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• Thursday April 29, 2010: Review session- 5 PM.
 Coverdell room S175.
 Please bring questions for discussion.


• May 3, 2010, noon: Deadline for CBIO6500 paper.
• Tuesday May 4, 2010: FINAL EXAM: Coverdell,
 room S175: 8-11 AM
CONTROL MEASUR2ES
   Vector control

   Medical Parasitology
       CBIO4500
     April 27, 2010

    Silvia N J Moreno
            PARASITE CONTROL
Prevention of Environmental Contamination: Antiparasite drugs.
Treated hosts should be protected from re-infection. Sanitation.
Destruction of Free-Living Stages: Protozoan cysts, helminth eggs
and infective larvae are often extremely resistant to toxic chemicals.
Destruction of Intermediate Hosts and Vectors: chemicals to kill snails, insecticides.
Altering the environmental conditions so the the target species do not find the suitable habitat
for its survival. Does not rely on public cooperation.
Destruction of Reservoir Hosts: dogs in leishmaniasis, game animals in trypanosomiasis
Prevention of Infection: Many infective stages gain entry in drinking water,
Cryptosporidium, Giardia, Dracunculus etc. These can be controlled by safe water supplies.
 Meat inspection to prevent Taenia. Bednets prevents mosquito bites. Shoes stops hookworm
larvae burrowing through the skin.
Prevention of Parasite Maturation: chemoprophylaxis and
                                          vaccination
                               Integrated Control
                                                              400,000 long-lasting
                                                              insecticide-treated bed nets
                                                              start the last leg of their
                                                              journey from a Red Cross
                                                              warehouse in Mozambique
                                                              into the hands of families
                                                              who need them
                         VECTOR CONTROL
Major vector-borne diseases of humans, and associated aetiological agents and
                              arthropod vectors
           DISEASE             PATHOGEN/PARASITE                       ARTHROPOD VECTOR
           Protozoan diseases
           Malaria         Plasmodium falciparum, Plasmodium           Anopheles spp. mosquitoes
                           vivax, P. ovale, P. malariae
           Leishmania      Leishmania spp.                             Lutzomyia and Phlebotomus spp.
                                                                       sandflies
           Trypanosomiasis  Trypanosoma brucei gambiense               Glossina spp
                            Trypanosoma brucei rhodesiense
           Chagas disease   Trypanosoma cruzi                          Triatomine spp
           Filarial nematodes
           Lymphatic        Brugia malayi, Brugia timori, Wuchereria   Anopheles, Culex, Aedes and
           filariasis       bancrofti                                  Ochlerotatus mosquitoes
           Onchocerciasis   Onchocerca volvulus                        Simulium spp. blackflies
           Viral diseases
           Dengue           DEN-1, DEN-2, DEN-3, DEN-4 flavivirus      Aedes aegypti mosquito
           hemorrhagic fever
           Yellow fever        Yellow fever flavivirus                 Aedes aegypti mosquito
           Encephalitis        Flavi-, alpha- and bunyaviruses         Various mosquito and ixodid tick
                                                                       species
         Global estimates of human mortality caused by
                     vector-borne diseases




The total numbers of human deaths that are attributed to specific vector-borne diseases are shown and can be compared with the numbers of human deaths
caused by two non-vector-borne diseases — HIV/AIDS and tuberculosis. The percentages of human deaths attributed to specific diseases as a percentage of the
total number of deaths attributed to all vector-borne diseases are shown in the pie chart. Mortality estimates are based on data collected from 112 countries by the
World Health Organization. Yellow fever estimate is based on data published by the Centers for Disease Control and Prevention. Nature reviews Microbiology 3:262 (2005).
       The global distribution and burden of major vector-borne
                                diseases




The distribution of mortality due to major vector-borne diseases in different WHO regions. Most vector-borne diseases occur in tropical and subtropical
regions of the world and the burden of these diseases is greatest in developing countries. Mortality estimates for all major vector-borne disease (in
parentheses) for each region are shown in thousands. Nature reviews Microbiology 3:262 (2005).
        The global distribution and burden of major vector-borne
                                 diseases




The burden of vector-borne disease in disability-adjusted life years (DALYs) for all major vector-borne diseases in WHO regions
(thousands). One DALY is defined as one lost year of 'healthy' life. The burden of disease is a measurement of the gap between the
current health of a population and an ideal situation where everyone in the population lives into old age in full health. Morbidity and
mortality estimates are based on data published by the WHO. Nature reviews Microbiology 3:262 (2005).
                                         VECTOR CONTROL
Vector control has proven successful for
disease control:
      Malaria: eradication of malaria from most of the temperate-
            climate countries in the northern hemisphere
      Onchocerca: the insecticide phase of the Onchocerciasis
            Control Prgramme (OCP) in West Africa has almost
            eliminated onchocerciasis from11 countries
            (www.who.int/ocp/index.htm)

