Examining the role of macrolides and host immunity in combatting filarial parasites
Identifieur interne : 000F67 ( Pmc/Curation ); précédent : 000F66; suivant : 000F68Examining the role of macrolides and host immunity in combatting filarial parasites
Auteurs : Doug S. CarithersSource :
- Parasites & Vectors [ 1756-3305 ] ; 2017.
Abstract
Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in
Url:
DOI: 10.1186/s13071-017-2116-6
PubMed: 28410595
PubMed Central: 5391593
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Examining the role of macrolides and host immunity in combatting filarial parasites</title>
<author><name sortKey="Carithers, Doug S" sort="Carithers, Doug S" uniqKey="Carithers D" first="Doug S." last="Carithers">Doug S. Carithers</name>
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<front><div type="abstract" xml:lang="en"><p>Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in <italic>Brugia malayi</italic>
microfilaria and an ML-induced suppression of secretory protein release by <italic>B. malayi</italic>
microfilariae was demonstrated in vitro. It is hypothesized here that suppression of these ES proteins prevents the filarial worm from interfering with the host’s complement cascade, reducing the ability of the parasite to evade the immune system. Live microfilariae and/or larvae, thus exposed, are attacked and presented to the host’s innate immune mechanisms and are ultimately killed by the immune response, not the ML drug. These live, exposed filarial worms stimulate development of innate, cellular and humoral immune responses that when properly stimulated, are capable of clearing all larvae or microfilariae present in the host, regardless of their individual sensitivity to MLs. Additional research in this area can be expected to improve our understanding of the relationships among filarial worms, MLs, and the host immune system, which likely would have implications in filarial disease management in humans and animals.</p>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Parasit Vectors</journal-id>
<journal-id journal-id-type="iso-abbrev">Parasit Vectors</journal-id>
<journal-title-group><journal-title>Parasites & Vectors</journal-title>
</journal-title-group>
<issn pub-type="epub">1756-3305</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">28410595</article-id>
<article-id pub-id-type="pmc">5391593</article-id>
<article-id pub-id-type="publisher-id">2116</article-id>
<article-id pub-id-type="doi">10.1186/s13071-017-2116-6</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Examining the role of macrolides and host immunity in combatting filarial parasites</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Carithers</surname>
<given-names>Doug S.</given-names>
</name>
<address><email>Doug.Carithers@boehringer-ingelheim.com</email>
</address>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.418412.a</institution-id>
<institution></institution>
<institution>Boehringer Ingelheim,</institution>
</institution-wrap>
3239 Satellite Boulevard, Duluth, GA 30096 USA</aff>
</contrib-group>
<pub-date pub-type="epub"><day>14</day>
<month>4</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>14</day>
<month>4</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection"><year>2017</year>
</pub-date>
<volume>10</volume>
<elocation-id>182</elocation-id>
<history><date date-type="received"><day>21</day>
<month>10</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>28</day>
<month>3</month>
<year>2017</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2017</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p>Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in <italic>Brugia malayi</italic>
microfilaria and an ML-induced suppression of secretory protein release by <italic>B. malayi</italic>
microfilariae was demonstrated in vitro. It is hypothesized here that suppression of these ES proteins prevents the filarial worm from interfering with the host’s complement cascade, reducing the ability of the parasite to evade the immune system. Live microfilariae and/or larvae, thus exposed, are attacked and presented to the host’s innate immune mechanisms and are ultimately killed by the immune response, not the ML drug. These live, exposed filarial worms stimulate development of innate, cellular and humoral immune responses that when properly stimulated, are capable of clearing all larvae or microfilariae present in the host, regardless of their individual sensitivity to MLs. Additional research in this area can be expected to improve our understanding of the relationships among filarial worms, MLs, and the host immune system, which likely would have implications in filarial disease management in humans and animals.</p>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Avermectin</kwd>
<kwd><italic>Brugia malayi</italic>
</kwd>
<kwd><italic>Brugia timori</italic>
</kwd>
<kwd><italic>Dirofilaria immitis</italic>
</kwd>
<kwd>Macrocyclic lactones</kwd>
<kwd>Excretory-secretory apparatus</kwd>
<kwd>ES proteins</kwd>
<kwd>Filarial worms</kwd>
<kwd>Immunity</kwd>
<kwd>Ivermectin</kwd>
<kwd>Macrolides</kwd>
<kwd>Milbemycin</kwd>
<kwd><italic>Onchocerca cervicalis</italic>
</kwd>
<kwd><italic>Onchocerca volvulus</italic>
</kwd>
<kwd><italic>Wuchereria bancrofti</italic>
</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2017</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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