Using the Fruit Fly to Unravel the Complexity of Innate Immunity
Animals are born with a defensive program known as innate immunity, which helps them fend off the intrusion of pathogens or deleterious (cancer) cells. Unlike adaptive immunity, innate immunity evolved earlier and is much more broadly conserved across species.
Studies conducted in fruit flies (D. melanogaster) have led to the discovery of key components and mechanisms of innate immunity in humans, which was recognized by the 2011 Nobel Prize in Physiology or Medicine. The lack of adaptive immunity in fruit flies may appear to be a drawback in understanding human disease. Yet this is precisely what makes them a unique model for dissecting complex innate immune responses without the confounds of adaptive immune responses.
In the past, our lab has studied innate immune response against arbovirus infection, which spreads through an intermediate host, such as mosquitos. We revealed an important innate immune response to be rapid apoptosis, a well-contained form of cell death that often requires the expression of pro-apoptotic genes.
Led by serendipitous findings, we are now interested in understanding how innate immunity becomes dysregulated in aging animals and the interaction between innate immunity and cancer.
Innate immunity against arbovirus infection – rapid induction of apoptosis (RIA)
Genetic research in fruit flies has revealed that a group of pro-apoptotic genes—reaper, hid, grim, and sickle—play a pivotal role in regulating apoptosis in insects. These insights are especially applicable to mosquitos, which cause millions of deaths yearly, with many victims being children. Using advanced bioinformatics strategies, we have identified several reaper/grim-like genes in mosquito genomes (Zhou et al. 2005). Interestingly, these genes are transcriptionally activated with in an hour of viral infection to mediate the infected cells’ rapid induction of apoptosis (RIA) (Liu et al., 2011).
These insights may be key to curbing viral infections spread by mosquitos. Viruses hijack the resources of the infected cell to proliferate and prepare for consequent waves of infection. This process is terminated by the RIA of the infected cells. In contrast, if cells fail to launch RIA—or if the response is timid—the virus will proliferate in the cell, leading to necrosis and further spread of the virus (Liu et al. 2011; 2013, Ayers et al. 2021).
We recently obtained evidence that RIA is responsible for mediating resistance to the dengue and Zika viruses in the mosquito vector Aedes aegypti (Ayers, 2021). This finding helps to explain why certain populations (strains) of vector mosquitoes are resistant to the virus. We anticipate this knowledge will help predict the susceptibility of mosquito populations and thus promote more efficient control of mosquito-borne diseases.
Interestingly, RIA following viral infection has only been observed in live animals infected with viruses. The process was not observed in insect cell lines. Taking advantage of the genetic manipulability of the fruit fly model, we showed that RIA is mediated by P53 (Liu et al. 2013) and requires an intergenic region whose accessibility is subject to epigenetic control (Zhang et al. 2008).
Zhou L*, Jiang G, Chan G, Santos CP, Severson DW, Xiao L. (2005) Michelob_X Is the Missing Inhibitor of Apoptosis Protein Antagonist in Mosquito Genomes. EMBO Rep. (This article was recommended by Faculty of 1000) (NCBI; Full text) (*Corresponding author)
Zhang Y, Lin N, Carroll P, Chan G, Guan B, Xiao H, Yao B, Wu S, and Zhou L. (2008) Epigenetic Blocking of An Enhancer Region Controls Irradiation-Induced Pro-apoptotic Gene Expression in Drosophila Embryos. Developmental Cell. (NCBI, Full text)
Liu B, Becnel J, Zhang Y, and Zhou L (2011) Induction of Reaper Ortholog Mx in Mosquito Midgut Cells following Baculovirus Infection. Cell Death and Differentiation (NCBI; Full text) – This was the first report of induction of RHG genes following viral infection.
Liu, B., Behura SK, Schneemann A, Becnel J, Clem RJ, Severson DW, and Zhou L, (2013) P53-Mediated Rapid Induction of Apoptosis Conveys Resistance to Viral Infection in Drosophila. PLoS Pathogens (Open Access)
Ayers JB, Coatsworth HG, Kang S, Dinglasan RR, Zhou L. Clustered rapid induction of apoptosis limits ZIKV and DENV-2 proliferation in the midguts of Aedes aegypti. Communications Biol. 2021 Jan 15;4(1):69. (Open Access)
Inflammaging and cancer
Innate immunity is essential for defense against infection. In the absence of infection, however, the innate immune response may linger, which is often associated with advanced age and referred to as inflammaging. Inflammaging is implicated in many age-related diseases, such as neurodegenerative diseases and cancer, yet the mechanism remains enigmatic. One of the leading theories suggests that innate immune genes misfire when their epigenetic control is eroded during aging.
Our laboratory has discovered that human alpha anti-trypsin (hAAT), an immune modulator, potently suppresses inflammaging in fruit flies. Follow-up RNA-Seq analyses have indicated that the same innate immune pathway is suppressed by hAAT in senescent human HCA2 cells and aging fruit flies (Yuan et al. 2018). This finding indicates that the underlying mechanisms of inflammaging are well conserved, and the fruit fly is poised to reveal the essential aspects of this process.
Yuan Y, DiCiaccio B, Li Y, Elshikha AS, Titov D, Brenner B, Seifer L, Pan H, Karic N, Akbar MA, Lu Y, Song S, Zhou L. Anti-inflammation effects of human alpha-1 antitrypsin. Aging Cell. 2018
Yuan Y, Van Belkum M, O’Brien A, Garcia A, Troncoso K, Elshikha AS, Zhou L, Song S. Human Alpha 1 Antitrypsin Suppresses NF-κB Activity and Extends Lifespan in Adult Drosophila. Biomolecules. 2022
Bioinformatics and machine learning:
Bioinformatics approaches have always been an integrated part of our research. Using advanced bioinformatics strategies, Our lab has always used advanced bioinformatics approaches as an integral part of our research. Using customized strategies, we have identified divergent pro-apoptotic genes (Zhou 2005), developed a novel method to identify conserved regulatory modules (Meng et al. 2006; 2007), and mined cancer exome data to identify genes important for lung cancer (Sundaresan 2017). Current projects in this area are using machine learning to estimate biological age of fruit flies with RNA-Seq data and also developing a knowledge database for cross-genome comparison of serpins.
Zhou L. (2005) The ‘unique key’ feature of the Iap-binding motifs in RHG proteins. Cell Death Differ.12(8):1148-51.
Meng H, Banerjee A, Zhou L. (2006) BLISS: Binding-site Level Identification of Shared Signal-modules in related DNA regulatory sequences. BMC Bioinformatics 7:287.
Meng H, Banerjee A, Zhou L. (2007) A web-based analysis tool for identifying shared regulatory modules. Bioinformatics 23(23):3249
Sundaresan V, Lin VT, Liang F, Kaye FJ, Kawabata-Iwakawa R, Shiraishi K, Kohno T, Yokota J, Zhou L. Significantly mutated genes and regulatory pathways in SCLC-a meta-analysis. Cancer Genet. 2017
GMS6014 – Application of Bioinformatics in Genetics Research.
GMS6232 – Advanced Application of Bioinformatics.
Postdoc fellow: MIT
Ph.D.,University of Massachusetts at Amherst
B. Medicine, Beijing Medical University