19 research outputs found
The genetic basis of host preference and resting behavior in the major African malaria vector, Anopheles arabiensis
Malaria transmission is dependent on the propensity of Anopheles mosquitoes to bite
humans (anthropophily) instead of other dead end hosts. Recent increases in the usage of
Long Lasting Insecticide Treated Nets (LLINs) in Africa have been associated with reductions in highly anthropophilic and endophilic vectors such as Anopheles gambiae s.s., leaving species with a broader host range, such as Anopheles arabiensis, as the most
prominent remaining source of transmission in many settings. An. arabiensis appears to be
more of a generalist in terms of its host choice and resting behavior, which may be due to
phenotypic plasticity and/or segregating allelic variation. To investigate the genetic basis of host choice and resting behavior in An. arabiensis we sequenced the genomes of 23
human-fed and 25 cattle-fed mosquitoes collected both in-doors and out-doors in the Kilombero Valley, Tanzania. We identified a total of 4,820,851 SNPs, which were used to conduct the first genome-wide estimates of “SNP heritability”for host choice and resting
behavior in this species. A genetic component was detected for host choice (human vs cow
fed; permuted P = 0.002), but there was no evidence of a genetic component for resting
behavior (indoors versus outside; permuted P = 0.465). A principal component analysis
(PCA) segregated individuals based on genomic variation into three groups which were
characterized by differences at the 2Rb and/or 3Ra paracentromeric chromosome inversions. There was a non-random distribution of cattle-fed mosquitoes between the PCA clusters, suggesting that alleles linked to the 2Rb and/or 3Ra inversions may influence host
choice. Using a novel inversion genotyping assay, we detected a significant enrichment of
the standard arrangement (non-inverted) of 3Ra among cattle-fed mosquitoes (N = 129)
versus all non-cattle-fed individuals. Thus, tracking the frequency of the 3Ra in An. arabiensis populations may be of use to infer selection on host choice behavior within these vector populations; possibly in response to vector control. Controlled
host-choice assays are needed to discern whether the observed genetic component has a
direct relationship with innate host preference. A better understanding of the genetic basis
for host feeding behavior in An. arabiensis may also open avenues for novel vector control
strategies based on driving genes for zoophily into wild mosquito populations
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Neutrophil cathepsin G proteolysis of protease-activated receptor 4 generates a novel, functional tethered ligand
Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease-activated receptor (PAR) amino termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular mechanism of CatG-induced PAR4 activation is unknown. We show that blockade of the canonical PAR4 thrombin cleavage site did not alter CatG-induced platelet aggregation, suggesting CatG cleaves a different site than thrombin. Mass spectrometry analysis using PAR4 N-terminus peptides revealed CatG cleavage at Ser67-Arg68. A synthetic peptide, RALLLGWVPTR, representing the tethered ligand resulting from CatG proteolyzed PAR4, induced PAR4-dependent calcium flux and greater platelet aggregation than the thrombin-generated GYPGQV peptide. Mutating PAR4 Ser67or Arg68 reduced CatG-induced calcium flux without affecting thrombin-induced calcium flux. Dog platelets, which contain a conserved CatG PAR4 Ser-Arg cleavage site, aggregated in response to human CatG and RALLLGWVPTR, while mouse (Ser-Gln) and rat (Ser-Glu) platelets were unresponsive. Thus, CatG amputates the PAR4 thrombin cleavage site by cleavage at Ser67-Arg68 and activates PAR4 by generating a new functional tethered ligand. These findings support PAR4 as an important CatG signaling receptor and suggest a novel therapeutic approach for blocking platelet-neutrophil-mediated pathophysiologies. © 2022 by The American Society of Hematology.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]