Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi
Identifieur interne : 003251 ( Istex/Corpus ); précédent : 003250; suivant : 003252Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi
Auteurs : George A. Punkosdy ; Vida A. Dennis ; Barbara L. Lasater ; George Tzertzinis ; Jeremy M. Foster ; Patrick J. LammieSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2001-08-01.
Abstract
The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia‐specific immune responses were assayed in a group of Brugia malayi–infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.
Url:
DOI: 10.1086/322023
Links to Exploration step
ISTEX:6C00FDF13A2963AABFD4B1931452EDEB724EF92BLe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi</title><author><name sortKey="Punkosdy, George A" sort="Punkosdy, George A" uniqKey="Punkosdy G" first="George A." last="Punkosdy">George A. Punkosdy</name><affiliation><mods:affiliation>Department of Cellular Biology, University of Georgia, Athens, and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Dennis, Vida A" sort="Dennis, Vida A" uniqKey="Dennis V" first="Vida A." last="Dennis">Vida A. Dennis</name><affiliation><mods:affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</mods:affiliation></affiliation></author><author><name sortKey="Lasater, Barbara L" sort="Lasater, Barbara L" uniqKey="Lasater B" first="Barbara L." last="Lasater">Barbara L. Lasater</name><affiliation><mods:affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</mods:affiliation></affiliation></author><author><name sortKey="Tzertzinis, George" sort="Tzertzinis, George" uniqKey="Tzertzinis G" first="George" last="Tzertzinis">George Tzertzinis</name><affiliation><mods:affiliation>New England Biolabs, Beverly, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Foster, Jeremy M" sort="Foster, Jeremy M" uniqKey="Foster J" first="Jeremy M." last="Foster">Jeremy M. Foster</name><affiliation><mods:affiliation>New England Biolabs, Beverly, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Lammie, Patrick J" sort="Lammie, Patrick J" uniqKey="Lammie P" first="Patrick J." last="Lammie">Patrick J. Lammie</name><affiliation><mods:affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: pjl1@cdc.gov</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:6C00FDF13A2963AABFD4B1931452EDEB724EF92B</idno><date when="2001" year="2001">2001</date><idno type="doi">10.1086/322023</idno><idno type="url">https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">003251</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">003251</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi</title><author><name sortKey="Punkosdy, George A" sort="Punkosdy, George A" uniqKey="Punkosdy G" first="George A." last="Punkosdy">George A. Punkosdy</name><affiliation><mods:affiliation>Department of Cellular Biology, University of Georgia, Athens, and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Dennis, Vida A" sort="Dennis, Vida A" uniqKey="Dennis V" first="Vida A." last="Dennis">Vida A. Dennis</name><affiliation><mods:affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</mods:affiliation></affiliation></author><author><name sortKey="Lasater, Barbara L" sort="Lasater, Barbara L" uniqKey="Lasater B" first="Barbara L." last="Lasater">Barbara L. Lasater</name><affiliation><mods:affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</mods:affiliation></affiliation></author><author><name sortKey="Tzertzinis, George" sort="Tzertzinis, George" uniqKey="Tzertzinis G" first="George" last="Tzertzinis">George Tzertzinis</name><affiliation><mods:affiliation>New England Biolabs, Beverly, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Foster, Jeremy M" sort="Foster, Jeremy M" uniqKey="Foster J" first="Jeremy M." last="Foster">Jeremy M. Foster</name><affiliation><mods:affiliation>New England Biolabs, Beverly, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Lammie, Patrick J" sort="Lammie, Patrick J" uniqKey="Lammie P" first="Patrick J." last="Lammie">Patrick J. Lammie</name><affiliation><mods:affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: pjl1@cdc.gov</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>University of Chicago Press</publisher><date type="published" when="2001-08-01">2001-08-01</date><biblScope unit="volume">184</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="385">385</biblScope><biblScope unit="page" to="389">389</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia‐specific immune responses were assayed in a group of Brugia malayi–infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>George A. Punkosdy</name><affiliations><json:string>Department of Cellular Biology, University of Georgia, Athens, and</json:string><json:string>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</json:string></affiliations></json:item><json:item><name>Vida