Michael A Riehle

Interests

Research

Mosquito Biology;Vector-borne diseases;Malaria;Dengue;Zika;Longevity;Mitochondria;Mitochondrial dynamics;Mitochondrial biogenesis

Teaching

Medical and Veterinary Entomology;Insect Physiology

Courses

Scholarly Contributions

Journals/Publications

• Riehle, M. A., Carriere, Y., Gouge, D. H., Ernst, K. C., Walker, K. R., Madera Garcia, V., Brophy, M., Nair, S., Li, S., Williamson, D., Arnbrister, J., Chen, M., & Joy, T. (2022). Assessing near-infrared spectrophotometry (NIRS) for evaluation of Aedes aegypti population age structure in Arizona. Insects, 13(4), 360. doi:https://doi.org/10.3390/insects13040360
• Hun, L. V., Cheung, K. W., Brooks, E., Zudekoff, R., Luckhart, S., & Riehle, M. A. (2021). Increased insulin signaling in the Anopheles stephensi fat body regulates metabolism and enhances the host response to both bacterial challenge and Plasmodium falciparum infection. Insect biochemistry and molecular biology, 139, 103669.
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  In vertebrates and invertebrates, the insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) cascade is highly conserved and plays a vital role in many different physiological processes. Among the many tissues that respond to IIS in mosquitoes, the fat body has a central role in metabolism, lifespan, reproduction, and innate immunity. We previously demonstrated that fat body specific expression of active Akt, a key IIS signaling molecule, in adult Anopheles stephensi and Aedes aegypti activated the IIS cascade and extended lifespan. Additionally, we found that transgenic females produced more vitellogenin (Vg) protein than non-transgenic mosquitoes, although this did not translate into increased fecundity. These results prompted us to further examine how IIS impacts immunity, metabolism, growth and development of these transgenic mosquitoes. We observed significant changes in glycogen, trehalose, triglycerides, glucose, and protein in young (3-5 d) transgenic mosquitoes relative to non-transgenic sibling controls, while only triglycerides were significantly changed in older (18 d) transgenic mosquitoes. More importantly, we demonstrated that enhanced fat body IIS decreased both the prevalence and intensity of Plasmodium falciparum infection in transgenic An. stephensi. Additionally, challenging transgenic An. stephensi with Gram-positive and Gram-negative bacteria altered the expression of several antimicrobial peptides (AMPs) and two anti-Plasmodium genes, nitric oxide synthase (NOS) and thioester complement-like protein (TEP1), relative to non-transgenic controls. Increased IIS in the fat body of adult female An. stephensi had little to no impact on body size, growth or development of progeny from transgenic mosquitoes relative to non-transgenic controls. This study both confirms and expands our understanding of the critical roles insulin signaling plays in regulating the diverse functions of the mosquito fat body.
• Oringanje, C., Delacruz, L. R., Han, Y., Luckhart, S., & Riehle, M. A. (2021). Overexpression of Activated AMPK in the Midgut Impacts Mosquito Metabolism, Reproduction and Resistance. Genes, 12(1).
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  Mitochondrial integrity and homeostasis in the midgut are key factors controlling mosquito fitness and anti-pathogen resistance. Targeting genes that regulate mitochondrial dynamics represents a potential strategy for limiting mosquito-borne diseases. AMP-activated protein kinase (AMPK) is a key cellular energy sensor found in nearly all eukaryotic cells. When activated, AMPK inhibits anabolic pathways that consume ATP and activates catabolic processes that synthesize ATP. In this study, we overexpressed a truncated and constitutively active α-subunit of AMPK under the control of the midgut-specific carboxypeptidase promotor in the midgut of female . As expected, AMPK overexpression in homozygous transgenic mosquitoes was associated with changes in nutrient storage and metabolism, decreasing glycogen levels at 24 h post-blood feeding when transgene expression was maximal, and concurrently increasing circulating trehalose at the same time point. When transgenic lines were challenged with , we observed a significant decrease in the prevalence and intensity of infection relative to wild type controls. Surprisingly, we did not observe a significant difference in the survival of adult mosquitoes fed either sugar only or both sugar and bloodmeals throughout adult life. This may be due to the limited period that the transgene was activated before homeostasis was restored. However, we did observe a significant decrease in egg production, suggesting that manipulation of AMPK activity in the mosquito midgut resulted in the re-allocation of resources away from egg production. In summary, this work identifies midgut AMPK activity as an important regulator of metabolism, reproduction, and innate immunity in , a highly invasive and important malaria vector species.
