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Lyme disease: a complex interaction between reservoirs en
route to human infection.
Lyme disease is currently one of the Center for
Disease Control’s Top 10 emerging infectious diseases
worldwide. It can be caused by at least 3 different
Borrelia bacteria, which are Gram-negative spirochetes
(spirilla). In the US Borrelia burgdorferi sensu lato is
chiefly responsible. Lyme disease is named after the
village of Lyme, Connecticut, where a cluster of cases
was diagnosed in 1975. Intensive investigation into the
cause began immediately. It was soon established that
Lyme disease is carried by ticks; in fact it is the most
common tick-borne disease in the Northern Hemisphere.
Figure 1: Borrelia burgdorferi the
major cause of Lyme disease in the
Lyme disease is causing focal epidemics as it spreads in
US1.
the northeastern and upper midwestern US. These epidemics
are thought to be a result of the
large increase in deer in areas where humans are living. The deer tick needs the white-tailed
deer to reproduce successfully. Reducing the numbers of primary hosts may help break the
deer tick reproductive cycles and their ability to flourish in suburban and rural areas. In the US it
has been suggested that reducing the deer population in areas with the highest Lyme disease
rates from current levels of 60 or more deer per square mile to 8 to 10 per square mile could
reduce tick numbers down to levels too low to spread Lyme and other tick-borne diseases.
Lyme disease is a zoonosis, that is, B. burgdorferi is transmitted to humans and deer from a
natural reservoir among rodents by the hard-bodied deer ticks that feed on both sets of hosts.
Deer are the most common hosts for adult stage ticks; humans are “accidental” hosts because
the bacteria from infected people are not
transmitted to other hosts. B. burgdorferi
bacteria are transmitted from nymph ticks
to rodents like the white-footed mouse,
and then back to larval ticks. The
transmission is essential to maintain a
reservoir of B. burgdorferi because there is
no direct transmission of bacteria from
female tick to her offspring. Rodents
therefore form an essential bridge that
allows bacteria to be transmitted from one
generation of deer tick to the next. It works
like this: The nymph tick typically feeds on
the rodent for several days, so that it
becomes chronically infected with B.
burgdorferi, particularly in the skin. Figure 2: Black legged deer ticks maintain the
Then the rodent efficiently passes the reservoir of B. burgdorferi in nature. The Nymph form
bacteria back to the next generation of
is most responsible for human infection because it is
uninfected ticks when they are fed
so small it often goes unnoticed.
upon again months later.
1
The vector
The nymph tick (as shown in figure 2) is also the major vector that transmits the bacteria to
humans. When the tick bites a human two important events occur: First, the B. burgdorferi , still
in the tick is exposed to warm mammalian blood. This causes it to change the surface protein it
produces to a form that helps it transmit to humans. If the feeding ticks are removed before this
activation within the tick is complete, i.e. within 24-36 hours, the bacteria will not transmit
successfully to humans. In fact, human infection is quite rare, with only about 1% of recognized
tick bites resulting in Lyme disease. The second event is that B. burgdorferi is injected into the
human along with tick saliva. The saliva contains substances that disrupt the immune response
at the site of the bite preventing the host feeling an itch or pain from the bite, and providing a
protective environment that allows the bacteria to survive.
Figure Error! No text of specified style in document.: The Life-cycle of Lyme Disease. The
2-year cycle of deer ticks has four stages: eggs, larvae, nymphs, and adults (as shown in
figure 2). Larvae hatch in the summer. They are uninfected, but soon acquire B.
burgdorferi by feeding on infected rodents. The infected larvae molt into nymphs in the
fall and are dormant through the winter. Infected nymphs feed on rodents in the late
spring and early summer. This sets up a natural reservoir of B. burgdorferi. The
chronically infected rodents then transmit B. burgdorferi to the next generation of
The
natural larval-stage
cycle of B. ticks.
burgdorferi
is ticks
important
in how
disease inoccurs.
First,
Lyme
uninfected
Nymph
can also
feedLyme
on humans
the late
spring
disease
is
endemic
only
in
regions
were
all
the
essential
elements
of
the
natural
cycle
exist,
and summer causing a peak of human Lyme disease. The nymph ticks molt into adultsi.e.
in the fall - their preferred host is deer.