However there is paucity of effective vector-
control programmes: past neglect in this area of                    Abandoned village near the Volta river high blindness rates resulted in the
                                                                    depopulation of entire villages.
research, potential environmental impact of existing
agents, reduction of their effectiveness because of
resistance and other biological complexities of vector
populations.
DTT spraying does reduce disease
transmission but environmentalists
have opposed to their use on large
scale. Bednets impregnated with
pyerethroids offer a simple and
effective approach to reduce
vector-human contact and
transmission. Limited adoption of
this approach, improper use and                                               The result has been increased activity
the emergence of vector                                                       and productivity in many of these areas.
                                                                              New villages in areas formerly
populations with resistance to                                                uninhabitable because of river blindness
pyrethroids limit their effectiveness.
                           VECTOR CONTROL
Advances in vector genomics: an important
advance is the sequencing of the genome of the
A. gambiae mosquito (Science, 2002 298:129). The
genome of Aedes aegypti (Science (2007) 316:1718-23)
(yellow fever) was also sequenced, and a project
is in place for the genome of Glossina morsitans
(Tsetse fly vector). This information will provide
opportunities for understanding better vectors
and devising new methods for their control.


Vector biology is poised to explore new
strategies for vector-based disease control:
    Mosquitos refractory to pathogen infection
    Novel insecticides targets
    Understanding the molecular basis for vector
       behavior, ecology and host-parasite-
       vector interactions
            Manipulation of insect vector by their parasite
• Parasites alter their host in some way.
  Does this alteration affect transmission? (increase would
 be favorable for a successful parasite)

• Parasite undergo a period of growth, development and
 sometimes reproduction within their vector.
         Parasite fitness is linked to vector fitness.
Two factors that would improve parasite success:                                Lutzomyia longipalpis feeding
    Vector longevity
    Fast Development
Host manipulation by parasite:
Hematophagy: Infection results in altered vector feeding
 behavior. Most-studied examples in parasite affecting vector
 feeding behavior: Leishmania and plasmodium.
Fecundity, blood feeding, and infection: Blood is important
 for the vector and the parasite. Parasite-induced fecundity
 reduction. Allows vector survival until transmission
                                                                 Anopheles albimanus mosquito feeding on a human arm. This
 can occur?                                                      mosquito is a vector of malaria and mosquito control is a very
                                                                 effective way of reducing the incidence of malaria.
Infection and survivorship: Do infected mosquitoes live
 longer? High infectivity also results in increase in mortality. Studies
 are not conclusive.
            Manipulation of insect vector by their parasite
Hematophagy:
Malaria-infected mosquitoes: Infected
mosquitoes makes many attempts to feed, each
time depositing parasites at the feeding site.
ADP stimulates platelet recruitment to the wound
site. Apyrase is an enzyme which degrades ADP
and is present in the mosquito saliva and would
inhibit host hemostasis promoting easier and longer
blood feeding.
Apyrase activity is reduced in the salivary glands of
P. gallinaceum- infected Aedes Aegypti
resulting in an increase in the times of the
median blood location time.

One study showed that P. falciparum infected An. gambiae
bite more hosts and also that infected mosquitoes were
more likely to take multiple meals and become fully
engorged. This would increase their chances for
transmission.
          Leishmania manipulates sandfly feeding to
                 enhance its transmission
Hematophagy:
•Difficulty in ingesting a blood meal leads to
 more probing. Increased probing favors
 transmission of the parasite.
• Metacyclic promastigotes of L. mexicana are
 regurgitated from the midgut accompanied by
 a secretory gel (PSG) and with sand fly saliva.
• The major component of the gel is filamentous
 proteophosphoglycan (fPPG) a parasite
 secretion.
• The resulting blockage interferes with feeding
 and limits the volume of blood a fly can obtain;
 and this could explain why infected flies probe
 the skin more frequently and spend more time
 feeding.
• Experiments with Phlebotomus chinensis showed
 that flies were more likely to transmit L. donovani to
 hamsters when they probed and took no blood
 compared to those infected flies that took a blood
 meal.
   Transmission from the Vertebrate host



