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1. Higher temperature accelerates the aging-dependent weakening of the melanization immune response in mosquitoes

   https://doi.org/10.1371/journal.ppat.1011935  

   Martin, Lindsay E.; Hillyer, Julián F. (January 2024, PLOS Pathogens)

   McGraw, Elizabeth A. (Ed.)

   The body temperature of mosquitoes, like most insects, is dictated by the environmental temperature. Climate change is increasing the body temperature of insects and thereby altering physiological processes such as immune proficiency. Aging also alters insect physiology, resulting in the weakening of the immune system in a process called senescence. Although both temperature and aging independently affect the immune system, it is unknown whether temperature alters the rate of immune senescence. Here, we evaluated the independent and combined effects of temperature (27°C, 30°C and 32°C) and aging (1, 5, 10 and 15 days old) on the melanization immune response of the adult female mosquito, Anopheles gambiae. Using a spectrophotometric assay that measures phenoloxidase activity (a rate limiting enzyme) in hemolymph, and therefore, the melanization potential of the mosquito, we discovered that the strength of melanization decreases with higher temperature, aging, and infection. Moreover, when the temperature is higher, the aging-dependent decline in melanization begins at a younger age. Using an optical assay that measures melanin deposition on the abdominal wall and in the periostial regions of the heart, we found that melanin is deposited after infection, that this deposition decreases with aging, and that this aging-dependent decline is accelerated by higher temperature. This study demonstrates that higher temperature accelerates immune senescence in mosquitoes, with higher temperature uncoupling physiological age from chronological age. These findings highlight the importance of investigating the consequences of climate change on how disease transmission by mosquitoes is affected by aging. 

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2. Warmer environmental temperature accelerates aging in mosquitoes, decreasing longevity and worsening infection outcomes

   https://doi.org/10.1186/s12979-024-00465-w  

   Barr, Jordyn_S; Martin, Lindsay_E; Tate, Ann_T; Hillyer, Julián_F (September 2024, Immunity & Ageing)

   Abstract BackgroundMost insects are poikilotherms and ectotherms, so their body temperature is predicated by environmental temperature. With climate change, insect body temperature is rising, which affects how insects develop, survive, and respond to infection. Aging also affects insect physiology by deteriorating body condition and weakening immune proficiency via senescence. Aging is usually considered in terms of time, or chronological age, but it can also be conceptualized in terms of body function, or physiological age. We hypothesized that warmer temperature decouples chronological and physiological age in insects by accelerating senescence. To investigate this, we reared the African malaria mosquito,Anopheles gambiae, at 27 °C, 30 °C and 32 °C, and measured survival starting at 1-, 5-, 10- and 15-days of adulthood after no manipulation, injury, or a hemocoelic infection withEscherichia coliorMicrococcus luteus. Then, we measured the intensity of anE. coliinfection to determine how the interaction between environmental temperature and aging shapes a mosquito’s response to infection. ResultsWe demonstrate that longevity declines when a mosquito is infected with bacteria, mosquitoes have shorter lifespans when the temperature is warmer, older mosquitoes are more likely to die, and warmer temperature marginally accelerates the aging-dependent decline in survival. Furthermore, we discovered thatE. coliinfection intensity increases when the temperature is warmer and with aging, and that warmer temperature accelerates the aging-dependent increase in infection intensity. Finally, we uncovered that warmer temperature affects both bacterial and mosquito physiology. ConclusionsWarmer environmental temperature accelerates aging in mosquitoes, negatively affecting both longevity and infection outcomes. These findings have implications for how insects will serve as pollinators, agricultural pests, and disease vectors in our warming world. 

