically
decreased the time needed for and
cost of identifying CTL epitopes.
CTL epitopes may lead to the development
of a subunit vaccine (hepatitis
B vaccine is an example) or diagnostic
tests for West Nile virus.
The CTL epitope can be used to find
virus-specific antibodies for an
enzyme-linked immunosorbent assay.
It may even be possible to use
CTL epitopes to test for the antigen
itself.
Use of the pathogen’s genome to
identify infecting organisms. An infection
can be diagnosed on the basis
of detection of microbial DNA in a
clinical specimen. Many pathogens
can be identified. Human immunodeficiency
virus (HIV), hepatitis viruses,
Borrelia burgdorferi (the agent
responsible for Lyme disease), and
mycobacteria are just a few of the
pathogens that can be identified
from their genomic sequences. The
results of these diagnostic tests are
used to initiate, evaluate, and alter
antiinfective therapy.
Although tuberculosis cases increased
dramatically a decade ago,
their frequency is now decreasing;
new cases occur primarily in defined
high-risk groups.8
However, infection
by antimicrobial-resistant Mycobacterium
tuberculosis is quite
common. DNA fingerprinting for
the detection and species identification
of mycobacteria is replacing the
traditional culture and sensitivity
testing of these organisms.9
Restriction
fragment length polymorphism
is the specific molecular technique
used for DNA fingerprinting. This
technique relies on certain bacterial
enzymes, called restriction enzymes,
Figure 1. Generation of cytotoxic T lymphocyte (CTL) epitopes from the genetic sequence of a hypothetical pathogen. This gene is
transcribed into messenger RNA (mRNA) (step not shown); the mRNA is then translated into a protein. The sequence of the protein made
depends on the sequence of the genomic DNA. CTL epitopes are generated from the translated protein. Each hypothetical peptide can be
tested individually or after selection by using computer modeling. With a sequence of only 20 amino acids, 11 peptides were generated in
the example shown.
Nucleic acid sequence of pathogen
TTT CAG GAG ATT CGA CCA GTG ACC CAG CGC AAC ATT GCG AAT AGT CAA TGT GGG CGG CCC
Phe Gln Glu Ile Arg Pro Val Thr Gln Arg Asn Ile Ala Asn Ser Gln Cys Gly Arg Pro
CLINICAL FRONTIERS Pharmacogenomics and infectious diseases
1628 Am J Health-Syst Pharm—Vol 59 Sep 1, 2002
that recognize and cut DNA with
specific nucleotide patterns. By relying
on previously identified differences
in the genomic DNA of the
pathogen, DNA fragments of various
lengths can be separated; the pattern
of fragments is characteristic of a
particular isolate. DNA fingerprinting
is significantly faster than culturing
mycobacteria, which can take
weeks. Drug-resistant isolates can be
identified on the basis of unique genomic
sequences found in these bacteria.
The epidemiology of an outbreak
can be monitored with this
technique, because the sensitivity of
the typing allows a particular strain
to be followed as it is passed from
person to person.
Yet another genetic tool that can
affect drug therapy is the measurement
of viral load. Antiviral therapy
for the treatment of HIV infection,
chronic hepatitis B, and chronic hepatitis
C often depends on the ability
to detect viral RNA or DNA in clinical
specimens. Most assays of viral
load depend on enzymatic amplification
of either the viral nucleic acids
or the signal for detection.10 For example,
labeled DNA probes for conserved
genomic regions of HIV are
hybridized with clinical specimens.
The labeled probes can be detected
by the signal they give off, either color
or chemiluminescence. The intensity
of the signal is proportional to
the number of copies of viral RNA in
the specimen. The various assays can
detect a minimum of 200–10,000
copies of HIV RNA per milliliter of
plasma. An assay for viral load that is
under development involves direct
detection of the viral genome. Again,
a labeled probe specific for a conserved
area of the viral genome is
used. However, capillary electrophoresis
is used to detect the hybridized
probe. Capillary electrophoresis
is exquisitely sensitive, allowing the
detection of as few as 2000 copies of
HIV RNA in 1 mL of plasma.11
Use of the pathogenic genome to
determine antimicrobial resistance.
The broad use of antimicrobials has
been accompanied by increasing bacterial
resistance. Mutations in the
bacterial genome allow certain isolates
to escape and flourish despite
the presence of antimicrobials. The
emerging resistance of several bacteria
is problematic—Staphylococcus
aureus, Streptococcus pneumoniae,
Pseudomonas aeruginosa, and E. coli
are a few.