A. Dennis</name><affiliations><json:string>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</json:string></affiliations></json:item><json:item><name>Barbara L. Lasater</name><affiliations><json:string>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</json:string></affiliations></json:item><json:item><name>George Tzertzinis</name><affiliations><json:string>New England Biolabs, Beverly, Massachusetts</json:string></affiliations></json:item><json:item><name>Jeremy M. Foster</name><affiliations><json:string>New England Biolabs, Beverly, Massachusetts</json:string></affiliations></json:item><json:item><name>Patrick J. Lammie</name><affiliations><json:string>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</json:string><json:string>E-mail: pjl1@cdc.gov</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>other</json:string></originalGenre><abstract>The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia‐specific immune responses were assayed in a group of Brugia malayi–infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. 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malayi</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>University of Chicago Press</publisher><availability><p>© 2001 by the Infectious Diseases Society of America</p></availability><date>2001-07-03</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi</title><author xml:id="author-0000"><persName><forename type="first">George A. </forename><surname>Punkosdy</surname></persName><affiliation>Department of Cellular Biology, University of Georgia, Athens, and</affiliation><affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Vida A. </forename><surname>Dennis</surname></persName><affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Barbara L. </forename><surname>Lasater</surname></persName><affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</affiliation></author><author xml:id="author-0003"><persName><forename type="first">George </forename><surname>Tzertzinis</surname></persName><affiliation>New England Biolabs, Beverly, Massachusetts</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Jeremy M. </forename><surname>Foster</surname></persName><affiliation>New England Biolabs, Beverly, Massachusetts</affiliation></author><author xml:id="author-0005" corresp="yes"><persName><forename type="first">Patrick J. </forename><surname>Lammie</surname></persName><email>pjl1@cdc.gov</email><affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation></author><idno type="istex">6C00FDF13A2963AABFD4B1931452EDEB724EF92B</idno><idno type="DOI">10.1086/322023</idno></analytic><monogr><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="PublisherID">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>University of Chicago Press</publisher><date type="published" when="2001-08-01"></date><biblScope unit="volume">184</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="385">385</biblScope><biblScope unit="page" to="389">389</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2001-07-03</date></creation><abstract><p>The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia‐specific immune responses were assayed in a group of Brugia malayi–infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.</p></abstract></profileDesc><revisionDesc><change when="2001-07-03">Created</change><change when="2001-08-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="other">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>University of Chicago Press</publisher-name>
</publisher>
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<article-meta>
<article-id pub-id-type="doi">10.1086/322023</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Concise communication</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Detection of Serum IgG Antibodies Specific for <italic>Wolbachia</italic> Surface Protein in Rhesus Monkeys Infected with <italic>Brugia malayi</italic>
<xref ref-type="fn" rid="fn1">
</xref>
</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Punkosdy</surname>
<given-names>George A. </given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dennis</surname>
<given-names>Vida A. </given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lasater</surname>
<given-names>Barbara L. </given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tzertzinis</surname>
<given-names>George </given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Foster</surname>
<given-names>Jeremy M. </given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Lammie</surname>
<given-names>Patrick J. </given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<aff id="aff1">
<label>1</label>Department of Cellular Biology, University of Georgia, Athens, and</aff>
<aff id="aff2">
<label>2</label>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</aff>
<aff id="aff3">
