What we do
Understanding immune system biology through the study of viral and parasitic infections.
Cover of issue featuring herpesvirus-helminth co-infection work.
Alterations of chronic viral infections by bystander parasitic infections
We are all infected with multiple viruses, bacteria, fungi, and parasites. The immune response to single pathogen infections has been extensively studied, but little is known about the immune response to coinfections. Specifically, we do not understand the impact of bystander infections on viral pathogenesis. My lab is pioneering the use of novel mouse models of multiple infections to investigate the complex interactions that occur during coinfection. We demonstrated through our mouse models that infections with intestinal parasites reactivate latent gammaherpesvirus infections (Reese, Science 2014; Wang, J Virol 2021). We recently discovered that when we alter the order of parasite and virus coinfection, we observe mechanistically distinct herpesvirus reactivation (Zarek, PLOS Path, 2023). Our work is some of the first to detail a mechanism for coinfection induced herpesvirus reactivation and we are one of the only labs investigating coinfection effects of DNA virus infection.
Model for NS3 induced cell death during MNV infection. Created with BioRender
Using Viruses to Discover Novel Cell Biology
In addition to our coinfection studies, we study viruses to uncover novel mechanisms of antiviral immunity. We aim to determine the mechanisms used by viruses to manipulate the cell, with the goal of finding novel ways to enhance antiviral immunity. We use diverse viruses, including herpesviruses and noroviruses to probe redox regulation of signaling pathways and programmed cell death during infection. Using these systems, we discovered that increased reactive oxygen species production during herpesvirus infection inhibits interferon production through redox regulation of the signaling adapter STING (Tao, eLife, 2020). We also discovered a new cell death protein encoded by noroviruses that promotes a novel form of cell death that is required for viral replication (Wang, Nature 2023).
We are also part of the Center of Excellence for Translational Research (CETR) grant “Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents”. Dr. Reese assumed leadership of Dr. Beth Levine’s project and the Levine Legacy Lab in February of 2021. Our objective is to develop strategies to increase autophagy in cells to target and treat viral infections, particularly priority pathogens such as West Nile Virsu, Zika Virus, and chikungunya virus. As part of this project, we are investigating novel proteins involved in authophagy/virophagy and screening for compounds that specifically disrupt Beclin-1/Bcl-2 binding to induce autophgy. This is part of a large collaborative project across multiple labs and institutions with leaders in the fields of autophagy and chemistry.
Figure created with BioRender.
Maternal Infection and Fetal Immune Programming
The crosstalk between mother and fetus significantly affects development of the fetal immune system. While we know that maternal diet, stress, smoking, microbiota, and even exposure to farm animals all influence neonatal immune development, we understand very little about the fundamental mechanisms that drive fetal immune programing. Recent associations of Zika virus infection in pregnant mothers to infant congenital abnormalities highlights the pressing need to understand the impact of maternal infections on fetal development. This need is even more apparent when one considers the hundreds of millions of mothers worldwide who harbor infections with helminths, malaria parasites, and HIV during pregnancy, all of which can alter immune responses without transmitting to the fetus. We aim to discover the relationship between maternal infection and altered fetal immune programming. We use our models of chronic infection, including Heligmosomoides polygyrus and murine gammaherpesvirus-68, to infect female mice prior to mating. Since neither of these pathogens transmit to the fetus, we can determine if the presence of maternal inflammation due to infection alters fetal immune programming. These studies will enhance our understanding of maternal-fetal interactions, but also have broad implications for efforts aimed at enhancing immunity in infants to vaccination or infection worldwide.
How does chronic infection change the immune system’s ability to respond to secondary challenges?
The state of the immune system and its ability to respond to challenge is a function of many variables, which include genetics, age, chronic disease, gut microbiome, and stress. Recent work suggests that a significant proportion of the variation in human immune response is driven by non-heritable or environmental influences. Chronic infections with pathogens (including mycobacteria, helminths, malaria parasites, and some types of viruses) affect a large proportion of the population.
In addition to the diseases caused by these pathogens directly, it is increasingly clear that these persistent infections change immunity to other unrelated pathogens and to vaccines. While epidemiological and clinical data demonstrate an association between bystander chronic infections and altered immune responses there is little mechanistic data to explain these associations.
A more detailed understanding of the immune mechanisms could improve vaccine efficacy and treatment of chronic infections. Using chronic viral and helminth infections, we seek to further define the role of co-infections on vaccine responses in the mouse system.