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Examining the role of macrolides and host immunity in combatting filarial parasites.

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 Brugia malayi microfilaria and an ML-induced suppression of secretory protein release by B. malayi 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.
PMID
Related Publications
Authors

Mayor MeshTerms
Keywords

Avermectin

Brugia malayi

Brugia timori

Dirofilaria immitis

ES proteins

Excretory-secretory apparatus

Filarial worms

Immunity

Ivermectin

Macrocyclic lactones

Macrolides

Milbemycin

Onchocerca cervicalis

Onchocerca volvulus

Wuchereria bancrofti

Journal Title parasites & vectors
Publication Year Start




PMID- 28410595
OWN - NLM
STAT- MEDLINE
DA  - 20170415
DCOM- 20170425
LR  - 20170425
IS  - 1756-3305 (Electronic)
IS  - 1756-3305 (Linking)
VI  - 10
IP  - 1
DP  - 2017 Apr 14
TI  - Examining the role of macrolides and host immunity in combatting filarial
      parasites.
PG  - 182
LID - 10.1186/s13071-017-2116-6 [doi]
AB  - 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 Brugia
      malayi microfilaria and an ML-induced suppression of secretory protein release by
      B. malayi 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.
FAU - Carithers, Doug S
AU  - Carithers DS
AD  - Boehringer Ingelheim, 3239 Satellite Boulevard, Duluth, GA, 30096, USA.
      [email protected]
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20170414
PL  - England
TA  - Parasit Vectors
JT  - Parasites & vectors
JID - 101462774
RN  - 0 (Anthelmintics)
RN  - 0 (Macrolides)
SB  - IM
MH  - Animals
MH  - Anthelmintics/*pharmacology
MH  - Biological Transport/drug effects
MH  - Brugia malayi/*drug effects/*immunology
MH  - Disease Models, Animal
MH  - Filariasis/*parasitology
MH  - Host-Pathogen Interactions/*drug effects
MH  - Humans
MH  - Macrolides/*pharmacology
PMC - PMC5391593
OTO - NOTNLM
OT  - Avermectin
OT  - Brugia malayi
OT  - Brugia timori
OT  - Dirofilaria immitis
OT  - ES proteins
OT  - Excretory-secretory apparatus
OT  - Filarial worms
OT  - Immunity
OT  - Ivermectin
OT  - Macrocyclic lactones
OT  - Macrolides
OT  - Milbemycin
OT  - Onchocerca cervicalis
OT  - Onchocerca volvulus
OT  - Wuchereria bancrofti
EDAT- 2017/04/16 06:00
MHDA- 2017/04/26 06:00
CRDT- 2017/04/16 06:00
PHST- 2016/10/21 [received]
PHST- 2017/03/28 [accepted]
AID - 10.1186/s13071-017-2116-6 [doi]
AID - 10.1186/s13071-017-2116-6 [pii]
PST - epublish
SO  - Parasit Vectors. 2017 Apr 14;10(1):182. doi: 10.1186/s13071-017-2116-6.

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