<label>3</label>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</aff>
<aff id="aff4">
<label>4</label>New England Biolabs, Beverly, Massachusetts</aff>
</contrib-group>
<author-notes>
<corresp>Reprints or correspondence: Dr. Patrick J. Lammie, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F‐13, 4770 Buford Hwy., Atlanta, GA 30341 (<email>pjl1@cdc.gov</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>8</month>
<year>2001</year>
</pub-date>
<pub-date pub-type="epub">
<day>3</day>
<month>7</month>
<year>2001</year>
</pub-date>
<volume>184</volume>
<issue>3</issue>
<fpage>385</fpage>
<lpage>389</lpage>
<history>
<date date-type="received">
<day>2</day>
<month>2</month>
<year>2001</year>
</date>
<date date-type="rev-recd">
<day>10</day>
<month>4</month>
<year>2001</year>
</date>
</history>
<copyright-statement>© 2001 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2001</copyright-year>
<abstract>
<p>The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether <italic>Wolbachia,</italic> symbiotic bacteria living within filarial nematodes, may be involved in disease progression, <italic>Wolbachia</italic>‐specific immune responses were assayed in a group of <italic>Brugia malayi</italic>–infected rhesus monkeys. Serum IgG antibodies specific for a major <italic>Wolbachia</italic> surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that <italic>Wolbachia</italic> may be important in understanding disease caused by filarial worms.</p>
</abstract>
</article-meta>
</front>
<body>
<p>Lymphatic filariasis is a debilitating parasitic disease affecting millions of people living throughout the tropics. Of these people, ∼25 million exhibit disfiguring manifestations of lymphedema or elephantiasis. Although our understanding of the disease mechanism is incomplete, it is thought that lymphatic damage caused by adult worms, host immune responses, and secondary bacterial infections are all likely to be involved in disease progression [<xref ref-type="bibr" rid="ref1">1</xref>, <xref ref-type="bibr" rid="ref2">2</xref>]. Recently, additional interest in this area has been sparked by the possibility that <italic>Wolbachia,</italic> intracellular symbiotic bacteria living within filarial worms, may play a role in pathogenesis. Although this idea was first proposed >20 years ago [<xref ref-type="bibr" rid="ref3">3</xref>], only recently has experimental evidence in support of this hypothesis been generated [<xref ref-type="bibr" rid="ref4">4</xref>
<xref ref-type="bibr" rid="ref5">
</xref>–<xref ref-type="bibr" rid="ref6">6</xref>].</p>
<p>If <italic>Wolbachia</italic> is involved in pathogenesis, then infected hosts may display <italic>Wolbachia</italic>‐specific immune responses. Studies designed to relate <italic>Wolbachia</italic>‐specific immune responses to the natural history of infection and disease in humans are complicated by the fact that longitudinal specimens are difficult to obtain. As an alternative, <italic>Brugia malayi</italic>–infected rhesus monkeys are an excellent laboratory model for filariasis. In the present study, we used a recombinant form of a major <italic>Wolbachia</italic> surface protein (WSP) [<xref ref-type="bibr" rid="ref7">7</xref>] and serum samples from a previous longitudinal study involving <italic>B. malayi</italic>–infected rhesus monkeys [<xref ref-type="bibr" rid="ref8">8</xref>, <xref ref-type="bibr" rid="ref9">9</xref>] to characterize host antibody responses to <italic>Wolbachia</italic> in lymphatic filariasis.</p>
<sec id="S1">
<title>Materials and Methods</title>
<p>
<italic>Animal infection. </italic>Fourteen male rhesus monkeys <italic>(Macaca mulatta)</italic> were used in this study. The monkeys were divided into 4 groups and were infected as follows: 5 monkeys were infected with a bolus of 200 <italic>B. malayi</italic> third‐stage larvae (L3) in RPMI 1640 medium (bolus‐infected group), as described elsewhere [<xref ref-type="bibr" rid="ref9">9</xref>]. Two monkeys were infected by repeated inoculations of 25 <italic>B. malayi</italic> L3 at ∼1‐month intervals over a period of 48 months (41 total trickle infections; trickle infection group). Five monkeys were initially infected with a bolus of 200 <italic>B. malayi</italic> L3 and then, after 96 weeks, were challenged by 41 inoculations of 25 <italic>B. malayi</italic> L3 at 1‐month intervals (bolus + trickle infection group). Two control monkeys received injections of only RPMI 1640 medium. All injections were made subcutaneously in the lower right leg. Microfilaremia was monitored every 2 weeks via blood drawn at night. Serum samples were collected before infection and at ∼4‐week intervals after infection. All serum samples were labeled alphanumerically and were assayed by an investigator blinded to the infection status of the monkeys.</p>
<p>
