Animal models of microbial infection

The innate immune response provides the first line of defense against pathogens by responding to foreign molecules within the cell that are a signature of pathogenic infection, such as cyclic dinucleotides, cytosolic DNA or double-stranded RNA, by-products of bacterial and viral infections.  Forward genetic screens help identify candidate genes which may be essential for an immune response.  Upon identification, reverse genetics can be used to mutate the identified gene and determine if the mutant protein results in loss-of-function.

Using a knockout mouse model, we found that P58IPK (Goodman et al., 2009):

  1. Benefitted the host during influenza virus infection by protecting it from a lethal “cytokine storm,” or a hyperactive inflammatory response. 

  2. Reduced lung pathology and prolonged survival. 

  3. Enhanced the virus’ capacity to replicate in a longer-surviving host through its inhibition of PKR.

 

Translating what was already known about STING (stimulator of interferon genes) in mammalian models, we found that STING function is evolutionarily conserved in Drosophila and even retains its function in the mammalian system.  By generating a loss-of-function STING mutant in the fly, we showed that the protein initiates a cyclic dinucleotide-mediated immune response during bacterial infection (Martin and Hiroyasu et al., 2018).

Using a genetic screening approach, we identified insulin signaling as an important mechanism for an immune response to West Nile virus infection in flies.  We used this information to design experiments in vector mosquitoes and show that insulin signaling reduced West Nile virus infection in adult Culex quinquefasciatus via an Akt-ERK-JAK/Stat signaling axis that was independent of anti-viral RNA interference activity (Ahlers et al., 2019).

Our goal to use the Drosophila model to study pathogenic infections is multi-faceted. The use of a genetically and physiologically tractable model system allows for types of experimentation that cannot easily be performed in mammals, but the results can be extrapolated to form new hypotheses for experimentation in mammals and lead to therapeutics for microbial and vector-borne disease.

 

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