One mechanism of resistance to
fluoroquinolones occurs as a result of
a mutation in the quinolone-binding
site of DNA gyrase or topoisomerase
IV. Both of these bacterial enzymes
are involved in bacterial DNA replication.
Fluoroquinolones bind to the
enzyme–DNA complex, preventing
DNA replication and causing bacterial
cell death. The identified mutations
result in a change in an amino
acid at the site where fluoroquinolones
bind to the enzymes. When a mutation
in either of these enzymes occurs,
fluoroquinolones are less effective in
treating the infection. High-level resistance
is conferred when both enzymes
are mutated.12
Genetic tests of antimicrobial resistance
would be extremely valuable for
determining the appropriateness of
antimicrobial use as soon as possible
after the start of therapy. Methicillinresistant
S. aureus is a good example
of a pathogen amenable to such testing.
The methicillin resistance phenotype
is expressed when S. aureus
continues to grow when cultured in
the presence of oxacillin, a process
that takes about 24 hours. Methicillin
resistance is mediated by alterations
of penicillin-binding protein
PBP2a. The mecA gene controls the
production of PBP2a. Therefore,
strains of S. aureus possessing a mecA
gene are methicillin resistant. The
standard for the detection of mecA is
the polymerase chain reaction
(PCR),13 but PCR-based assays are
generally performed only in reference
laboratories. However, a commercially
available kit (Velogene, ID
Biomedical) can detect this gene by
using a fluoroscein-labeled mecA
probe. Both PCR and DNA probe
technology can produce results in less
than three hours. The use of this
probe-based genetic test for resistance
can dramatically decrease the time
needed to document resistance, which
may lead to optimized antimicrobial
therapy and improved control of the
spread of resistant bacteria.13
Measuring the genomic effect of
drug administration
Amphotericin B is a very effective
but toxic antifungal agent. Recent investigations
of the effect of this agent
on gene expression help explain both
its efficacy and toxicity. Amphotericin
B has immunomodulatory properties,
including the production of
proinflammatory cytokines. Rogers
et al.14 measured mRNA expression
and cytokine production in human
cells exposed to amphotericin B in
culture. Both mRNA expression and
cytokine production were increased
by exposure to amphotericin B.
These results suggest a mechanism
for toxicity of amphotericin B, as well
as an additional mechanism of action.
The induction of proinflammatory
cytokine gene expression may be
related to some of the infusion-related
toxicities that are characteristic of a cytokine
release, including fever, nausea,
chills, and hypotension. Proinflammatory
cytokines also activate monocytes
and macrophages and promote
chemotaxis. These activities then enhance
the immune response of the individual
to the infection.
Genetic determinants of host
susceptibility to infection
Not all those exposed to a particular
pathogen become infected. The
processes involved in the development
of infection are likely the virulence
of the pathogen and the host’s
susceptibility.
The host response that prevents
an infection or leads to the elimination
of the pathogen and recovery
from infection is a therapeutic target
Am J Health-Syst Pharm—Vol 59 Sep 1, 2002 1629
CLINICAL FRONTIERS Pharmacogenomics and infectious diseases
that has yet to be tapped. Such targets
include the innate immune system
and the adaptive immune system.
These mechanisms are inordinately
complex. However, some techniques
and strategies may facilitate discovery
of the mechanisms of a protective
immune response.
Mouse models of infectious diseases
are very well developed tools
for investigators. Animal models are
useful because environment and exposure
can be highly controlled. Research
animals may be genetically
homogeneous, and their genetics can
be manipulated. For example, investigators
can attempt to delete a specific
gene during the embryonic
stage. If the gene deletion is successful
and the mice survive to breed, the
gene deletion can be passed on to
future generations. The necessary assumption
with these models is that
the disease-susceptibility gene is the
same for the animal species and humans.
Limited experience suggests
that this assumption sometimes holds
up. However, the identification of genetic
and biochemical mechanisms is
what makes murine models of disease
susceptibility most valuable.15 Once
these pathways are identified, similar
mechanisms in humans—and the genetic
control of these mechanisms—
can be sought.
A second strategy for identifying
genetic disease susceptibility is the
identification of candidate genes.