<italic>WSP expression and purification. B. malayi</italic> genomic DNA extractions were performed by grinding a pool of adult worms in DNAzol (Gibco BRL), according to the manufacturer’s instructions. Polymerase chain reaction primers were designed to amplify and directionally clone the entire coding sequence of the <italic>Wolbachia wsp</italic> gene minus the predicted N‐terminal signal sequence (European Molecular Biology Laboratory accession no. AJ252061) [<xref ref-type="bibr" rid="ref7">7</xref>] into the <italic>Kpn</italic>1 and <italic>Pst</italic>1 restriction sites of the pQE41 expression vector (Qiagen). The forward primer was engineered to contain a thrombin cleavage site (shown underlined), so that WSP could be cleaved from its fusion partner (forward, 5′‐CGG GTA CCC <underline>CTG GTT CCG CGT GGA TCC</underline> CCT GTT GGT CCA ATA GCT G‐3′; reverse, 5′‐CAA CTG CAG TTA GAA ATT AAA CGC TAT TCC‐3′). Plasmids containing inserts were transformed into <italic>Escherichia coli</italic> JM109 competent cells (Promega), and a positive clone was selected by growth on Luria‐Bertani plates containing carbenicillin. The identity of the resulting positive clone was confirmed by automated DNA sequencing. Expression of the recombinant WSP fusion protein was induced by the addition of isopropyl‐β‐<sc>d</sc>‐thiogalactopyranoside to a final concentration of 1 m<italic>M</italic>. The recombinant fusion protein was purified by using a nickel–nitrilotriacetic acid (Ni‐NTA) column in the presence of 8 <italic>M</italic> urea, according to the manufacturer’s instructions (Qiagen). WSP protein then was cleaved from the dihydrofolate reductase (DHFR) fusion partner by overnight incubation with thrombin at room temperature, and pure WSP protein was isolated by passing the cleaved protein over a Ni‐NTA column again to bind the DHFR fraction plus any uncleaved protein. Expression of recombinant WSP was monitored by SDS‐PAGE and by immunoblotting with a cross‐reactive rabbit anti‐WSP polyclonal antibody raised against WSP from arthropod <italic>Wolbachia</italic> (a gift from S. O’Neill, Yale University) [<xref ref-type="bibr" rid="ref10">10</xref>]. Protein concentration was determined by using the bicinchoninic acid protein microassay (Pierce Biotechnology).</p>
<p>
<italic>ELISA. </italic>Filarial‐specific IgG1 antibody titers were determined as described elsewhere [<xref ref-type="bibr" rid="ref11">11</xref>]. In brief, 96‐well plates were coated with <italic>B. malayi</italic> adult worm antigen (2 μg/mL) diluted in 0.1 <italic>M</italic> NaHCO<sub>3</sub> by overnight incubation at 4°C. Plates then were blocked with 0.3% PBST (0.1 <italic>M</italic> PBS + 0.3% Tween‐20) for 1 h at 4°C. Serum samples (1&rcolon;50 in 0.05% PBST) then were added in duplicate. A standard curve consisting of 2‐fold serial dilutions (1&rcolon;10 to 1&rcolon;1280) of a human serum sample with a known antifilarial IgG1 concentration was included on every plate. After washing, plates were incubated with a biotinylated mouse anti–human IgG1 secondary antibody (1&rcolon;1000; Zymed) and streptavidin/alkaline phosphatase (1&rcolon;500; Gibco BRL), with another washing step between. Plates then were developed by the addition of 0.1% <italic>p</italic>‐nitrophenylphosphate in 3 m<italic>M</italic> MgCl<sub>2</sub> and 10% diethanolamine at pH ∼9.8. Plate absorbance was read with a UVmax microplate reader (405 nm; Molecular Devices), and antibody levels were determined by comparison with the standard curve.</p>
<p>Anti‐WSP IgG antibodies were determined similarly, the only differences being in the concentration of secondary antibody and incubation times. First, 96‐well plates were coated with WSP (0.5 μg/mL). Following overnight blocking, serum samples diluted in 0.3% PBST (1&rcolon;50) were added in duplicate and were incubated overnight at 4°C. A standard curve consisting of 2‐fold serial dilutions (1&rcolon;10 to 1&rcolon;1280) of serum from a human with a high anti‐WSP antibody titer was also included on every plate. The next day, plates were washed, and 50 μL of a mouse anti–human IgG secondary antibody (1&rcolon;500; Zymed) was added for 2 h. Subsequent steps were performed as above.</p>
</sec>
<sec id="S2">
<title>Results</title>
<p>All 12 monkeys that were given subcutaneous injections of infective larvae developed patent <italic>B. malayi</italic> infections. Following a 10–12‐week prepatent period, all monkeys in the bolus infection group, both monkeys in the trickle infection group, and 2 monkeys in the bolus + trickle group became microfilaremic and remained so throughout the entire study (<xref ref-type="table" rid="tb1">table 1</xref>). The other 3 monkeys in the bolus + trickle group (F‐660, F‐712, and F‐585) became amicrofilaremic 15, 26, and 27 weeks after the bolus infection, respectively. One of these monkeys (F‐585) became microfilaremic again following the initiation of trickle infections and remained microfilaremic. In addition, these same 3 monkeys (F‐660, F‐712, and F‐585) developed ⩾1 episode of unilateral pitting lymphedema of the entire lower right leg and foot (site of L3 inoculation).</p>