• Simão-Gurge, R. M., Thakre, N., Strickland, J., Isoe, J., Delacruz, L. R., Torrevillas, B. K., Rodriguez, A. M., Riehle, M. A., & Luckhart, S. (2021). Activation of Pantothenate Kinase and Coenzyme A Biosynthesis Reduces Infection with Diverse Species in the Mosquito Host. Biomolecules, 11(6).
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  Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite and the mouse parasite 17XNL. We identified two putative PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC doses to examine the effects of manipulating PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both species. This work establishes the CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria.
• Comeau, G., Zinna, R. A., Scott, T., Ernst, K., Walker, K., Carrière, Y., & Riehle, M. A. (2020). Vertical Transmission of Zika Virus in Produces Potentially Infectious Progeny. The American journal of tropical medicine and hygiene, 103(2), 876-883.
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  Vertical transmission, or pathogen transfer from female to offspring, can facilitate the persistence of emerging arboviruses, such as Zika virus (ZIKV), through periods of low horizontal transmission or adverse environmental conditions. We aimed at determining the rate of vertical transmission for ZIKV in its principal vector, , and the vector competence of vertically infected progeny. females that consumed a blood meal provisioned with ZIKV were maintained under three temperature conditions (27°C, 30°C, and 33°C) following the infectious blood meal and allowed to complete three reproductive cycles. The overall vertical transmission rate was 6.5% (95% CI = 3.9-9.9). Vertical transmission of ZIKV was observed across all temperature conditions and virus detected in adult progeny up to 2 weeks postemergence. In total, 3.4% (95% CI = 1.6-6.2) of adult progeny produced saliva with ZIKV, indicating their vector competence. These results suggest the virus may be maintained in populations without a vertebrate host for short periods.
• Jeffrey Gutierrez, E., Walker, K. R., Ernst, K. C., Riehle, M. A., & Davidowitz, G. (2020). Size as a Proxy for Longevity in Aedes aegypti (Diptera: Culicidae) Mosquitoe. Journal of Medical Entomology, 57, 1228-1238.
• Jeffrey Gutiérrez, E. H., Walker, K. R., Ernst, K. C., Riehle, M. A., & Davidowitz, G. (2020). Size as a Proxy for Survival in Aedes aegypti (Diptera: Culicidae) Mosquitoes. Journal of medical entomology, 57(4), 1228-1238.
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  The Aedes aegypti mosquito is the primary vector of dengue, yellow fever, chikungunya, and Zika viruses. Infection with the dengue virus alone occurs in an estimated 400 million people each year. Likelihood of infection with a virus transmitted by Ae. aegypti is most commonly attributed to abundance of the mosquito. However, the Arizona-Sonora desert region has abundant Ae. aegypti in most urban areas, yet local transmission of these arboviruses has not been reported in many of these cities. Previous work examined the role of differential Ae. aegypti longevity as a potential explanation for these discrepancies in transmission. To determine factors that were associated with Ae. aegypti longevity in the region, we collected eggs from ovitraps in Tucson, AZ and reared them under multiple experimental conditions in the laboratory to examine the relative impact of temperature and crowding during development, body size, fecundity, and relative humidity during the adult stage. Of the variables studied, we found that the combination of temperature during development, relative humidity, and body size produced the best model to explain variation in age at death. El mosquito Aedes aegypti es el vector primario de los virus de dengue, fiebre amarilla, chikungunya y Zika. Solamente las infecciones con los virus de dengue ocurren en aproximadamente 400 millones de personas cada año. La probabilidad de infección con un virus transmitido por Ae. aegypti es frecuentemente atribuido a la abundancia del mosquito. No obstante, la región del desierto de Arizona-Sonora tiene una abundancia de Ae. aegypti en la mayoría de las áreas urbanas, pero la transmisión local de estos arbovirus no ha sido reportada en muchas de estas ciudades. Trabajos previos han examinado el rol de las diferencias de longevidad en Ae. aegypti como explicación potencial por estas discrepancias en la transmisión. Para determinar que factores fueron asociados con longevidad en Ae. aegypti en la región, colectamos huevos de ovitrampas en Tucson, Arizona y los criamos debajo de múltiples condiciones experimentales en el laboratorio para examinar el impacto relativo de temperatura y competencia para nutrición durante desarrollo, tamaño del cuerpo, capacidad reproductiva, y humedad relativa durante adultez. De las variables estudiados, encontramos que la combinación de temperatura durante desarrollo, humedad relativa, y tamaño del cuerpo produjo el mejor modelo para explicar variación en edad al tiempo de la muerte.
