Protective Vaccination of Mice Against Blood-Stage Malaria Impacts Hepatic Expression of Genes Encoding Acute-Phase Proteins and IL-6 Family Members

In response to vaccination and/or infectious agents, the liver produces acute-phase proteins (APPs) driven by IL-6, which circulate in blood plasma as components of the humoral innate defense. This study investigates the liver of mice for possible effects of protective vaccination against primary blood-stage infections of <i>Plasmodium chabaudi</i> malaria on the expression of genes encoding APPs and IL-6 family members. Female Balb/c mice were vaccinated with a non-infectious vaccine prior to challenge with 10⁶<i>P. chabaudi-</i>infected erythrocytes, resulting in about 80% survival of otherwise lethal infections. Gene expression microarrays were used to determine the relative transcript levels of genes in the livers of vaccinated and unvaccinated mice on days 0, 1, 4, 8, and 11 <i>p.i.</i> (<i>post infectionem</i>). Vaccination induced significant (<i>p</i>-value < 0.05) differences in the expression of malaria-responsive genes toward the end of crisis on day 11 <i>p.i.</i>, when mice recovered from infections. These genes include <i>Saa4</i>, <i>Apcs</i>, <i>Cp</i>, and <i>Crp</i>, encoding APPs described to inhibitorily interact with parasitic blood stages; the genes <i>F2</i>, <i>F7</i>, <i>F8</i>, <i>F9</i>, <i>F10</i>, and <i>F13b</i>, and <i>Plg</i>, <i>Plat</i>, and <i>Serpina5</i>, encoding proteins balancing coagulation vs. fibrinolysis dysregulated by malaria, respectively; the genes <i>Hc</i>, <i>C8a</i>, <i>C8b</i>, <i>C8g</i>, and <i>C9</i>, encoding components of lytic complement membrane attack complex (MAC); and <i>Cfh</i>, <i>Cfi</i>, and <i>C4bp</i>, encoding complement-regulatory proteins. Vaccination accelerated, albeit differently, the malaria-induced activation of all three complement pathways, evidenced as higher transcript levels of <i>C1qa</i>, <i>C1qb</i>, <i>C1qc</i>, <i>Fcna</i>, <i>Cfp</i>, <i>C3</i>, <i>Cfh</i>, <i>C8a</i>, and <i>C9</i> on day 4 <i>p.i.</i>, <i>C1ra</i>, <i>C1s</i>, and <i>C2</i> on day 1 <i>p.i.</i>, and <i>Serping1</i>, encoding the multifunctional protease inhibitor C1INH, on day 0 <i>p.i.</i> Protective vaccination may also accelerate downregulation of the malaria-promoting lethality of IL-6 trans-signaling, which may contribute to an overall accelerated recovery of mice from otherwise lethal blood-stage malaria.