<p>Assays for WSP‐specific IgG demonstrated detectable humoral responses in serum samples from only 2 of the 12 infected monkeys. Of interest, these 2 WSP‐responding monkeys were also the same monkeys that developed lymphedema after becoming amicrofilaremic (F‐660 and F‐712). For monkey F‐660, we saw an initial anti‐WSP peak of 878 arbitrary units (U) around week 20 postinfection (PI) (<xref ref-type="fig" rid="Fig1">figure 1<italic>A</italic>
</xref>). This corresponded to the point at which this monkey became amicrofilaremic and was immediately followed by an episode of lymphedema. Furthermore, this period of anti‐WSP reactivity was closely associated with a peak of antifilarial IgG1 antibodies 25 weeks PI (<xref ref-type="fig" rid="Fig1">figure 1<italic>A</italic>
</xref>). After initiation of trickle infections at 96 weeks, another increase in antifilarial IgG1 (10.7 μg/mL) and anti‐WSP IgG (1016 U) occurred that peaked at weeks 109 and 115 PI, respectively (13 and 19 weeks after trickle infection). Monkey F‐660 later showed a third broader peak in anti‐WSP IgG (978 U) around week 140 PI (46 weeks after trickle infection), coincident with a second episode of lymphedema from weeks 132 to 176 PI (38–82 weeks after trickle infection). Unlike the previous 2 peaks, this peak did not appear to be accompanied by an increase in antifilarial IgG1.</p>
<p>Monkey F‐712 experienced a similar course of infection with 3 episodes of anti‐WSP reactivity (<xref ref-type="fig" rid="Fig1">figure 1<italic>B</italic>
</xref>). The first anti‐WSP episode occurred at 25 weeks PI, 1 week before this monkey became amicrofilaremic. In contrast to the initial anti‐WSP response in monkey F‐660, the initial response in monkey F‐712 was not accompanied by an episode of lymphedema. This monkey did, however, experience 2 other anti‐WSP IgG responses that were temporally associated with lymphedema and peaked at weeks 165 and 214 PI (69 and 118 after trickle infection). All 3 peaks of WSP antibody reactivity were also associated with increases in antifilarial antibodies.</p>
<p>In the other 10 infected monkeys, no anti‐WSP reactivity was detected above background at any point during infection, even among monkeys that became amicrofilaremic. For example, monkey F‐585 showed no anti‐WSP response when it became amicrofilaremic 27 weeks after the initial infection (<xref ref-type="fig" rid="Fig1">figure 1<italic>C</italic>
</xref>). This monkey also experienced an episode of lymphedema from weeks 134 to 182 PI (38–86 weeks after trickle infection) that was not accompanied by anti‐WSP reactivity, but the monkey remained microfilaremic throughout this time. Monkey F‐661 also showed no evidence of anti‐WSP reactivity throughout the entire study (<xref ref-type="fig" rid="Fig1">figure 1<italic>D</italic>
</xref>). This monkey remained microfilaremic except for a period during weeks 230–306 PI (134–210 weeks after trickle infection) and, like monkey F‐585, exhibited a low antifilarial IgG1 response after the initiation of the trickle infection. In their failure to develop WSP‐specific antibody responses, these 2 monkeys were representative of all remaining <italic>B. malayi</italic>–infected monkeys. In addition, control monkeys did not show anti‐WSP or antifilarial antibody reactivity (data not shown).</p>
</sec>
<sec id="S3">
<title>Discussion</title>
<p>We have demonstrated that a small proportion of <italic>B. malayi</italic>–infected rhesus monkeys exhibit IgG responses to a WSP. It is interesting to note that the 2 monkeys in which <italic>Wolbachia</italic>‐specific immune responses were detected both developed lymphedema after becoming amicrofilaremic. These results imply that WSP‐specific antibody responses may be a useful marker for either disease development or worm death.</p>
<p>Because <italic>Wolbachia</italic> bacteria are embedded within filarial worms, <italic>Wolbachia</italic> antigens will come into contact with components of the mammalian immune system only if bacterial products are somehow released from filarial worms. One plausible mechanism by which <italic>Wolbachia</italic> antigens could be released from filarial worms would be the release of bacteria or bacterial products after worm death. Because the mammalian host is home to several stages of the parasite life cycle, it is important to consider whether monkeys display <italic>Wolbachia</italic>‐specific antibody responses after the death of microfilaria, L3 infective larvae, and/or adult worms. Results from this study suggest that infected monkeys do not mount a detectable anti‐WSP IgG response after death of either L3 or microfilaria alone. Ten monkeys in this study were initially infected by injection of a large bolus of 200 infective larvae, many of which died and did not establish infection. In no instance, however, did we detect an anti‐WSP IgG response immediately after infection. Similarly, transitions from microfilaremia to amicrofilaremia that were not accompanied by elevated antifilarial IgG1 levels (<xref ref-type="fig" rid="Fig1">figure 1<italic>C</italic>