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3. Temperature and age, individually and interactively, shape the size, weight, and body composition of adult female mosquitoes

   https://doi.org/10.1016/j.jinsphys.2023.104525  

   Barr, Jordyn S.; Estevez-Lao, Tania Y.; Khalif, Marina; Saksena, Saksham; Yarlagadda, Sagnik; Farah, Ommay; Shivere, Yasmine; Hillyer, Julián F. (July 2023, Journal of Insect Physiology)

   Most insects are poikilotherms and ectotherms, so their body temperature fluctuates and closely aligns with the temperature of their environment. The rise in global temperatures is affecting the physiology of insects by altering their ability to survive, reproduce, and transmit disease. Aging also impacts insect physiology because the body deteriorates via senescence as the insect ages. Although temperature and age both impact insect biology, these factors have historically been studied in isolation. So, it is unknown whether or how temperature and age interact to shape insect physiology. Here, we investigated the effects of warmer temperature (27 °C, 30 °C and 32 °C), aging (1, 5, 10, and 15 days post-eclosion), and their interaction on the size and body composition of the mosquito, Anopheles gambiae. We found that warmer temperatures result in slightly smaller adult mosquitoes, as measured by abdomen and tibia length. Aging alters both abdominal length and dry weight in a manner that correlates with the increase in energetic resources and tissue remodeling that occurs after metamorphosis and the senescence-based decline that ensues later. Moreover, the carbohydrate and lipid contents of adult mosquitoes are not meaningfully affected by temperature but are altered by aging: carbohydrate content increases with age whereas lipid content increases over the first few days of adulthood and then decreases. Protein content decreases with both rising temperature and aging, and the aging-associated decrease accelerates at warmer temperatures. Altogether, temperature and age, individually and to a lesser extent interactively, shape the size and composition of adult mosquitoes. 

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4. Silencing Transglutaminase Genes TGase2 and TGase3 Has Infection-Dependent Effects on the Heart Rate of the Mosquito Anopheles gambiae

   https://doi.org/10.3390/insects13070582  

   Ramakrishnan, Abinaya; Hillyer, Julián F. (July 2022, Insects)

   Transglutaminases are pleiotropic enzymes that in mosquitoes participate in the formation of the mating plug and the wound-induced antimalarial response. Moreover, one transglutaminase, TGase3, negatively regulates the infection-induced aggregation of hemocytes on the heart. Given that TGase3 is an inhibitor of periostial hemocyte aggregation, we used RNAi-based gene silencing followed by intravital video imaging to scrutinize whether any of the three transglutaminases encoded in the genome of the mosquito, Anopheles gambiae, play a role in modulating the heart rate of uninfected and infected mosquitoes. Initially, we confirmed that an infection decreases the heart rate. Then, we uncovered that silencing TGase1 does not impact heart physiology, but silencing TGase2 results in a constant heart rate regardless of infection status, eliminating the infection-induced decrease in the heart rate. Finally, silencing TGase3 decreases the heart rate in uninfected mosquitoes but increases the heart rate in infected mosquitoes. We conclude that TGase2 and TGase3 modulate heart physiology and demonstrate that factors not classically associated with insect circulatory physiology are involved in the functional integration of the immune and circulatory systems of mosquitoes. 

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5. Activation of the immune deficiency pathway (IMD) reduces the mosquito heart rate via a nitric oxide-based mechanism

   https://doi.org/10.1016/j.jinsphys.2024.104738  

   Estévez-Lao, Tania Y; Martin, Lindsay E; Hillyer, Julián F (March 2025, Journal of Insect Physiology)

   The immune deficiency pathway (IMD) is an important component of the antibacterial, antimalarial and antiviral response in mosquitoes. The IMD pathway also drives the infection induced migration of hemocytes to the heart. During an infection, periostial hemocytes kill pathogens in areas of high hemolymph flow and produce nitric oxide that reduces the heart rate. Here, we investigated the consequences of repressing the IMD pathway by silencing the transcription factor, rel2, or activating the pathway by silencing the negative regulator, caspar, in Anopheles gambiae. In uninfected mosquitoes, repression of the IMD pathway does not affect the circulatory system. However, activating the IMD pathway decreases the heart rate, and this correlates with increased transcription and activity of nitric oxide synthase (NOS), but not increased transcription of the lysozymes, LysC1 or LysC2. In infected mosquitoes, however, activation of the IMD pathway does not affect the heart rate but repression of the pathway decreases the heart rate. This latter phenotype correlates with increased transcription and activity of nitric oxide synthase, which is likely due to an increase in infection intensity. In conclusion, we demonstrate that a major immune signaling pathway that regulates periostial hemocyte aggregation, the IMD pathway, reduces the heart rate via a nitric oxide-based mechanism. 

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