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The Abundant Larval Transcript-1 and -2 Genes of Brugia malayi Encode Stage-Specific Candidate Vaccine Antigens for Filariasis

Identifieur interne : 00A190 ( Main/Exploration ); précédent : 00A189; suivant : 00A191

The Abundant Larval Transcript-1 and -2 Genes of Brugia malayi Encode Stage-Specific Candidate Vaccine Antigens for Filariasis

Auteurs : William F. Gregory ; Agnes K. Atmadja ; Judith E. Allen ; Rick M. Maizels

Source :

RBID : PMC:101719

Descripteurs français

English descriptors

Abstract

Lymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodes Brugia and Wuchereria. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (alt-1 and alt-2), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression of alt-1 and alt-2 is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed to Brugia malayi show a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.


Url:
PubMed: 10858234
PubMed Central: 101719


Affiliations:


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<term>Base Sequence</term>
<term>Brugia malayi (genetics)</term>
<term>Brugia malayi (growth & development)</term>
<term>Brugia malayi (immunology)</term>
<term>Caenorhabditis elegans (genetics)</term>
<term>Caenorhabditis elegans (immunology)</term>
<term>DNA Primers (genetics)</term>
<term>Elephantiasis, Filarial (immunology)</term>
<term>Elephantiasis, Filarial (parasitology)</term>
<term>Elephantiasis, Filarial (prevention & control)</term>
<term>Gene Expression Regulation, Developmental</term>
<term>Genetic Variation</term>
<term>Gerbillinae</term>
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<term>Helminth Proteins (immunology)</term>
<term>Humans</term>
<term>Immunization</term>
<term>Introns</term>
<term>Larva (genetics)</term>
<term>Larva (immunology)</term>
<term>Male</term>
<term>Molecular Sequence Data</term>
<term>Sequence Homology, Amino Acid</term>
<term>Vaccines (genetics)</term>
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<term>Animaux</term>
<term>Antigènes d'helminthe (génétique)</term>
<term>Brugia malayi (croissance et développement)</term>
<term>Brugia malayi (génétique)</term>
<term>Brugia malayi (immunologie)</term>
<term>Caenorhabditis elegans (génétique)</term>
<term>Caenorhabditis elegans (immunologie)</term>
<term>Données de séquences moléculaires</term>
<term>Filariose lymphatique ()</term>
<term>Filariose lymphatique (immunologie)</term>
<term>Filariose lymphatique (parasitologie)</term>
<term>Gerbillinae</term>
<term>Humains</term>
<term>Immunisation</term>
<term>Introns</term>
<term>Larve (génétique)</term>
<term>Larve (immunologie)</term>
<term>Mâle</term>
<term>Protéines d'helminthes (génétique)</term>
<term>Protéines d'helminthes (immunologie)</term>
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<term>Helminth Proteins</term>
<term>Vaccines</term>
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<term>Brugia malayi</term>
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<term>Brugia malayi</term>
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<term>Brugia malayi</term>
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<term>Brugia malayi</term>
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<term>Larve</term>
<term>Protéines d'helminthes</term>
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<term>Brugia malayi</term>
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<term>Filariose lymphatique</term>
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<term>Elephantiasis, Filarial</term>
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<term>Régulation de l'expression des gènes au cours du développement</term>
<term>Similitude de séquences d'acides aminés</term>
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<front>
<div type="abstract" xml:lang="en">
<p>Lymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodes
<italic>Brugia</italic>
and
<italic>Wuchereria</italic>
. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (
<italic>alt-1</italic>
and
<italic>alt-2</italic>
), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression of
<italic>alt-1</italic>
and
<italic>alt-2</italic>
is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed to
<italic>Brugia malayi</italic>
show a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.</p>
</div>
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