</xref> and <xref ref-type="fig" rid="Fig1">1<italic>D</italic>
</xref>) were not associated with anti‐WSP responses. This absence of WSP reactivity suggests that death of L3 or microfilaria through attrition is not sufficient to induce anti‐WSP IgG responses. These results are in contrast to results showing that <italic>Dirofilaria immitis</italic>–infected cats universally mount antibody responses to WSP [<xref ref-type="bibr" rid="ref4">4</xref>]. Although the explanation for these differences is not entirely clear, perhaps the mechanism by which WSP is released differs between lymphatic‐ and nonlymphatic‐dwelling filarial worms. Alternatively, WSP responses in monkeys and humans (authors’ unpublished data) may be down‐regulated in a Th2‐predominant immune environment that accompanies active infection [<xref ref-type="bibr" rid="ref12">12</xref>].</p>
<p>In 2 of 3 monkeys that became amicrofilaremic after the bolus infection, the transition from microfilaremia to amicrofilaremia was accompanied by an anti‐WSP IgG response (<xref ref-type="fig" rid="Fig1">figure 1</xref>
<italic>A</italic> and 1<italic>B</italic>). In addition, monkey F‐660 showed a second similar episode of anti‐WSP reactivity ∼19 weeks after the initiation of the trickle infections (<xref ref-type="fig" rid="Fig1">figure 1<italic>A</italic>
</xref>). Although we have no direct way of assessing adult worm death in these monkeys, it is possible that, in addition to clearance of microfilaria, each of these 3 episodes was associated with the immunologically mediated death of adult worms. Evidence in support of this conclusion comes from the observation that each episode of WSP reactivity was accompanied by an increase in antifilarial IgG1 antibodies (<xref ref-type="fig" rid="Fig1">figure 1</xref>
<italic>A</italic> and 1<italic>B</italic>) and that both monkeys exhibited elevated T cell responses to adult filarial antigen [<xref ref-type="bibr" rid="ref9">9</xref>].</p>
<p>In this report, we also demonstrate an association between the development of lymphedema and WSP reactivity. Four of 5 observed episodes of lymphedema were temporally associated with increases in anti‐WSP IgG production (<xref ref-type="fig" rid="Fig1">figure 1</xref>
<italic>A</italic> and 1<italic>B</italic>). The single episode of lymphedema not associated with anti‐WSP reactivity occurred in a monkey that was microfilaremic (<xref ref-type="fig" rid="Fig1">figure 1<italic>C</italic>
</xref>). The explanation for the relationship between WSP reactivity and lymphedema is not clear, which reflects the uncertainty about whether the pathogenesis of filarial lymphedema is immune mediated or related to bacterial infections [<xref ref-type="bibr" rid="ref1">1</xref>]. On the one hand, patients with lymphedema, in many settings, are predominantly filarial antigen negative, which implies a relationship between disease status and antifilarial immune status [<xref ref-type="bibr" rid="ref13">13</xref>, <xref ref-type="bibr" rid="ref14">14</xref>]. Perhaps the development of lymphedema in monkeys is associated with immune‐mediated killing of adult worms, and WSP responses are only coincidentally associated with these events. On the other hand, opportunistic bacterial infections are known to significantly contribute to acute attacks of adenolymphangitis and disease progression [<xref ref-type="bibr" rid="ref15">15</xref>]. As an alternative explanation, <italic>Wolbachia</italic>‐specific antibody responses may be a marker or trigger of heightened antibacterial responses. In either case, further studies are needed to determine whether <italic>Wolbachia</italic> contributes to lymphedema development directly by stimulating B and T cell–dependent inflammation through antigen‐specific pathways or indirectly by stimulating effector cells that cross‐react with other bacterial antigens.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>The authors would like to thank Claudio Bandi (Universita di Milano) and Scott O’Neill (Yale University) for sharing unpublished data and reagents. We also thank Mark Eberhard and David Addiss (Centers for Disease Control and Prevention [CDC]) for critical review of the manuscript and Jeff Priest (CDC) for helpful discussions and technical assistance.</p>
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<surname>Netto</surname>