• Host attractiveness is
 enhanced possibly due to
 modified host odor and
 vectors such as tsetse flies
 feed more frequently on
 infected hosts.
• Host defensive behaviors
 may be reduced making
 feeding on infected hosts
 less risky.
              Manipulation of insect vector by their parasite
                    FECUNDITY, BLOOD FEEDING, AND INFECTION
• Blood feeding is essential for both:
  vector and parasite.
• Blood meal quantity and quality are                                Larval
  important for egg production.                                   development
• There is a reduction in fecundity          Gonotrophic
  (ability to reproduce) in plasmodium-        status                             Teneral
  infected mosquitoes, specially when                                            reserves
  oocysts are developed.
• This loss of fecundity may be                                                             Body size
                                             Blood meal
  attributed to reduced blood intake or
                                               quality
                                                              Mosquito
  intake of impoverished blood when                           fecundity
  mosquitoes fed on infected hosts.
• The most important reason for the
  reduced fecundity it is still not clear.                                        Number of
                                                                                   ovaries
• How can reduced fecundity benefit the          Blood meal
  parasite?                                        source
                                                                    Blood meal
  Since increased reproductive effort                                  size
  decreases lifespan; if vector
  survival results from fecundity
  reduction then the parasite
  increases its chances of
  successful transmission.
   Recommendations for vector control
• Genetic manipulation of vectors:
    Transgenic mosquitoes with impaired ability to transmit the parasite. This
    is attractive because is likely to be economically viable and relatively “low
    technology”.

• Vector immunity and vector-parasite interactions:
    Genome projects would help identify novel targets in the mosquito gut and
    salivary glands involved in digestion of the blood meal and host-parasite-
    vector interactions which could be used to develop vaccines that block
    the transmission of parasites and mosquito immune regulators or „smart
    sprays‟ that disrupt the development of the parasite in the mosquito.

• Vector behavior and other approaches to vector control:
    Elucidating the molecular basis of many mosquito behavior may be an
    expensive research investment, but the simple traps and repellant devises
    anticipated from this research could be easily adopted in malaria-endemic
    countries
           Genetic manipulation of vectors

Two broad categories:
• Genetic modification of mosquito
populations. Could be achieved by
releasing transgenic mosquitoes
carrying genes whose products impair
pathogen development.

• Population suppression: use of
sterile insect technique (SIT) in
conjunction with “release of insects
carrying a dominant lethal” (RIDL).
Insects are transformed with a
transgene whose product suppresses
                                       A transgenic mosquito carrying a gene that confers
offspring production, leading to a     resistance to the malaria parasite. The mosquito can be
decrease of the vector population.     recognized as transgenic by the green fluorescence of the
                                       eye facets. http://news.mongabay.com/2007/0319-mosquitoes.html
               Genetic manipulation of vectors
Controversial but attractive and potentially self-
 propagating. Many questions need to be
 addressed first about the feasibility and
 consequences of this approach. Serious issues
 are: reduced fitness of modified vectors, the
 ecological impact of transgenic arthropods and
 the evolutionary consequences of their release.

In addition scientists need:
• Methodologies to introduce foreign genes into
 vectors mosquitoes (e.g. transposable elements)
• Promotores that can drive the expression of
 foreign genes in the correct tissues and at the                           Laser scanner image of transgenic mosquito larvae. The white
                                                                           areas of high fluorescent intensity indicate a high level of
 appropriate times need to be characterized                                transgene expression - particularly in the gut of the larvae
• Find “blocking gene products” capable of
 interfering with parasite development in the
 mosquito. Deleterious effects of these gene
 products on the mosquito should be considered
 and avoided.

                       The transformation technique involves the microinjection of
                       the recombinant DNA into the posterior end of mosquito
                       embryos (fresh laid eggs) prior to pole cell formation.
                Genetic manipulation of vectors
• Transgenic: A genetically modified
 organism (GMO): an organism
 whose genetic material has been
 altered using genetic engineering
 techniques. DNA molecules from
 different sources are combined in
 vitro into one molecule to create a
 new gene. This DNA is transferred
 into an organism and causes the
 expression of modified or novel
 traits. In transgenic mosquitoes the
 idea is to alter the transmission of
 the malaria parasite.
• The appropriate tools are needed       Confocal fluorescence and transmission microphotographs of putative
 for the transfer of genetic material.   homozygous (left) transgenic larvae expressing EGFP compared with
                                         a wild-type mosquito (right).
 A plasmid containing the gene for
 Green Fluorescent Protein (EGFP),
 was created Nature 405:959
 (2000).
•Pre-blastoderm embryos were
 injected with the plasmid and an
 average of 29% of the injected
 ones survived. From these, 50%
 were fluorescent.
Effector strategies that could inactivate malaria
         parasites within the mosquito
One example of a Parasite-secreted
protein: CHITINASE                                                      CHITIN