• Luckhart, S., & Riehle, M. A. (2020). Midgut Mitochondrial Function as a Gatekeeper for Malaria Parasite Infection and Development in the Mosquito Host. Frontiers in cellular and infection microbiology, 10, 593159.
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  Across diverse organisms, various physiologies are profoundly regulated by mitochondrial function, which is defined by mitochondrial fusion, biogenesis, oxidative phosphorylation (OXPHOS), and mitophagy. Based on our data and significant published studies from , and mammals, we propose that midgut mitochondria control midgut health and the health of other tissues in vector mosquitoes. Specifically, we argue that trade-offs among resistance to infection, metabolism, lifespan, and reproduction in vector mosquitoes are fundamentally controlled both locally and systemically by midgut mitochondrial function.
• Riehle, M. A., Walker, K. R., Ernst, K. C., Carriere, Y., Zinna, R., & Comeau, G. (2020). Impact of Zika virus vertical transmission in the mosquito Aedes aegypti. American Journal of Tropical Medicine and Hygiene, 103(2), 876-883. doi:10.4269/ajtmh.19-0698
• Hun, L. V., Luckhart, S., & Riehle, M. A. (2019). Increased Akt signaling in the fat body of Anopheles stephensi extends lifespan and increases lifetime fecundity through modulation of insulin-like peptides. Journal of insect physiology, 118, 103932.
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  Insulin-like peptides (ILPs) and the insulin/insulin-like growth factor 1 signaling (IIS) cascade regulate numerous physiological functions, including lifespan, reproduction, immunity, and metabolism, in diverse eukaryotes. We previously demonstrated that in female Anopheles stephensi and Aedes aegypti mosquitoes, activation of the IIS cascade in the fat body led to a significant increase in lifespan. In this work, we elucidated two putative mechanisms in A. stephensi behind the observed lifespan extension and assessed whether this lifespan extension confers an overall fitness advantage to the mosquito. Specifically, we demonstrated that increased Akt signaling in the mosquito fat body following a blood meal significantly suppressed the expression of ILP2 in the head. Moreover, overexpression of active Akt in the fat body altered the expression of a putative insulin binding protein ortholog, Imaginal morphogenesis protein-Late 2 (Imp-L2), in response to transgene expression. Combined, these two factors may act to reduce overall levels of circulating ILP2 or other ILPs in the mosquito, in turn conferring increased survival. We also examined the impact increased fat body IIS had on lifetime fecundity and demonstrated that transgenic female mosquito populations had higher lifetime fecundity relative to non-transgenic sibling controls. These studies provide new insights into the complex hormonal and molecular mechanisms regulating the interplay between IIS, aging, and reproduction in this important vector of human malaria parasites.
• Hun, L., Luckhart, S., & Riehle, M. A. (2019). Increased insulin signaling in the fat body of Anopheles stephensi mosquitoes extends lifespan through modulation of Insulin-like Peptides (ILP) expression leading to increased lifetime fecundity.. Insect Molecular Biology.
• Souvannaseng, L., Hun, L. V., Baker, H., Klyver, J. M., Wang, B., Pakpour, N., Bridgewater, J. M., Napoli, E., Giulivi, C., Riehle, M. A., & Luckhart, S. (2018). Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection. PLoS pathogens, 14(11), e1007418.
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  Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.
• Souvannaseng, L., Hun, L. V., Baker, H., Klyver, J., Pakpour, N., Bridgewater, J., Giulivi, C., Riehle, M. A., & Luckhart, S. (2018). Moderate inhibition of JNK extends longevity and improves resistance to Plasmodium falciparum infection in the Asian malaria vector Anopheles stephensi. PLoS Pathogens.
