Can we exploit pathogens, parasites or slower acting/less lethal chemical insecticides to alter the ability of vectors to transmit disease and to develop interventions that will not be undermined by evolution of resistance by the vector?

For a number of years we’ve been investigating the potential for development of novel biological insecticides based on natural insect killing fungi. These biopesticides work via contact but instead of causing instant knock down, the fungal infection acts more subtly to reduce adult mosquito longevity. Since malaria parasites take around 2 weeks to develop within the mosquito, products that act relatively late in life to reduce mosquito longevity can still be highly effective at blocking malaria transmission. We have shown that fungi are infective against Anopheles, Aedes and Culex mosquitoes and exhibit complete resistance breaking (i.e. work against all insecticide resistant mosquitoes) creating exciting possibilities for use in insecticide resistance management strategies. Various critics of the approach have suggested that a fungal product is unlikely to work because it won’t be effective under African conditions. However, we have just finalized a persistence study demonstrating that fungal spores can remain infective on mud tiles (a realistic substrate) under tropical conditions for 6 months, which is as long as any of the current chemical insecticides approved for use by the WHO. We have also just discovered that prior to death, fungal-infected mosquitoes suffer impaired responsiveness to human odor cues. Making mosquitoes anosmic (akin to giving them a ‘head cold’) to reduce odor related host location is a radical departure from the fast-acting neurotoxin paradigm. Rapid killing of mosquitoes does reduce transmission but it also maximizes selection pressure for resistance. It’s an intriguing possibility that perhaps all we need is to make mosquitoes sick. Very little attention has been given to alternative modes of action yet impaired olfaction, or other common side effects of fungal infection such as reduced flight, increased susceptibility to predation, energetic stresses, altered immune function, increased susceptibility to conventional insecticides etc. could all contribute to altered mosquito population age structure and reduced vectorial capacity. A sub-lethal biopesticide would represent a genuinely new addition to the mosquito control tool kit.

More generally, the mosquito biopesticide falls into a category of products we have defined as ‘Late Life Acting’ insecticides. The LLA approach targets the old infectious mosquitoes so emphasizes malaria control rather than mosquito control. This is an important distinction not appreciated in current insecticide target product profiles. By acting slowly, LLAs can still block transmission but enable mosquitoes to achieve part of their lifetime reproductive output, reducing selection pressure for resistance. Thus we have proposed that it should be possible to design insecticides for malaria control that are essentially ‘evolution proof’.

We’re trying to progress this research theme along various fronts with partial support from NIH and IVCC. We are also extending the approach to other targets including houseflies and bedbugs.

Key papers include:

  • Darbro, J.M., Johnson, P., Thomas, M.B., Ritchie, S., Kay, B.H. & Ryan, P.A. (accepted). Effects of Beauveria bassiana on survival, blood-feeding success and fecundity of Aedes aegypti in laboratory and semi-field conditions. American Journal of Tropical Medicine and Hygiene.
  • Glunt, K.D., Thomas, M.B. & Read, A.F. (2011). The effects of age, exposure history and malaria infection on the susceptibility of Anopheles mosquitoes to low concentrations of pyrethroid. PLoS One 6(9): e24968.
  • Blanford S., Shi W., Christian R, Marden, J.H., Koekemoer, L.L., Brooke, B.D., Coetzee, M., Read, A.F. & Thomas, M.B. (2011). Lethal and pre-lethal effects of a fungal biopesticide contribute to substantial and rapid control of malaria vectors. PLoS One 6(8): e23591.
  • George J., Blanford, S., Domingue, M.J., Thomas, M.B., Read, A.F. & Baker T.C. (2011). Reduction in host-finding behaviour in fungus-infected mosquitoes is correlated with reduction in olfactory receptor neuron responsiveness. Malaria Journal 10:219.
  • Darbro,J.M, Graham,R.I., Kay,B.H., Ryan,P.A. & Thomas,M.B. (2011). Evaluation of entomopathogenic fungi as potential biological control agents of the dengue mosquito, Aedes aegypti (Diptera: Culicidae). Biocontrol Science and Technology 21: 1027-1047.
  • Farenhorst, M., Hilhorst, A., Thomas, M.B. & Knols, B.G.J. (2011). Development of fungal applications on netting substrates for malaria vector control. Journal of Medical Entomology 48: 305-313.
  • Howard, A.F.V., N’Guessan, R. Koenraadt, C.J.M, Asidi, A., Farenhorst, M., Akogbéto, M., Thomas, MB, Knols, B.G.J. & Takken, W. (2010). The entomopathogenic fungus Beauveria bassiana reduces instantaneous blood feeding in wild multi-insecticide-resistant Culex quinquefasciatus mosquitoes in Benin, West Africa. Parasites & Vectors 3:87.
  • Farenhorst, M., Knols, B.G.J., Thomas, M.B., Howard, A.F.V., Takken, W., Rowland, M. & N’Guessan R. (2010). Synergy in efficacy of fungal entomopathogens and permethrin against West African insecticide-resistant Anopheles gambiae mosquitoes. PLoS One 5(8): e12081.
  • Kikankie, C.K., Brooke, B.D., Knols, B.G.J., Koekemoer, L.L., Farenhorst, M., Hunt, R.H., Thomas, M.B. & Coetzee, M. (2010). The infectivity of the entomopathogenic fungus Beauveria bassiana to insecticide-resistant and susceptible Anopheles arabiensis mosquitoes at two different temperatures. Malaria Journal 9:71.
  • Koella, J.C., Lynch, P.A., Thomas, M.B. & Read, A.F. (2009). Towards evolution-proof malaria control with insecticides. Evolutionary Applications 2: 469-480.
  • Farenhorst, M., Mouatcho, J.C., Kikankie, C.K., Brooke, B.D., Hunt, R.H., Thomas, M.B., Koekemoer, L.L., Knols, B.G.J. & Coetzee, M. (2009). Fungal infection counters insecticide resistance in African malaria mosquitoes. Proceedings of the National Academy of Sciences 106: 17443–17447.
  • Darbro, J., & Thomas, M.B. (2009). Spore persistence and likely aeroallergenicity of entomopathogenic fungi used for mosquito control. American Journal of Tropical Medicine and Hygiene 80: 992-997.
  • Blanford, S., Read, A.F. & Thomas, M.B. (2009). Thermal behaviour of Anopheles stephensi in response to infection with malaria and fungal entomopathogens. Malaria Journal 8:71.
  • Read, A.F., Lynch, P.A. & Thomas, M.B. (2009). How to make evolution-proof insecticides for malaria control. PLoS Biology 7(4).
  • Bell, A.S., Blanford, S., Jenkins, N.E., Thomas, M.B. & Read, A.F. (2009). Real-time quantitative PCR for analysis of candidate fungal biopesticides against malaria: technique validation and first applications. Journal of Invertebrate Pathology 100: 160-169.
  • Hancock, P.A., Thomas, M.B., Godfray, H.C.J. (2009). An age-structured model to evaluate the potential of novel malaria-control interventions: a case study of fungal biopesticide sprays. Proceedings of the Royal Society of London B 276: 71-80.
  • Thomas, M.B. & Read, A.F. (2007). Can fungal biopesticides control malaria? Nature Reviews Microbiology 5: 377-383.
  • Blanford, S., Chan, B.H.K., Jenkins, N.E., Sim, D., Turner, R.J., Read, A.F. & Thomas, M.B. (2005). Fungal pathogen reduces potential for malaria transmission. Science 308: 1638-1641.