• Ookinetes secrete chitinases that
facilitate their crossing of the peritrophic
matrix.
• Parasite strains carrying mutations or
gene knockouts of chitinase are
markedly impaired in their ability to form
oocysts.
• Feeding anti-chitinase antibodies to
mosquitoes also impaired the
development of oocysts.
• Involvement of other proteins in
parasite development has been
implicated in a study where monoclonal
antibodies made to parasite proteins           Ookinete (O) penetration of the chitin-containing peritrophic matrix
secreted by ookinetes in culture bind P.       (PM) of the mosquito midgut. The parasite is exiting the bloodmeal
                                               on the left, producing chitinase focally to disrupt the peritrophic
gallinaceum zygotes and ookinetes in           matrix, en route to the microvilli of the midgut epithelial surface at
diverse patterns of spatial localization       the right. Trends in parasitology, (2001) 17:269
and temporal expression.
                                      Another example
• The ookinete cross the midgut epithelium and
  differentiate into oocyst which after 10-15 days liberate
  sporozoites into the hemocel. The development of the
  parasite in the mosquito is completed when sporozoites
  cross the salivary gland epithelium.
• Scientists identified a peptide (SM1 for salivary gland-
  and midgut-binding peptide 1) that binds specifically to
  the two epithelia that are traversed by the parasite: the
  distal lobes of the salivary glands and the lumenal
  surface of the midgut. SM1 inhibits crossing of the two
  epithelia by the parasites.
• The idea is that if you can produce SM1 into the gut
  lumen when with a blood meal the Plasmodium
  development would be blocked.                               Detection of AgCP[SM1]4
• They created a synthetic gene AgCP[SM1]4.                   transgenic mosquitoes by
                                                              transformation marker-mediated
  They used a promoter which is activated by a blood          fluorescence. Top, a wild-type
  meal, and a signal sequence to drive secretion of the       (non-transgenic) larva (middle)
  protein into thebmidgut lumen. The gene was inserted        flanked by transgenic larvae
  into a vector and transformed into the germ line of         viewed from the dorsal (top) or
                                                              ventral (bottom) sides. Bottom,
  Anopheles stephensi. Nature (2002) 417:452.17               the head of a wild-type (left) and
• The expression of the peptide produced a reduction in       a transgenic (right) mosquito.
                                                              The entire eye expresses GFP.
  the number of oocysts formed (69-95% inhibition) and        http://www.genomenewsnetwork
  also these transgenic mosquitos had fewer sporozoites       .org/articles/05_02/transgenic_m
  in their salivary glands                                    osquitoes.shtml
                      Population reduction: SIT and RIDL
SIT: Sterile Insect technique: male insects are mass-reared, sterilized by irradiation
and then released in large numbers in the infested areas in order to contribute to sterile
mating with wild mosquitoes. SIT lacks efficient methods
to select for males and irradiation-caused lethality.
RIDL: release of insects with a dominant lethal .
RIDL uses males carrying female dominant lethal
transgenes that can produce purely male offspring. In
the laboratory, this strain is maintained by using a
repressible system to control transgene expression;
absence of the repressor from the insect diet in the field
activates the lethal trait.          Sterilized male flies are mass released
                                                 across the target area by airplanes. The
This approach does not                           sexually sterile males, which outnumber
                                                 the wild-type males, mate with wild-type
appear suitable for malaria                      females resulting in infertile mating
control because of its                           events. This results in a decrease of the
                                                 pest levels and, if continued over several
susceptibility to immigration                    generations, the potential eradication of
from outside the target area.                    the pest from the target area. Nature
                                                 Biotechnology 23:433




 SIT has been used successfully to eradicate
 tsetse flies from Burkina Faso, Tanzania, Nigeria
 and Zanzibar where it eradicated Glossina austeni
 from the 1600 km2 Unguja Island.
                         Population replacement
                                                                                       A transgenic
An important issue to consider before                                                  mosquito
                                                                                       (Left) with
the release of genetically manipulated                                                 green
organisms is the fitness of the                                                        fluorescent
                                                                                       eyes, and a
mosquitoes carrying the transgene.                                                     non-
The transgenic insect needs to                                                         transgenic
                                                                                       mosquito
compete with the local populations to                                                  (Right), with
efficiently introgress the effector genes                                              no eye
                                                                                       fluorescence.
into the wild gene pool.                                                               The
Fitness is the relative success with                                                   transgenic
                                                                                       mosquito
which a genotype transmits its genes to                                                carries a gene
the next generation. Survival and                                                      that confers
                                                                                       resistant to
reproduction are the important                                                         the malaria
components.                                                                            parasite.

