Aedes aegypti Shows Increased Susceptibility to Zika Virus via Both In Vitro and In Vivo Models of Type II Diabetes

Abstract

Chronic conditions like type II diabetes (T2DM) have long been known to exacerbate many infectious diseases. For many arboviruses, including Zika virus (ZIKV), severe outcomes, morbidity and mortality usually only occur in patients with such pre-existing conditions. However, the effects of T2DM and other pre-existing conditions on human blood (e.g., hypo/hyperinsulinemia, hyperglycemia and hyperlipidemia) that may impact infectivity of arboviruses for vectors is largely unexplored. We investigated whether the susceptibility of Aedes aegypti mosquitoes was affected when the mosquitoes fed on “diabetic” bloodmeals, such as bloodmeals composed of artificially glycosylated erythrocytes or those from viremic, diabetic mice (LEPRDB/DB). Increasing glycosylation of erythrocytes from hemoglobin A1c (HgbA1c) values of 5.5–5.9 to 6.2 increased the infection rate of a Galveston, Texas strain of Ae. aegypti to ZIKV strain PRVABC59 at a bloodmeal titer of 4.14 log10 FFU/mL from 0.0 to 40.9 and 42.9%, respectively. ZIKV was present in the blood of viremic LEPRDB/DB mice at similar levels as isogenic control C57BL/6J mice (3.3 log10 FFU/mL and 3.6 log10 FFU/mL, respectively. When mice sustained a higher ZIKV viremia of 4.6 log10 FFU/mL, LEPRDB/DB mice infected 36.3% of mosquitoes while control C57BL/6J mice with a viremia of 4.2 log10 FFU/mL infected only 4.1%. Additionally, when highly susceptible Ae. aegypti Rockefeller mosquitoes fed on homozygous LEPRDB/DB, heterozygous LEPRWT/DB, and control C57BL/6J mice with viremias of ≈ 4 log10 FFU/mL, 54%, 15%, and 33% were infected, respectively. In total, these data suggest that the prevalence of T2DM in a population may have a significant impact on ZIKV transmission and indicates the need for further investigation of the impacts of pre-existing metabolic conditions on arbovirus transmission.

Diabetes mellitus as a risk factor for severe dengue fever and West Nile fever: A meta-analysis

“…In addition to dengue and WNF, several studies have shown the effect of DM on Zika virus disease, Japanese encephalitis, and yellow fever. Azar et al demonstrated increased susceptibility of Aedes aegypti that fed on “diabetic” bloodmeals to ZIKV by in vitro and in vivo modeling of type II DM and suggested that the prevalence of type II DM in the population may have a significant impact on ZIKV transmission [ 76 ]. Ahlers et al showed that mammalian insulin can trigger AKT and ERK signaling in mosquitoes, leading to the transcription of JAK/STAT-associated antiviral genes [ 77 ].…”

“…In DM subjects, this increase was significantly lower ( P = 0.025) [ 80 ]. Based on these reports, DM can be shown to increase the risk of adverse outcomes of mosquito-borne flavivirus infection [ 14 , 76 , 80 ].…”

Viral infection and host immune response in diabetes

“…In this section, we enlist some literature focusing on ZIKV, WNV, and JEV. Scanty reports exist of increased infectivity of ZIKV in Aedes aegypti mosquitoes who had their blood meals on Type 2 diabetic mice 178 but this study has not been extended to human subjects or a possible reverse link has not been established. ZIKV is known to alter host metabolic signaling cascades, as shown by a Drosophila ‐based study whereby suppression of insulin receptors promoted fly susceptibility to ZIKV infection 179 .…”

CD8+T cell response promotes viral clearance and reduces chances of severe testicular damage in mouse models of long-term Zika virus infection of the testes

“…ZIKV PRVABC59 was received from the World Reference Center for Emerging Viruses and Arboviruses, UTMB (WRCEVA) at Vero passage 4. The virus underwent two additional Vero cell passages to generate the stocks utilized in these studies, as previously described 41 .…”