Vector Immunity and Evolutionary Ecology: The Harmonious Dissonance

Abstract

Recent scientific breakthroughs have significantly expanded our understanding of arthropod vector immunity. Insights in the laboratory have demonstrated how the immune system provides resistance to infection, and in what manner innate defenses protect against a microbial assault. Less understood, however, is the effect of biotic and abiotic factors on microbial-vector interactions and the impact of the immune system on arthropod populations in nature. Furthermore, the influence of genetic plasticity on the immune response against vector-borne pathogens remains mostly elusive. Herein, we discuss evolutionary forces that shape arthropod vector immunity. We focus on resistance, pathogenicity and tolerance to infection. We posit that novel scientific paradigms should emerge when molecular immunologists and evolutionary ecologists work together.

Figure 1.. Arthropod immune signaling pathways.

The Immune Deficiency (IMD) pathway responds to DAP-type peptidoglycan (DAP-PGN) from mostly Gram-negative bacteria. DAP-type PGNs are recognized by transmembrane peptidoglycan-recognition proteins (PGRPs), leading to the translocation of the nuclear factor (NF)-κB-like factor, Relish, to the nucleus and upregulation of antimicrobial peptides (AMPs) [52]. AMPs are small cationic, amphipathic peptides that kill invading microbes by disrupting the pathogen membrane [6]. The Toll pathway responds to lysine-type peptidoglycan from Gram-positive bacteria and β-glucans from fungi. Recognition leads to a proteolytic cascade that cleaves the endogenous cytokine-like protein, Spätzle (Sptz). Spätzle binds to the Toll receptor, causing the translocation of NF-κB-like factor Dorsal (or Dif) to the nucleus and the expression of AMPs [9]. The janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway responds to the endogenous cytokine unpaired (Upd) that is secreted by hemocytes in response to infection. Binding of unpaired to the Dome receptor leads to dimerization and translocation of STAT to the nucleus and production of AMPs [112]. The RNA interference (RNAi) pathway recognizes double-stranded RNA (dsRNA) derived from invading viruses. dsRNA is cleaved by Dicer and then loaded onto the RNA-induced silencing complex (RISC). The small interfering (siRNA)-RISC complex induces an anti-viral state by binding to complementary RNAs through base-pairing, causing cleavage and degradation of viral RNA [113, 114]. Excellent reviews discuss these mechanistic processes elsewhere [7, 9, 112, 114, 115].

Figure 2.. Resistance and tolerance to infection in arthropod vectors.

Two vectors from populations that differ in their tolerance to microbes will have the same fitness, proxied by survival and reproduction, at different microbe densities. Thus, the less tolerant mosquito (orange) needs to invest more in resistance to maintain that level of fitness relative to the more tolerant vector (blue). Higher tolerance can facilitate greater transmission through allowing more microbes to persist for longer, and/or muting the effects of pathogenicity on host survival, lengthening the transmission period. Circles highlight the placement, in microbe density by fitness space, of the two vectors pictured above.

Figure 3.. Contextual pathogenicity in arthropod-borne pathogens.

When microbes transmitted by arthropods cause disease in humans, they are often referred to as pathogens. Biotic and abiotic factors determine whether the microbe is virulent to arthropods. For instance, Anaplasma phagocytophilum and Borrelia burgdorferi likely play an important role in tick immune education and fitness [–46]. Conversely, the tick bite favors a more pathogenic role upon microbial transmission because of the different genetic landscape and the host immune status. These considerations underwrite contextual pathogenicity, where microbes that humans often consider virulent, may not be harmful to arthropod vectors.

Figure 4.. Molecular mechanisms of trained immunity.

Innate immunity can induce immunological memory through mechanisms that are distinct from adaptive processes. Training the immune response results in a shift from oxidative phosphorylation (OxPhos) to glycolysis to rapidly produce energy in the form of adenosine triphosphate (ATP). This metabolic shift may remain active for several days within the cell after the stimulus has been removed or cleared. Metabolic shifts induce epigenetic changes to alter expression of targeted genes. Common epigenetic marks associated with trained immunity are trimethylation (me3) and acetylation (ac) events on lysine 4 and 27 of histone 3 [21, 60, 71, 116]