Fitness costs:
Burden from the transgene product: Transgenic insects may express multiple genes (a
fluorescent marker and an anti-pathogen effector protein. In addition constructs for RIDL
contain a repressible transactivator protein for tight control of the system.
Insertional mutagenesis: Disruption of native gene function. Fitness reduction through this
strategy is not frequent. Viability is not changed because any random insertion is likely to be
deleterious.
                           Insect immunity
This approach studies vector immune responses, and its effect on parasite transmission.
The idea is to develop vaccines that block parasite transmission and antimalarial
 agents that target vector immunity and parasite development.

Insect Killing mechanisms:
• Antimicrobial peptides: defensin and cecropin genes in A. gambiae. Highly induced
  by malaria infection
• Melanotic encapsulation: Two mechanisms: Cellular encapsulation mediated by
  haemocytes that surround and attach to the microorganism to form a capsule that
  becomes melanized. Humoral encapsulation is the formation of a melanized
  proteinaceous capsule around the microorganism without participation of haemocytes.
• Phagocytosis: involves killing of microorganisms through engulfment and subsequent
  degradation by haemocytes. It is mediated by pattern recognition receptors that can
  bind to the particle and trigger intracellular cascades leading to its internalization
  through an actin-dependent mechanism.
                       Other research initiatives
Understanding vector biology
Mosquitoes show a remarkable preference for
humans as hosts for blood-feeding
They are highly susceptible to infection
Olfaction plays a crucial role in shaping
behaviors such as host seeking and feeding
and determines their vectorial capacity.

Research on the behavior of vectors:
 • Modification of vector behavior for disease
 control
 • Basic research to understand the genetic and
 environmental components of vector behavior and
 reproductive biology
 • Mosquito genomics: comparative genomics to
 provide information about lineage-specific
 adaptations, population biology, ecology and
 genetics, dynamics, regulation and variation of
 vector populations, and vector survival strategies.
 • The gene families implicated in olfactory
 processes are regarded as promising novel
 targets for the design of mosquito attractants
 and/or repellents.
                      Other research initiatives
                  Investigating mechanisms of insecticide resistance




• At present, the control of malaria vectors relies
 extensively on the use of indoor house spraying with
 residual insecticides and the use of insecticide-
 impregnated bednets.
• The problem is the lack of available licensed insecticides
 and the growing resistance.
• Novel targets and the understanding of resistance are
 also important areas of research.
• Scientists are trying to identify specific members of the
 detoxification enzymes whose expression are elevated in
 insecticide-resistant populations
                       Other research initiatives


Entomology and epidemiology studies:
correlation of entomological measures of risk
to infection and disease, evaluation of the
impact of interventions on epidemiology and
disease, and quantitative analysis of mosquito
biology, disease and control.                    Sandfly habitat in Jacarepagua district on the outskirts of Rio de
                                                 Janeiro.
  Infrastructure initiatives:
Development of field-study centers for long-term research programmes, research
centers of excellence in disease-endemic countries, multi-disciplinary research
strategies, databases to monitor long-term and an infrastructure network to facilitate
studies and training and the provision of opportunities for technology transfer and
recruitment

  Network Development:
Creating an international consortium to integrate the results of laboratory and field-
based approaches to develop and compare new and existing strategies; promoting
the rapid communication of scientific advances, making particular use of internet-
based resources; promoting recruitment and training and improving present strategies
                            SUMMARY
• Progress has been made towards a better
 understanding of parasite biology and the
 potential manipulation of its host for its own
 benefit (transmission and metacyclogenesis).
• New tools are available and are being
 produced for the production of transgenic
 vectors.
• Fitness of the transgenic population in the
 wild is a problem to be solved.
• Mosquito control measures are often
 complicated by the presence of multiple
 vectors in the same area. In Africa, as many
 as five different anopheline species can
 function as malaria vectors, either
 simultaneously or seasonally.
• The A. gambiae genome has been completed
 so the number of neutral genetic markers for
 estimating gene glow between populations
 has increased.

				
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