• Ernst, K. C., Walker, K. R., Reyes-Castro, P., Joy, T. K., Castro-Luque, A. L., Diaz-Caravantes, R. E., Gameros, M., Haenchen, S., Hayden, M. H., Monaghan, A., Jeffrey-Guttierez, E., Carrière, Y., & Riehle, M. R. (2017). Aedes aegypti (Diptera: Culicidae) Longevity and Differential Emergence of Dengue Fever in Two Cities in Sonora, Mexico. Journal of medical entomology.
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  Dengue virus, primarily transmitted by the Aedes aegypti (L.) mosquito, has rapidly expanded in geographic extent over the past several decades. In some areas, however, dengue fever has not emerged despite established Ae. aegypti populations. The reasons for this are unclear and have sometimes been attributed to socio-economic differences. In 2013 we compared Ae. aegypti adult density and population age structure between two cities in Sonora, Mexico: Hermosillo, which has regular seasonal dengue virus transmission, and Nogales, which has minimal transmission. Larval and pupal abundance was greater in Nogales, and adult density was only higher in Hermosillo during September. Population age structure, however, was consistently older in Hermosillo. This difference in longevity may have been one factor that limited dengue virus transmission in Nogales in 2013, as a smaller proportion of Ae. aegypti females survived past the extrinsic incubation period.
• Ernst, K. C., Walker, K. R., Reyes-Castro, P., Joy, T. K., Castro-Luque, A. L., Diaz-Caravantes, R., Gameros, M., Haenchen, S., Hayden, M., Monaghan, A., Jeffrey Guttierez, E., Carriere, Y., & Riehle, M. A. (2016). Aedes aegypti (Diptera: Culicidae) Longevity and Differential Emergence of Dengue Fever in Two Cities in Sonora, Mexico. Journal of Medical Entomology.
• Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., Adhihetty, P. J., Adler, S. G., Agam, G., Agarwal, R., Aghi, M. K., Agnello, M., Agostinis, P., Aguilar, P. V., Aguirre-Ghiso, J., , Airoldi, E. M., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1-222.
• Pietri, J. E., Pakpour, N., Napoli, E., Song, G., Pietri, E., Potts, R., Cheung, K. W., Walker, G., Riehle, M. A., Starcevich, H., Giulivi, C., Lewis, E. E., & Luckhart, S. (2016). Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism. The Biochemical journal, 473(20), 3487-3503.
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  Insulin-like peptides (ILPs) play important roles in growth and metabolic homeostasis, but have also emerged as key regulators of stress responses and immunity in a variety of vertebrates and invertebrates. Furthermore, a growing literature suggests that insulin signaling-dependent metabolic provisioning can influence host responses to infection and affect infection outcomes. In line with these studies, we previously showed that knockdown of either of two closely related, infection-induced ILPs, ILP3 and ILP4, in the mosquito Anopheles stephensi decreased infection with the human malaria parasite Plasmodium falciparum through kinetically distinct effects on parasite death. However, the precise mechanisms by which ILP3 and ILP4 control the response to infection remained unknown. To address this knowledge gap, we used a complementary approach of direct ILP supplementation into the blood meal to further define ILP-specific effects on mosquito biology and parasite infection. Notably, we observed that feeding resulted in differential effects of ILP3 and ILP4 on blood-feeding behavior and P. falciparum development. These effects depended on ILP-specific regulation of intermediary metabolism in the mosquito midgut, suggesting a major contribution of ILP-dependent metabolic shifts to the regulation of infection resistance and parasite transmission. Accordingly, our data implicate endogenous ILP signaling in balancing intermediary metabolism for the host response to infection, affirming this emerging tenet in host-pathogen interactions with novel insights from a system of significant public health importance.
• Arik, A. J., Hun, L. V., Quicke, K., Piatt, M., Ziegler, R., Scaraffia, P. Y., Badgandi, H., & Riehle, M. A. (2015). Increased Akt signaling in the mosquito fat body increases adult survivorship. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 29(4), 1404-13.
