GIVE

Dr. Derrick Mathias

Assistant Professor

Research Interests

Transmission cycles of vector-borne pathogens and parasites are complex and involve biological processes that occur at multiple scales, ranging from molecular interactions at the sub-cellular level to organismal interactions at the ecosystem level. For mosquito-borne agents, for example, successful transmission requires the presence and frequent interaction of both competent mosquitoes and competent hosts. For both types of organisms, competence further requires permissive immune systems and the ability of pathogens or parasites to infect specific cell types and develop (e.g., Plasmodium parasites) and/or replicate (e.g., arboviruses) as the case may be. On the vector side, competence is influenced by genetics of the vector, genetics of the pathogen or parasite, and non-genetic factors, which may be partitioned into internal (e.g., microbiota) and external (e.g., ambient temperature) factors.

Within the vector, competence-determining factors may be investigated by physiological compartment. For most mosquito-borne diseases, the causal agent enters the midgut lumen in a blood meal and gets transmitted horizontally to new hosts through saliva. For the agent to get from point A to B, it must negotiate a series of physiological barriers in the mosquito, which at a minimum include (i) infection of the midgut epithelium, (iii) replication and escape into the hemocoel (i.e., open circulatory system), (iii) infection of the salivary gland epithelium, and (iv) escape from salivary gland cells into the secretory cavity. My research program focuses on factors that cause variation in vector competence to address the question of why some blood-feeding insects and ticks are competent for a given agent, while others are not. Variation in vector competence is most pronounced between species or higher taxa (e.g., only anopheline mosquitoes transmit parasites that cause human malaria but rarely transmit arboviruses) but also occurs at the sub-species level within and between populations. My long-term objective is to use tools of molecular and evolutionary biology to tease apart genetic and non-genetic determinants of vector competence within populations and examine the extent to which competence-determining mechanisms are shared across vector-borne disease systems. Inherent in this strategy is the belief that investigating basic biology will yield insights that may be exploited to interrupt transmission cycles and control or prevent disease.

My lab primarily focuses mosquito-borne diseases, malaria in particular, but has begun to investigate arboviruses either endemic to the southeastern U.S. (epizootic hemorrhagic disease virus in white-tailed deer) or pose an imminent threat (Zika virus). For each disease system of interest I am asking a variety of questions that includes the list below.

 

Malaria:

  • Which molecules expressed on the Anopheles midgut surface are involved in Plasmodium infection of midgut epithelial cells? How conserved are these molecules among competent anopheline species? What role do they play in limiting competence among mosquito species compared to the innate immune response? Can the infection process be inhibited by antibodies or small molecules co-ingested in a blood meal that target vector-parasite interactions?
  • How are refractory phenotypes (i.e., resistant to parasite infection) genetically constructed in natural mosquito populations? How plastic are these phenotypes under various environmental conditions? How plastic are they for various strains and species of Plasmodium?
  • Does refractoriness to Plasmodium infection confer refractoriness to other parasites (e.g., filarial worms)?

 

Epizootic hemorrhagic disease:

  • Surveillance data on epizootic hemorrhagic disease virus (EHDV) and its potential vectors suggest that biting midge (family Ceratopogonidae) species other than Culicoides sonorensis are vectors of EHDV in the Southeast. Which of the Culicoides species native to the Southeast contribute to virus transmission?
  • Which molecules expressed on the Culicoides midgut surface are involved in virus infection of epithelial cells via endocytosis? How conserved are these molecules among competent ceratopogonid species? Can this process be inhibited by antibodies or small molecules co-ingested in a blood meal?

 

Zika virus:

  • Published studies of vector competence indicate that geographic origin of vector and virus strongly influence rates of dissemination and transmission. Which genes in the vector most influence competence for a given strain?
  • Like most mosquito-borne viruses, Zika virus has a single-stranded RNA genome with a relatively high mutation rate. Comparisons of strains from Africa and the Americas reveal divergence on the order of 10% at the nucleotide level and 4% at the amino acid level. How has this divergence influenced vector competence for North American mosquitoes? Can we identify amino acid substitutions in the genome that promote or limit adaptation to local vector populations?
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