2
the northeast and mid-Atlantic coastal states, and the Great Lakes regions in the US. Second,
most human infections occur in the spring and summer months, when outdoor activities bring
people into contact with feeding nymph ticks. These ticks are extremely small (approximately 1
mm in length) and are often not discovered for several days, allowing the B. burgdorferi to be
activated and transmitted.
Lyme Disease Signs and Symptoms
Like syphilis, which is also caused by B. burgdorferi bacteria, Lyme disease progresses through
several stages and affects many organs. The incubation period from infection to the onset of
symptoms is usually one to two weeks, but can be much shorter (days), or much longer (months
to years). The classic sign of Stage 1 infection is a circular ‘bull’s eye’ rash at the site of the bite
caused by an inflammatory response to the bacteria. The ‘bull’s eye’ rash is seen in about 80%
of patients. During Stage 2 the bacteria enter the bloodstream and spread to the joints, heart,
nervous system, and distant skin sites where they cause a variety of symptoms such as fever,
headache, muscle soreness and fatigue. Some patients also suffer from neurological problems
like facial paralysis (Bell’s palsy) and encephalitis leading to memory loss. Left untreated, Stage
2 symptoms may progress to Stage 3 that involves chronic inflammation of the joints, the heart,
the central nervous system and the skin. (this process if summarized in Figure 4).
Figure 4: Stages of Lyme disease:
Lyme can persist for many years
and infects a large number of
organs. It can be extremely difficult
to eradicate once the bacteria have
entered the brain, joints and heart.
Diagnosing Lyme Disease
Lyme disease is usually first
diagnosed by the ‘bulls eye’ rash,
facial paralysis or arthritis together
with a history of possible exposure to
infected ticks. Most but not all
patients with Lyme disease will
develop the bulls-eye rash, but many
may not recall a tick bite.
Since Borrelia bacteria are very hard to grow in the laboratory, serological tests measuring
antibody levels are used to confirm infection. Clinical samples are taken from blood or from
cerebrospinal fluid (CSF) via lumbar puncture. Unfortunately, the blood screens only detect 64%
of all infections at early stages of the disease. This rises to 100% in people with advanced
symptoms, such as arthritis. For this reason more sensitive and accurate methods of
identification are needed.
3
Preventing Lyme Disease Infection
Personal Removing ticks within 36 hours can
reduce transmission rates to close to zero. Protective
clothing should include a hat and long-sleeved shirts
and long trousers that are tucked into socks or boots.
Outdoor pets can bring ticks into the house.
Treatment Antibiotics are the primary treatment for
Lyme disease, but not always very effective. Up to
one third of Lyme disease patients who have
completed a course of antibiotic treatment continue to
have symptoms. A few doctors attribute these
symptoms to persistent infection with Borrelia, or
coinfection with other tick-borne infections. Other
doctors believe that the initial infection may cause an
autoimmune reaction that continues to cause serious
symptoms even after the bacteria have been
eliminated.
Lyme Disease vocabulary
Figure 5: Adult ticks overwinter
on white-tailed deer, which are
pests in areas were Lyme
disease is endemic
Gram-negative
Spirochete
Zoonosis,
Borella burgdorferi
Endemic
Inflammatory response
Neurological problems
Encephalitis
Serological tests
Cerebrospinal fluid (CSF)
Lumbar puncture
Autoimmune reaction
4
Malaria: The most important of all the parasitic diseases
Malaria, the most important of all parasitic diseases, occurs in many tropical and semitropical
regions. There are approximately 200 million to 300 million new cases annually, and an
estimated 2 million to 3 million people die of malaria each year. About 89% of these deaths
occur in Africa, and mostly to children under the age of 5. Of all infectious diseases malaria is
considered to have caused the greatest harm to the greatest number of people.
Malaria was endemic in some areas of the US in the 1800s but has since been eradicated with
DDT (as discussed later). Currently, the 1000 or so cases that are diagnosed in the US arise
from travelers who have been in an endemic area, or, rarely from infected mosquitoes that have
arrived in planes. But this may not necessarily continue. If climate change continues along its
current trajectory mosquitoes are expected to regain a foothold in many areas (in red on the
map) currently considered too temperate to support them.