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  Akt signaling regulates diverse physiologies in a wide range of organisms. We examine the impact of increased Akt signaling in the fat body of 2 mosquito species, the Asian malaria mosquito Anopheles stephensi and the yellow fever mosquito Aedes aegypti. Overexpression of a myristoylated and active form of A. stephensi and Ae. aegypti Akt in the fat body of transgenic mosquitoes led to activation of the downstream signaling molecules forkhead box O (FOXO) and p70 S6 kinase in a tissue and blood meal-specific manner. In both species, increased Akt signaling in the fat body after blood feeding significantly increased adult survivorship relative to nontransgenic sibling controls. In A. stephensi, survivorship was increased by 15% to 45%, while in Ae. aegypti, it increased 14% to 47%. Transgenic mosquitoes fed only sugar, and thus not expressing active Akt, had no significant difference in survivorship relative to nontransgenic siblings. Expression of active Akt also increased expression of fat body vitellogenin, but the number of viable eggs did not differ significantly between transgenic and nontransgenic controls. This work demonstrates a novel mechanism of enhanced survivorship through increased Akt signaling in the fat bodies of multiple mosquito genera and provides new tools to unlock the molecular underpinnings of aging in eukaryotic organisms.
• Johnson, A. A., & Riehle, M. A. (2015). Resveratrol Fails to Extend Life Span in the Mosquito Anopheles stephensi. Rejuvenation research, 18(5), 473-8.
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  Resveratrol, a plant polyphenol present in grape skins, has been theorized to account for the "French Paradox" by explaining how red wine may decrease the health risks associated with unhealthy diets. Resveratrol has been reported to extend life span in several different species. Other studies, however, have failed to find a resveratrol-induced life span effect. A recent meta-study analyzing previously published survival data concluded that, although resveratrol reliably and reproducibly extends life span in some species, its life span effects show diminished reliability in other organisms. The data are mixed, and it remains unclear how evolutionarily conserved resveratrol's effects on life span are. To gain further insight into this controversy, we studied the effects of various concentrations (200 μM, 100 μM, 50 μM, or 0 μM) of orally fed resveratrol on the life span of the mosquito Anopheles stephensi, an important vector of human malaria, under two different feeding treatments--sugar-fed only or sugar-fed with intermittent blood meals. Each treatment was repeated three times and both survivorship and mortality rates were analyzed for each replicate. For the majority of experiments, resveratrol failed to mediate a statistically significant effect on life span. Although there was one instance where resveratrol significantly increased life span, there were five other instances where resveratrol significantly decreased life span. We conclude from these data that, under normal conditions, resveratrol does not extend life span in A. stephensi.
• Neafsey, D. E., Waterhouse, R. M., Abai, M. R., Aganezov, S. S., Alekseyev, M. A., Allen, J. E., Amon, J., Arcà, B., Arensburger, P., Artemov, G., Assour, L. A., Basseri, H., Berlin, A., Birren, B. W., Blandin, S. A., Brockman, A. I., Burkot, T. R., Burt, A., Chan, C. S., , Chauve, C., et al. (2015). Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes. Science (New York, N.Y.), 347(6217), 1258522.
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  Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.
• Pietri, J. E., Pietri, E. J., Potts, R. A., Riehle, M. A., & Luckhart, S. (2015). Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.. Cellular Microbiology.
• Pietri, J. E., Pietri, E. J., Potts, R., Riehle, M. A., & Luckhart, S. (2015). Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi. Developmental and comparative immunology, 53(1), 134-44.
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  The insulin-like peptides (ILPs) and their respective signaling and regulatory pathways are highly conserved across phyla. In invertebrates, ILPs regulate diverse physiological processes, including metabolism, reproduction, behavior, and immunity. We previously reported that blood feeding alone induced minimal changes in ILP expression in Anopheles stephensi. However, ingestion of a blood meal containing human insulin or Plasmodium falciparum, which can mimic insulin signaling, leads to significant increases in ILP expression in the head and midgut, suggesting a potential role for AsILPs in the regulation of P. falciparum sporogonic development. Here, we show that soluble P. falciparum products, but not LPS or zymosan, directly induced AsILP expression in immortalized A. stephensi cells in vitro. Further, AsILP expression is dependent on signaling by the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3'-kinase (PI3K)/Akt branches of the insulin/insulin-like growth factor signaling (IIS) pathway. Inhibition of P. falciparum-induced ILPs in vivo decreased parasite development through kinetically distinct effects on mosquito innate immune responses. Specifically, knockdown of AsILP4 induced early expression of immune effector genes (1-6 h after infection), a pattern associated with significantly reduced parasite abundance prior to invasion of the midgut epithelium. In contrast, knockdown of AsILP3 increased later expression of the same genes (24 h after infection), a pattern that was associated with significantly reduced oocyst development. These data suggest that P. falciparum parasites alter the expression of mosquito AsILPs to dampen the immune response and facilitate their development in the mosquito vector.