Polymorphisms in candidate genes are
studied for possible biological relevance
in the disease. Family studies
looking at disease susceptibility and
genetic polymorphism are one method
of identifying such candidate
genes. Case–control studies can also
be done. Given the large number of
human genes—many with unknown
function—this method of identifying
susceptibility genes is limited at
present. For example, a gene with a
major effect may not be detected because
its function is not known.
To overcome our lack of knowledge
of the function of all genes,
total-genome scanning has been developed
to identify susceptibility
genes. Multiple affected and unaffected
family members are needed
for this analysis. Genetic markers
called microsatellites are spaced
throughout the genome. The cosegregation
of microsatellites and disease
assists investigators in narrowing
the search for the gene of interest.
Complex calculations are made of
the probability of linkage of the microsatellite
with the gene. Although
very time- and labor-intensive, totalgenome
scanning has the advantage
of identifying susceptibility genes
that previously were of unknown
function. A region on a chromosome
may be identified as having a high
probability of being associated with
the disease. Further experiments
must be performed to identify a specific
gene that may confer susceptibility
to infection. Genome scanning
is in progress for identifying susceptibility
genes; no results from human
studies are yet available.
An animal model and a candidate
gene strategy have been used to identify
a susceptibility gene for tuberculosis
and leprosy. Tuberculosis and
leprosy seem to have genetic determinants,
since a higher concordance
of infection was found in monozygotic
twins than in dizygotic twins
and siblings.16,17 The gene encoding
natural-resistance-associated macrophage
protein 1 (Nramp1) is associated
with natural resistance of mice
to Mycobacterium, Leishmania, and
Salmonella species infection.17
Nramp1 is a protein in the membrane
of the phagosome that probably
has an important role in limiting the
replication of these intracellularly
dwelling organisms in macrophages.18
A sequence comparison between
mouse and human genes found a
similar gene in humans. The expression
of this gene was similar to that
in mice. These findings suggest that
there may be a susceptibility gene in
humans as well. Indeed, several studies
found polymorphisms in the gene
for Nramp1 to be associated with leprosy
and tuberculosis.19,20 In one
study, individuals who were heterozygous
for an Nramp1 variant
were four times more likely to have
tuberculosis than those carrying the
more common variants of Nramp1.
20
The importance of a vigorous
cell-mediated immune response to
tuberculosis has long been appreciated.21
Not surprisingly, then, an association
has been made between
polymorphisms in the genes coding
for the T-helper-cell type 1 cytokines
interferon-γ and interleukin-12 and
susceptibility to tuberculosis. Isolated
patients and families lacking functional
copies of either of these genes have
been found to be exquisitely susceptible
to infection by M. tuberculosis.
22-25
The highly polymorphic HLA glycoproteins
are another example of
frequently studied candidate genes.
HLA class I glycoproteins are expressed
on the surface of every nucleated
human cell. They present endogenous
peptides derived from the
cell itself to cytotoxic T cells. HLA
class I glycoproteins play an important
role in viral infection. Since viruses
use their hosts’ cellular machinery
for replication, these cells present
viral proteins on their surfaces by using
HLA class I glycoproteins. The
presentation of viral peptides elicits a
cell-mediated immune response that
destroys the virally infected cell.
Conversely, HLA class II glycoproteins
expressed on an antigen-presenting
cell display antigenic peptides derived
from the pathogen. A T cell recognizes
the antigenic peptide as
foreign and initiates an immune response
to the antigen (Figure 2). The
antigenic peptide must fit into the
peptide-binding cleft. Both size and
the composition of the peptide determine
the fit. The peptide is typically
9–14 amino acids long. The sequence
of the peptide is determined by the
pathogen. However, the bulk and
charge of the constituent amino acids
determine if the peptide will fit into
the peptide-binding cleft. The poly-
CLINICAL FRONTIERS Pharmacogenomics and infectious diseases
1630 Am J Health-Syst Pharm—Vol 59 Sep 1, 2002
morphisms within both HLA class I
and class II glycoproteins occur almost
exclusively in the part of the
glycoprotein that makes up the
peptide-binding cleft. Depending on
the particular surface of the peptidebinding
cleft, some antigenic peptides
may be preferentially presented,
while others may not be presented at
all. The resulting diversity of the HLA
peptide-binding clefts is advantageous
for the survival of the species. The
diversity of the clefts across the population
translates into the ability to
recognize and generate an immune
response to virtually any pathogen.
