{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:29:07Z","timestamp":1790076547072,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Department of Energy Financial Assistance Award","award":["DE-EM0004391"],"award-info":[{"award-number":["DE-EM0004391"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Parasite drug resistance presents a major obstacle to controlling and eliminating vector-borne diseases affecting humans and animals. While vector-borne disease dynamics are affected by factors related to parasite, vertebrate host and vector, research on drug resistance in filarial parasites has primarily focused on the parasite and vertebrate host, rather than the mosquito. However, we expect that the physiological costs associated with drug resistance would reduce the fitness of drug-resistant vs. drug-susceptible parasites in the mosquito wherein parasites are not exposed to drugs. Here we test this hypothesis using four isolates of the dog heartworm (Dirofilaria immitis)\u2014two drug susceptible and two drug resistant\u2014and two vectors\u2014the yellow fever mosquito (Aedes aegypti) and the Asian tiger mosquito (Ae. albopictus)\u2014as our model system. Our data indicated that while vector species had a significant effect on vectorial capacity, there was no significant difference in the vectorial capacity of mosquitoes infected with drug-resistant vs. drug-susceptible parasites. Consequently, contrary to expectations, our data indicate that drug resistance in D. immitis does not appear to reduce the transmission efficiency of these parasites, and thus the spread of drug-resistant parasites in the vertebrate population is unlikely to be mitigated by reduced fitness in the mosquito vector.<\/jats:p>","DOI":"10.3390\/pathogens10010002","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T20:39:29Z","timestamp":1608669569000},"page":"2","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug Resistance in Filarial Parasites Does Not Affect Mosquito Vectorial Capacity"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-5629","authenticated-orcid":false,"given":"Erik","family":"Neff","sequence":"first","affiliation":[{"name":"Savannah River Ecology Laboratory, University of Georgia, Drawer E, Aiken, SC 29802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5596-7380","authenticated-orcid":false,"given":"Pablo D.","family":"Jimenez Castro","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"},{"name":"Grupo de Parasitolog\u00eda Veterinaria, Universidad Nacional de Colombia, Bogot\u00e1 11001000, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray M.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-0429","authenticated-orcid":false,"given":"Guha","family":"Dharmarajan","sequence":"additional","affiliation":[{"name":"Savannah River Ecology Laboratory, University of Georgia, Drawer E, Aiken, SC 29802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"ref_1","unstructured":"WHO (2017). Global Vector Control Response 2017\u20132030, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nature15535","article-title":"The Effect of Malaria Control on Plasmodium falciparum in Africa between 2000 and 2015","volume":"526","author":"Bhatt","year":"2015","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cibulskis, R.E., Alonso, P., Aponte, J., Aregawi, M., Barrette, A., Bergeron, L., Fergus, C.A., Knox, T., Lynch, M., and Patouillard, E. (2016). Malaria: Global progress 2000\u20132015 and Future Challenges. Infect. Dis. Poverty, 5.","DOI":"10.1186\/s40249-016-0151-8"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1186","DOI":"10.1016\/S2214-109X(20)30286-2","article-title":"The Global Distribution of Lymphatic Filariasis, 2000\u20132018: A Geospatial Analysis","volume":"8","author":"Cromwell","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E338","DOI":"10.1016\/S1473-3099(19)30261-0","article-title":"Antimalarial Drug Resistance in Africa: The Calm before the Storm?","volume":"19","author":"Conrad","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Churcher, T., Chanda, E., Coetzee, M., Davenport, M., Diabate, A., Djimde, A., Dondorp, A.M., Donnelly, M., Hemingway, J., and Huijben, S. (2017). malERA: An Updated Research Agenda for Insecticide and Drug Resistance in Malaria Elimination and Eradication. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002450"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tyagi, B.K. (2018). Progress in the Treatment and Control of Lymphatic Filariasis. Lymphatic Filariasis: Epidemiology, Treatment and Prevention\u2014The Indian Perspective, Springer.","DOI":"10.1007\/978-981-13-1391-2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1752-4571.2010.00178.x","article-title":"Consequences of Immunopathology for Pathogen Virulence Evolution and Public Health: Malaria as a Case Study","volume":"4","author":"Long","year":"2011","journal-title":"Evol. Appl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1038\/543S50a","article-title":"The Riddle of Resistance","volume":"543","author":"Eisenstein","year":"2017","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1752-4571.2007.00012.x","article-title":"Evolutionary