• Drexler, A. L., Pietri, J. E., Pakpour, N., Hauck, E., Wang, B., Glennon, E. K., Georgis, M., Riehle, M. A., & Luckhart, S. (2014). Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi. PLoS pathogens, 10(6), e1004231.
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  Insulin and insulin-like growth factor signaling (IIS) regulates cell death, repair, autophagy, and renewal in response to stress, damage, and pathogen challenge. Therefore, IIS is fundamental to lifespan and disease resistance. Previously, we showed that insulin-like growth factor 1 (IGF1) within a physiologically relevant range (0.013-0.13 µM) in human blood reduced development of the human parasite Plasmodium falciparum in the Indian malaria mosquito Anopheles stephensi. Low IGF1 (0.013 µM) induced FOXO and p70S6K activation in the midgut and extended mosquito lifespan, whereas high IGF1 (0.13 µM) did not. In this study the physiological effects of low and high IGF1 were examined in detail to infer mechanisms for their dichotomous effects on mosquito resistance and lifespan. Following ingestion, low IGF1 induced phosphorylation of midgut c-Jun-N-terminal kinase (JNK), a critical regulator of epithelial homeostasis, but high IGF1 did not. Low and high IGF1 induced midgut mitochondrial reactive oxygen species (ROS) synthesis and nitric oxide (NO) synthase gene expression, responses which were necessary and sufficient to mediate IGF1 inhibition of P. falciparum development. However, increased ROS and apoptosis-associated caspase-3 activity returned to baseline levels following low IGF1 treatment, but were sustained with high IGF1 treatment and accompanied by aberrant expression of biomarkers for mitophagy, stem cell division and proliferation. Low IGF1-induced ROS are likely moderated by JNK-induced epithelial cytoprotection as well as p70S6K-mediated growth and inhibition of apoptosis over the lifetime of A. stephensi to facilitate midgut homeostasis and enhanced survivorship. Hence, mitochondrial integrity and homeostasis in the midgut, a key signaling center for IIS, can be targeted to coordinately optimize mosquito fitness and anti-pathogen resistance for improved control strategies for malaria and other vector-borne diseases.
• Jiang, X., Peery, A., Hall, A. B., Sharma, A., Chen, X. G., Waterhouse, R. M., Komissarov, A., Riehle, M. M., Shouche, Y., Sharakhova, M. V., Lawson, D., Pakpour, N., Arensburger, P., Davidson, V. L., Eiglmeier, K., Emrich, S., George, P., Kennedy, R. C., Mane, S. P., , Maslen, G., et al. (2014). Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi. Genome biology, 15(9), 459.
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  Anopheles stephensi is the key vector of malaria throughout the Indian subcontinent and Middle East and an emerging model for molecular and genetic studies of mosquito-parasite interactions. The type form of the species is responsible for the majority of urban malaria transmission across its range.
• Pakpour, N., Riehle, M. A., & Luckhart, S. (2014). Effects of ingested vertebrate-derived factors on insect immune responses. Current opinion in insect science, 3, 1-5.
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  During the process of blood feeding insect vectors are exposed to an array of vertebrate-derived blood factors ranging from byproducts of blood meal digestion to naturally occurring products in the blood including growth hormones, cytokines and factors derived from blood-borne pathogens themselves. In this review, we examine the ability of these ingested vertebrate blood factors to alter the innate pathogen defenses of insect vectors. The ability of these factors to modify the immune responses of insect vectors offers new intriguing targets for blocking or reducing transmission of human disease-causing pathogens.
• Riehle, M. A. (2014). Genome sequence of the tsetse fly (Glossina morsitans): vector of African trypanosomiasis. Science (New York, N.Y.), 344(6182), 380-6.
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  Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub-Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein-encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology.