Figure 1: Climate
Change and Malaria
The Malaria parasite and its vector
Malaria in humans is caused by 4 species of
parasites: Plasmodium protozoa ( P. falciparum, P.
vivax, P. ovale, and P. malariae). The four species
vary in their ability to cause disease because they
prefer red blood cells of different ages.
Plasmodium falciparum is the most deadly
because it invades red blood cells of all ages.
Figure 2: Plasmodium falciparum, one of
the 4 plasmodium protozoa that causes
malaria seen in a blood culture with red
blood cells
5
Transmission of the parasite to humans occurs through the
bite of infected female anopheles mosquitoes (as shown in
Figure 3). The parasite is injected from the mosquito
salivary gland into humans when it takes a blood meal. The
parasite then travels rapidly to the liver, where it takes up
residence in order to mature. Mature plasmodium leaves
the liver and enters red blood cells, where it divides so
much that the red blood cells become full of parasite, and
burst (Figure 4).
Figure 3: The female anopheles mosquito that acts as a
vector for transmission of the malaria protozoa. Her
abdomen is distended with blood. If the blood contains
plasmodium she can reinfect another human when she
feeds again.
Figure 4: Plasmodium merozoites
bursting out of red blood cells.
The Anopheles mosquito acts as a vector, transmitting the malaria parasite to humans. Infected
humans act as the only actual reservoir.
The Natural Cycle of Malaria
The life cycle of the malaria parasite is rich in fascinating detail. Let’s start at the beginning of
the cycle with the infected female Anopheles mosquito, which has the parasite in her salivary
glands. When she feeds on a human the parasite is injected into the bloodstream and
immediately travels to the liver. It can enter liver cells within 30 minutes. Over the next week or
two the parasite in the form of plasmodium sporozites multiply in liver cells to generate large
numbers.
At the same time they also
mature to a form that is
capable of infecting red
blood
cells
the
merozoite. The mature
merozoite is then released
into
the
bloodstream,
where it invades red blood
cells. Again the parasite
divides and matures. After
another 2-3 days the
infected red blood cells
burst, releasing yet more
parasite into the blood
stream to infect more red
blood cells (Figure 5).
6
Figure 5: Life cycle of the Plasmodium parasite.
While this is happening a small number of the merozoites develop further into male and female
forms. If a mosquito feeds again from the human reservoir it can take in the male and female
forms. They then develop in the mosquito into the sporozites and the cycle repeats itself.
Malaria Signs and Symptoms
The symptoms of malaria are intense and generally show up within a month of infection as a
very high fever, chills and, later on, anemia (low numbers of red blood cells). The symptoms
coincide with the release of large numbers of merozoites from the red blood cells, and occur
because the immune system has recognized the presence of a foreign invader and has put its
defense mechanisms on high alert. After the first parasites replicate in the red blood cells, the
infection becomes synchronized so that all infected red blood cells lyse at the same time. Other
symptoms of malaria are also caused by the immune system response and resemble influenza
(fever, muscle aches and generally feeling ill). Stomach pain can also occur because of liver
damage. Patients with symptoms of malaria are often misdiagnosed, especially if they don’t live
where malaria is endemic and if the physician does not ask about travel.
Diagnosing Malaria
Malaria is diagnosed in the laboratory by taking a thick smear of blood (8-12 cells deep) onto a
microscope slide and then using a Giemsa stain, which dyes the plasmodium merozoites blue
(As shown in Figure 6). Different types of plasmodia give different patterns of staining. PCR
analysis is more accurate than blood tests but is expensive and requires expertise. It isn’t useful
in developing countries. Unlike Lyme disease serological testing for malaria antibodies is of little
use for someone with acute infection because antibodies to the parasite do not develop for 3 – 5
weeks, but treatment must begin within 1 – 2 days to stop the infection from spreading to the
liver.
Figure 6: Giesma stain of thin blood film
showing P.falciparum merozoites infecting
red blood cells
Treatments and Prevention
Natural immunity to malaria is imperfect. The malaria
parasite has evolved several strategies to evade the
immune system. As a result, people who have lived
where malaria is endemic all their lives and show evidence of immune response will
nonetheless still get infected on a regular basis. However their infections are usually less
severe, suggesting that the immune system can control the infection somewhat.