Concepts in Predicting and Evaluating the Impact of Mass Chemotherapy Schistosomiasis Control Programmes on Parasites and their Hosts","volume":"1","author":"Webster","year":"2008","journal-title":"Evol. Appl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1126\/science.aad9279","article-title":"Parasites Resistant to the Antimalarial Atovaquone Fail to Transmit by Mosquitoes","volume":"352","author":"Goodman","year":"2016","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S1471-4922(02)02281-X","article-title":"Why is the Effect of Malaria Parasites on Mosquito Survival still Unresolved?","volume":"18","author":"Ferguson","year":"2002","journal-title":"Trends Parasitol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Erickson, S.M., Xi, Z., Mayhew, G.F., Ramirez, J.L., Aliota, M.T., Christensen, B.M., and Dimopoulos, G. (2009). Mosquito Infection Responses to Developing Filarial Worms. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000529"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1016\/j.cub.2019.09.047","article-title":"Variation in Tolerance to Parasites Affects Vectorial Capacity of Natural Asian Tiger Mosquito Populations","volume":"29","author":"Dharmarajan","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0065-308X(08)00204-2","article-title":"Chapter 4 Heartworm Disease in Animals and Humans","volume":"Volume 6610","author":"McCall","year":"2008","journal-title":"Advances in Parasitology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.cvsm.2009.06.003","article-title":"Heartworm Biology, Treatment, and Control","volume":"39","author":"Bowman","year":"2009","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_17","first-page":"283","article-title":"The Role of Arthropods in the Development of Animal\u2014Models for Filariasis Research","volume":"16","author":"McCall","year":"1981","journal-title":"J. Ga. Entomol. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.vetpar.2008.10.093","article-title":"Prevalence and Geographic Distribution of Dirofilaria immitis, Borrelia burgdorferi, Ehrlichia canis, and Anaplasma phagocytophilum in Dogs in the United States: Results of a National Clinic-based Serologic Survey","volume":"160","author":"Bowman","year":"2009","journal-title":"Vet. Parasitol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1017\/S003118201500061X","article-title":"The Emergence of Macrocyclic Lactone Resistance in the Canine Heartworm Dirofilaria immitis","volume":"142","author":"Wolstenholme","year":"2015","journal-title":"Parasitology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1053\/j.tcam.2011.09.004","article-title":"Evidence for Macrocyclic Lactone Anthelmintic Resistance in Dirofilaria immitis","volume":"26","author":"Geary","year":"2011","journal-title":"Top. Companion Anim. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.pt.2010.01.003","article-title":"Public Health Issues Concerning the Widespread Distribution of Canine Heartworm Disease","volume":"26","author":"Lee","year":"2010","journal-title":"Trends Parasitol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1053\/j.tcam.2011.07.001","article-title":"Macrocyclic lactones and Dirofilaria immitis Microfilariae","volume":"26","author":"Bowman","year":"2011","journal-title":"Top. Companion Anim. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ijpddr.2019.04.004","article-title":"Macrocyclic Lactone Anthelmintic-induced Leukocyte Binding to Dirofilaria immitis Microfilariae: Influence of the Drug Resistance Status of the Parasite","volume":"10","author":"Berrafato","year":"2019","journal-title":"Int. J. Parasitol. Drug Resist."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.vetpar.2020.109125","article-title":"Using Population Genetics to Examine Relationships of Dirofilaria immitis based on both Macrocyclic Lactone-Resistance Status and Geography","volume":"283","author":"Sanchez","year":"2020","journal-title":"Vet. Parasitol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1756-3305-5-138","article-title":"Heartworms, macrocyclic lactones, and the specter of resistance to prevention in the United States","volume":"5","author":"Bowman","year":"2012","journal-title":"Parasites Vectors"},{"key":"ref_26","first-page":"1","article-title":"Drug Resistance in Parasitic Diseases","volume":"26","author":"Ertabaklar","year":"2020","journal-title":"Eur. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.pt.2004.08.001","article-title":"Drug Resistance in Nematodes of Veterinary Importance: A Status Report","volume":"20","author":"Kaplan","year":"2004","journal-title":"Trends Parasitol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1475-2875-12-453","article-title":"Selection for Chloroquine-sensitive Plasmodium falciparum by Wild Anopheles arabiensis in Southern Zambia","volume":"12","author":"Mharakurwa","year":"2013","journal-title":"Malar. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1126\/science.1185410","article-title":"The Selection Landscape of Malaria Parasites","volume":"328","author":"Mackinnon","year":"2010","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3711","DOI":"10.1073\/pnas.1909369117","article-title":"Activation of Mosquito Immunity Blocks the Development of Transmission-stage Filarial Nematodes","volume":"117","author":"Edgerton","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature12231","article-title":"Vector Transmission Regulates Immune Control of Plasmodium Virulence","volume":"498","author":"Spence","year":"2013","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jinsphys.2014.02.012","article-title":"A Blood-free Protein Meal Supporting Oogenesis in the Asian Tiger Mosquito, Aedes albopictus (Skuse)","volume":"64","author":"Pitts","year":"2014","journal-title":"J. Insect Physiol."},{"key":"ref_33","unstructured":"Johnson, P. (2020, February 08). Miscellaneous Functions for GLMMs. Available online: https:\/\/github.com\/pcdjohnson\/GLMMmisc."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Michalski, M.L., Griffiths, K.G., Williams, S.A., Kaplan, R.M., and Moorhead, A.R. (2011). The NIH-NIAID Filariasis Research Reagent Resource Center. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001261"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1093\/jmedent\/18.5.434","article-title":"Comparative Susceptibility of 4 Strains of Aedes aegypti (Diptera, Culicidae) to Infection with Dirofilaria immitis","volume":"18","author":"Buxton","year":"1981","journal-title":"J. Med. Entomol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0304-4017(00)00242-9","article-title":"Competence of Aedes albopictus and Culex quinquefasciatus as Vector of Dirofilaria immitis after Blood Meal with Different Microfilarial Density","volume":"90","author":"Lai","year":"2000","journal-title":"Vet. Parasitol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-ento-010715-023530","article-title":"Mosquito Immunobiology: The Intersection of Vector Health and Vector Competence","volume":"63","author":"Bartholomay","year":"2018","journal-title":"Annu. Rev. Entomol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.vetpar.2005.04.004","article-title":"Evaluation of Efficacy of Heartworm Preventive Products at the FDA","volume":"133","author":"Hampshire","year":"2005","journal-title":"Vet. Parasitol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.vetpar.2011.04.012","article-title":"Macrocyclic Lactone Resistance in Dirofilaria immitis","volume":"181","author":"Bourguinat","year":"2011","journal-title":"Vet. Parasitol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13071-014-0494-6","article-title":"Establishment of Macrocyclic Lactone Resistant Dirofilaria immitis Isolates in Experimentally Infected Laboratory Dogs","volume":"7","author":"Pulaski","year":"2014","journal-title":"Parasites Vectors"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"48","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting Linear Mixed-Effects Models Using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.18637\/jss.v069.i01","article-title":"Least-Squares Means: The R Package lsmeans","volume":"69","author":"Lenth","year":"2016","journal-title":"J. Stat. Softw."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shipley, B. (2016). Cause and Correlation in Biology: A User\u2019s Guide to Path Analysis, Structural Equations and Causal Inference with R, Cambridge University Press.","DOI":"10.1017\/CBO9781139979573"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/2041-210X.12512","article-title":"PIECEWISESEM: Piecewise Structural Equation Modeling in R for Ecology, Evolution, and Systematics","volume":"7","author":"Lefcheck","year":"2016","journal-title":"Methods Ecol. Evol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1890\/12-0976.1","article-title":"The AIC Model Selection Method Applied to Path Analytic Models Compared using a D-Separation Test","volume":"94","author":"Shipley","year":"2013","journal-title":"Ecology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Murphy, M. (2020, October 21). Semeff: Automatic Calculation of Effects for Piecewise Structural Equation Models. Available online: https:\/\/CRAN.R-project.org\/package=semEff.","DOI":"10.32614\/CRAN.package.semEff"},{"key":"ref_47","unstructured":"Soetaert, K. (2020, October 21). Diagram: Functions for Visualising Simple Graphs (Networks), Plotting Flow Diagrams. Available online: https:\/\/CRAN.R-project.org\/package=diagram."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.32614\/RJ-2017-046","article-title":"Visualization of Regression Models Using visreg","volume":"9","author":"Breheny","year":"2017","journal-title":"R J."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/1\/2\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:21Z","timestamp":1760179701000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/1\/2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,22]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["pathogens10010002"],"URL":"https:\/\/doi.org\/10.3390\/pathogens10010002","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,22]]}}}