The type of antigenic peptide that is
displayed in the peptide-binding
cleft is an important factor in the immune
response that is generated.
Numerous studies have been conducted
to identify susceptibility genes
for tuberculosis. HLA class II types
have been associated with susceptibility
in various populations. Marquet
and Schurr15 reviewed associations between
HLA class II and pulmonary tuberculosis
that have been found in
several populations.
Figure 2. Human leukocyte antigen (HLA) polymorphism as a significant target of genetic
determinants of the host response to infectious diseases.
T-cell receptor
Antigen-presenting cell
Bacteria undergoing digestion
in phagosome. Antigenic peptides
generated for presentation on HLA
glycoprotein
Polymorphic regions
in peptide-binding cleft
HLA class II glycoprotein
displaying antigenic
peptide
T lymphocyte
The identification of diseasesusceptibility
genes improves diagnostics,
should aid in understanding
the pathogenesis of infectious
diseases, and may lead to new therapeutic
strategies. Public health initiatives
to prevent disease may be targeted
at individuals and populations
most susceptible to infection.
Genetic predictors of the
response to therapy and vaccines
Pharmacogenomics distinguishes
itself by focusing on genetic influences
on drug responses. In addition to
the genome of the pathogen, which
may encode resistance factors, the host
genome must be considered. The variability
of drug effects is high; some of
the variability may be explained
through single-gene effects.
Several polymorphic cytokine
genes exist, including the gene encoding
interleukin-10 (IL-10), a Th2
cytokine. Th2 responses are associated
with the production of large
amounts of antibodies. In general,
the cytokines that stimulate a Th1 response
inhibit a Th2 response and
vice versa. Interferon alfa is used to
treat chronic hepatitis C by stimulating
cell-mediated immune responses
and antiviral activity. Although interferon
alfa is the primary treatment
for chronic hepatitis C, response
rates are only about 50%, even when
it is used in combination with other
antiviral agents.26 A vigorous cellmediated
immune response may be
predicted from the cytokine milieu of
an infected individual. Patients with
chronic hepatitis C were five times
more likely to have a favorable response
to interferon alfa if they carried
the IL-10 genetic polymorphism
that results in low expression of IL-
10 than if they did not.27 Conversely,
individuals whose genotype was associated
with high IL-10 production
were much less likely to respond to
interferon alfa treatment (odds ratio,
0.22). The IL-10 genotype may predict
the response to interferon alfa.
Alternative therapies must be developed
for individuals with chronic
hepatitis C who carry the IL-10 polymorphism
associated with high cytokine
production.
Vaccination relies on immunologic
memory to induce a response
that protects against disease upon
subsequent exposures. Ideally, the
immune response to the vaccine
should resemble that induced by the
natural infection to produce protective
immunity.28-32 Some apparently
healthy individuals do not mount an
immune response to a particular vaccine.
The response to measles vaccine
provides an example.
A study of the antibody response
to measles vaccine was conducted
among healthy schoolchildren.33 Ten
percent of the population was seronegative,
and seronegative individuals
were clustered in families. This
observation is certainly suggestive of
a genetic effect. The investigator pursued
identification of a genetic effect
with HLA genes as the candidate
genes. Both HLA class I and class II
alleles were associated with measles
vaccine responses. HLA-B7, HLA-
Am J Health-Syst Pharm—Vol 59 Sep 1, 2002 1631
CLINICAL FRONTIERS Pharmacogenomics and infectious diseases
B51, HLA-DRB1*13, and HLADQA1*01
were associated with a
measles vaccine response.33-36 Homozygosity
at HLA-B, HLA-DR, and
HLA-DQA1 was associated with a
measles vaccine nonresponse.33,35 It
could be hypothesized that lack of
diversity in antigen presentation may
explain decreased vaccine response.
Using vaccines as probes of the
immune system is a novel means of
identifying disease susceptibility
genes. Vaccines are administered to
large populations. Generally, a protective
immune response has been
identified. People who do not mount
the protective immune response can
be compared with those who do by
using the strategies described.
Conclusion
Pharmacogenomics has the potential
to revolutionalize the prevention,
diagnosis, and treatment of infectious
diseases. The genome of the
pathogen and the human genome
will probably yield multiple targets
for drug development. Nevertheless,
the interplay between the host and
the pathogen adds a daunting layer
of complexity.
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