Presentations

• Riehle, M. A. (2021, November). Insulin signaling and the mosquito fat body: what we know and where we go next. ESA National Meeting. Denver, CO.
• Riehle, M. A. (2021, Spring). Targeting signaling pathways to manipulate mosquito biology and pathogen transmission. ESA Pacific Branch Meeting. Virtual.
• Nair, S., Arnbrister, J., Li, S., Williamson, D., Ernst, K. C., Riehle, M. A., Gouge, D. H., & Walker, K. R. (2020, November). Impacts of ULV adulticiding on the vectorial capacity of the Zika vector, Aedes aegypti. 2020 Entomological Society of America Virtual Annual Meeting. November 11–25, 2020.
• Nair, S., Nair, S., Arnbrister, J., Arnbrister, J., Li, S., Li, S., Williamson, D., Williamson, D., Ernst, K. C., Ernst, K. C., Riehle, M. A., Riehle, M. A., Gouge, D. H., Gouge, D. H., Walker, K. R., & Walker, K. R. (2020, November). Impacts of ULV adulticiding on the vectorial capacity of the Zika vector, Aedes aegypti. 2020 Entomology Virtual Annual Meeting. November 11 – 25, 2020.
• Ernst, K. C., Riehle, M. A., & Walker, K. R. (2019, July). Unravelling the social and biological determinants of arboviral transmission in the Arizona-Sonora border region.. 8th International Symposium on Insect Molecular Biology. Sitges, Spain.
• Luckhart, S., Torrevillas, B., & Riehle, M. A. (2019, July). Networked life history traits, metabolism, and anti-Plasmodium resistance in the major malaria vector Anopheles stephensi.. 8th International Symposium on Insect Molecular Biology. Sitges, Spain.
• Riehle, M. A. (2019, March). Insulin signaling in mosquitoes: A novel mechanism for controlling malaria and dengue. ALVSCE Poster Forum.
• Riehle, M. A. (2019, March). Manipulating cell signaling in mosquitoes to control malaria.. University of Georgia seminar series. Athens, GA.
• Oringanje, C., & Riehle, M. A. (2018, November). Impact of increased AMP-activated protein kinase in the midgut of Anopheles stephensi on fitness and metabolism. ESA. Vancouver, BC.
• Riehle, M. A. (2018, March). Assessing the impact of temperature on the extrinsic incubation period and transovarial transmission of Zika virus in Aedes aegypti.. Mini symposium on virus genomics and phylodynamics. University of Arizona.
• Riehle, M. A. (2018, November). Cross-kingdom biology in malaria – shared cell signaling and responses of mosquitoes and humans to parasite infection. ESA. Vancouver, BC.
• Riehle, M. A. (2018, November). Vectors living at the ecological edge and the impact on human arbovirus transmission. ESA. Vancouver, BC.
• Weitemier, T. D., Walker, K. R., Riehle, M. A., & Ernst, K. C. (2018, October). Evidence and variation in nectar feeding from wild Aedes aegypti mosquitoes from an arid environment. Society of Vector Ecology. Yosemite, California.
• Riehle, M. A. (2017, November). Assessing the impact of temperature on the extrinsic incubation period and transovarial transmission of Zika virus in Aedes aegypti. ESA National Meeting. Denver, CO.
• Riehle, M. A. (2017, Spring). Manipulating mosquito fitness through insulin signaling and mitochondrial dynamics. ESA Pacific Branch. Portland, OR.
• Riehle, M. A. (2017, Spring). Theoretical Approaches to Using Genetic Manipulation to Control Mosquito Disease Transmission. Arizona Vector Control Workshop. Pheonix, AZ.
• Walker, K. R., Ernst, K. C., Riehle, M. A., Joy, T., & Reyes Castro, P. (2017, March). Ecology of Aedes aegypti and public perception of mosquitoes in the Arizona/Sonora border region. 2017 Arizona Vector Control Conference. Phoenix, AZ: Arizona Dept. of Health Services.
• Riehle, M. A. (2016, January). Manipulating IIS in the mosquito to control fitness and parasite resistance. UC Davis invited department presentation. UC DAvis.
• Riehle, M. A. (2016, November). Building a better mosquito – Why?!. Microlunch. UA: School of Animal & Comparative Biomedical Sciences.
• Riehle, M. A. (2016, September). Mosquito-borne viruses and their journey through the mosquito vector. Science Cafe. Borderlands Brewery: College of Public Health.
• Walker, K. R., Ernst, K. C., Castro-Reyes, P., & Riehle, M. A. (2016, October). Ecologia de Aedes aegypti y el Riesgo de Dengue en la Region de Arizona/Sonora [in Spanish]. Simposio Binacional: Exploracion de los Aspectos Ambientales y de Salud del Zika, Dengue Chikungunya y la Fiebre Manchada,. Nogales, Sonora: U.S. EPA.
• Walker, K. R., Joy, T. K., Ernst, K. C., Riehle, M. A., & Daniel, W. (2016, September). Understanding the Zika vector in the desert southwest.. Science Café –. Tucson, AZ: Southwest Environmental Health Sciences Center, University of Arizona.
• Walker, K. R., Joy, T. K., Ernst, K. C., Riehle, M. A., & Daniel, W. (2016, September). Understanding the Zika vector in the desert southwest.. Volunteer Leadership Engagement Day with the Wildcat for Life and National Leadership Councils. Tucson, AZ: University of Arizona.
• Ernst, K. C., Hayden, M., Riehle, M., Walker, K. R., & Riehle, M. A. (2014, August). Differential Emergence of Dengue in the Arizona-Sonora Desert Region: Understanding the Role of Social and Environmental Factors.”. International Society for Environmental Epidemiology.
• Ernst, K. C., Hayden, M., Walker, K. R., Castro, L., Diaz, R., Reyes-Castro, P., Monaghan, A., Haenchen, S., & Riehle, M. A. (2014, November). Diferencias en el riesgo del dengue a través del norte de México. Prevención de riesgos para la salud de las poblaciones vulnerables..