Antimalarial drugs are based on quinine (a molecule isolated from tree bark), which stops the
parasite from degrading the hemoglobin in red blood cells, thereby blocking a major source of
nutrition. The major antimalarial drug used to be chloroquine, a quinine derivative, which
accounts for the popularity of gin and tonic in the tropics - tonic contains quinine (Figure 7).
Unfortunately, the parasite can develop resistance to the drug. Chloroquine-resistant malaria is
7
now widespread in most of Southeast Asia, South America and
Africa, and a cocktail of other anti-malarials a must be used.
Figure 7: Gin and tonic was a
popular cocktail in the tropics
because tonic contains quinine –
at the time an effective
antimalarial
Malaria Control - DDT - For and Against
Malaria remains a major public health challenge in many parts of the world. The World Health
Organization (WHO) estimates that in 2008 there were 243 million cases, resulting in 863,000
deaths. One way to eliminate infection is to eradicate the mosquito vector. Spraying with
pesticide, especially DDT has been effective but controversial: Its use in this context has been
called everything from a "miracle weapon [that is] like Kryptonite to the mosquitoes," to "toxic
colonialism”.
DDT (dichlorodiphenyltrichloroethane) was
first used with great success to control malaria
among civilians and troops in the second half
of World War II. In response the WHO started
an anti-malaria campaign in the 1950s and
1960s that relied heavily on DDT. Initially the
results were promising. For example, in Sri
Lanka, the program reduced cases from about
3 million per year before spraying to just 29 in
1964. Then the program was halted to save
money, and malaria rebounded to 600,000
cases in 1968 - 1969. About the same time
public awareness that DTT can persist in both
humans and the environment led many
governments to restrict or curtail its use. Once
the mainstay of anti-malaria campaigns, as of
2008 only 12 countries still use DDT, including
India and some southern African states.
Figure 8: After DDT was a success against
malaria and typhoid in WW2 the WHO
instigated malaria eradication programs to
spray mosquitoes.
There is no doubt that when used properly DTT can significantly curb malaria, however DDT
resistance in mosquitoes, which is largely due to its overuse in agriculture, has greatly reduced
its effectiveness in many parts of the world. Current WHO guidelines require that before DTT is
used in any area it must first be confirmed that local mosquitoes are susceptible to it. Some
countries that still use DDT have shown that alternative insecticides are less effective – in South
Africa malaria incidence increased dramatically when the insecticide was switched, but returning
to DDT and introducing new drugs brought malaria back under control. Similarly malaria cases
increased in South America after DDT use was stopped. Between 1993 and 1995 Ecuador
increased its use of DDT and saw a 61% reduction in malaria rates, while other countries that
gradually decreased DDT use at the same time saw large increases in malaria.
8
For spraying to be effective, at least 80% of
homes and barns in an area must be sprayed, so
if enough residents refuse spraying, the
effectiveness of the whole program can be
jeopardized. Resistance to DDT spraying comes
from the realization that people living in spraying
areas have levels of DTT and its breakdown
products in their bodies that are several orders of
magnitude higher than people who live elsewhere.
In addition, animal studies have shown that DTT
is a carcinogen. And there is also some evidence
in humans that DDT can cause cancer of the liver
pancreas and breast.
Figure 10: A mosquito bed net soaked in
Currently DDT remains on the WHO's list of
insecticide can give reasonable
recommended insecticides and its policy has
protection, if used properly, for $5.
shifted from recommending spraying only in areas
of seasonal or episodic transmission of malaria, to also advocating it in areas of continuous,
intense transmission, so DDT use is expected to rise. The major reason is the failure to curtail
malaria through drug treatment to kill the parasite, because of the increasing prevalence of
drug-resistant forms.
Malaria vocabulary
Endemic
Plasmodium protozoa
Salivary gland
Anopheles mosquito
Sporozite
Merozoite
Giemsa stain
PCR analysis
Serological tests
Chloroquine
DDT (dichlorodiphenyltrichloroethane)
Carcinogen.
9
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