<given-names>MJ</given-names>
</name>
<name>
<surname>Leal</surname>
<given-names>NC</given-names>
</name>
<name>
<surname>de Castro</surname>
<given-names>LG</given-names>
</name>
<name>
<surname>Piessens</surname>
<given-names>WF</given-names>
</name>
</person-group>
<article-title>Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes</article-title>
<source>Trans R Soc Trop Med Hyg</source>
<year>1999</year>
<volume>93</volume>
<fpage>413</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
</ref-list>
<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="Fig1" position="float">
<label>Figure 1. </label>
<caption>
<p>Representative composite graphs showing the course of infection and antibody responses of rhesus monkeys in the bolus + trickle group. Bar graph in each panel represents the period of time that each monkey remained microfilaremic <italic>(black bar)</italic> and/or experienced lymphedema <italic>(gray bar)</italic>. Line graphs represent anti–<italic>Wolbachia</italic> surface protein (WSP) IgG <italic>(solid line)</italic> and antifilarial IgG1 <italic>(dashed line)</italic> antibody responses. Anti‐WSP IgG values are given as arbitrary units on the left axis, and antifilarial IgG1 values are given as μg/mL equivalents of human antibody levels on the right axis. All animals were given the bolus infection at week 0, and the trickle infections were initiated at week 96. <italic>A,</italic> Monkey F‐660; <italic>B,</italic> monkey F‐712; <italic>C,</italic> monkey F‐585; <italic>D,</italic> monkey F‐661. Mf (+), microfilaremic.</p>
</caption>
<graphic mimetype="image" xlink:href="184-3-385-fig001.tiff"></graphic>
</fig>
<fig id="tb1" position="float">
<label>Table 1. </label>
<caption>
<p>Summary of infection outcome for rhesus monkeys in each of the 4 infection groups.</p>
</caption>
<graphic mimetype="image" xlink:href="184-3-385-tab001.tiff"></graphic>
</fig>
</sec>
<fn-group>
<fn id="fn1">
<p>Presented in part: 49th annual meeting of the American Society of Tropical Medicine and Hygiene, Houston, October 2000 (abstract 132).</p>
<p>All procedures involving animal experimentation were approved by the Tulane Regional Primate Research Center’s Institutional Animal Care and Use Committee before initiation of the study.</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Detection of Serum IgG Antibodies Specific for Wolbachia Surface Protein in Rhesus Monkeys Infected with Brugia malayi</title></titleInfo><name type="personal"><namePart type="given">George A. </namePart><namePart type="family">Punkosdy</namePart><affiliation>Department of Cellular Biology, University of Georgia, Athens, and</affiliation><affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vida A. </namePart><namePart type="family">Dennis</namePart><affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barbara L. </namePart><namePart type="family">Lasater</namePart><affiliation>Department of Parasitology, Tulane Regional Primate Research Center, Tulane University School of Medicine, Covington, Louisiana</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">George </namePart><namePart type="family">Tzertzinis</namePart><affiliation>New England Biolabs, Beverly, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeremy M. </namePart><namePart type="family">Foster</namePart><affiliation>New England Biolabs, Beverly, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Patrick J. </namePart><namePart type="family">Lammie</namePart><affiliation>Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia</affiliation><affiliation>E-mail: pjl1@cdc.gov</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other"></genre><originInfo><publisher>University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2001-08-01</dateIssued><dateCreated encoding="w3cdtf">2001-07-03</dateCreated><copyrightDate encoding="w3cdtf">2001</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia‐specific immune responses were assayed in a group of Brugia malayi–infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP‐specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2001</date><detail type="volume"><caption>vol.</caption><number>184</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>385</start><end>389</end></extent></part></relatedItem><identifier type="istex">6C00FDF13A2963AABFD4B1931452EDEB724EF92B</identifier><identifier type="DOI">10.1086/322023</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2001 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/covers/tiff</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/annexes/gif</uri></json:item><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/6C00FDF13A2963AABFD4B1931452EDEB724EF92B/annexes/pdf</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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