Poster Presentations

• Riehle, M. A., Joy, T., Ernst, K. C., Gouge, D. H., Carriere, Y., & Walker, K. R. (2020, November). How old is that mosquito? Age grading Aedes aegypti in the desert Southwest.. ESA National Meeting. Virtual.
• Walker, K. R., Carriere, Y., Gouge, D. H., Ernst, K. C., Joy, T., & Riehle, M. A. (2020, November). How old is that mosquito? Age grading Aedes aegypti in the desert Southwest.. ESA National Meeting. Virtual.
• Riehle, M. A. (2019, May). Insulin signaling in mosquitoes: A novel mechanism for controlling malaria and deng. College of Veterinary Medicine poster session.
• Riehle, M. A., Hun, L., Torrevillas, B., & Luckhart, S. (2019, July). Insulin signaling in the mosquito fat body: Impacts on lifespan, reproduction and immunity.. 8th International Symposium on Insect Molecular Biology. Sitges, Spain.
• Riehle, M. A., Ernst, K. C., Walker, K. R., & Joy, T. (2018, October). Age grading individual field collected Aedes aeg ypti mosquitoes: qPCR versus near - infrared spectrophotometry (NIRS). Society of Vector Ecology. Yosemite, California.
• Walker, K. R., Riehle, M. A., Gouge, D. H., & Ernst, K. C. (2018, October). Impacts of ULV adulticiding on the vectorial capacity of the Zika Vector. Society of Vector Ecology. Yosemite, California.
• Walker, K. R., Ernst, K. C., Joy, T., Reyes-Castro, P., Carriere, Y., Castro, L., Diaz-Cervantes, R., Gameros, M., Hayden, M., Monaghan, A., Haenchen, S., Guttierez-Jeffrey, E., & Riehle, M. A. (2015, September). Exploring differential emergence of dengue in two cities with established Aedes aegypti populations: A case study in Sonora, Mexico. 2015 Annual Meeting of the Society for Vector Ecology. Albuquerque, NM.

Creative Productions

• Walker, K. R., & Riehle, M. A. (2017. Why mosquitoes love us, but we don't love them. Live-stream video. University of Arizona: FIeldTrip Zoom.
  More info

  Live-stream educational presentations to elementary schools. Estimated 300 classes participated.