Genetic approaches to the study of host-virus interactions, genetics of susceptibility to virus infection, immune response to virus infection.
retrovirus, transferrin receptor, superantigen, toll receptor, mouse genetics, breast cancer, new world arenaviruses.
The use of both genetic and molecular approaches to the study of virus-host interactions in vivo provides us with insight into the processes that determine the susceptibility and resistance of individuals to viral infection and virus-induced cancer (approximately 20% of human cancers). Our interests lie in determining why viruses infect specific hosts and how in turn, host genes confer resistance to this infection. Our lab studies 2 different types of viruses, retroviruses like mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) which cause cancer in mice, and the new world arenaviruses, which cause hemorrhagic fever in humans.
The genetics of susceptibility is easily studied with naturally-occurring pathogens in inbred and genetically-manipulated mice. MMTV is an endemic oncogenic retrovirus that has been an infectious agent in mice for > 20 million years, while MLV has been in mice ~ 3 million years. Infectious MMTV is passed from mothers to offspring through milk and first spreads in lymphoid cells before infecting mammary epithelial cells; MLV is probably also milk-transmitted. These viruses serve as models for the human milk-borne retroviruses HIV-1 and HTLV1. MMTV causes breast cancer and MLV causes lymphomas when the viral genome inserts next to cellular oncogenes by activating their expression. Our studies focus on understanding the mechanisms that determine susceptibility to MMTV infection and virus-induced mammary tumors and we have identified a number of genes and mechanisms that confer resistance to infection by MMTV and MLV.
Genes of the intrinsic and innate immune system play a major role in susceptibility to infection. One gene which we recently discovered is involved in the control of MMTV and MLV infection is Apobec3. APOBEC3 proteins are packaged into virions and inhibit replication of viruses like HIV as well as murine retroviruses in newly infected cells by deaminating cytosine on the negative strand DNA intermediates and by inhibiting reverse transcriptase. We found that mouse APOBEC3 protein is packaged into MMTV and MLV particles and that APOBEC3 knockout mice are more susceptible to MMTV and MLV infection than their wild type littermates. These findings indicate that the APOBEC3 provides protection to mice against retroviral infection and represent the first demonstration that it functions during retroviral infection in vivo. We have also created transgenic mice expressing human APOBEC3 proteins that we are using to test novel anti-retroviral therapies.
Most recently, the lab has focused on host intrinsic immune factors that restrict virus infection by interacting with reversed-transcribed viral DNA including APOBEC3 and novel and known host sensors of cytosolic viral DNA. Using mice with naturally occurring genetic polymorphisms, mutant or knockout alleles of these intrinsic immune factors, the lab showed that APOBEC3 limits the levels of reverse transcripts that trigger cytosolic sensing and that the role of nucleic acid sensing in vivo is to increased expression of interferon-regulated restriction factors like APOBEC3 that in turn reduce viral load. These studies underscore the importance of the multiple layers of protection afforded by host factors.
We have recently extended our studies to new world arenaviruses like Junín virus. These viruses are endemic in new world rodents in South America and are spread to humans via aerosolization. Interestingly, both Junín virus and MMTV use transferrin receptor 1 (TfR1) for entry. We are currently studying how MMTV and Junín virus use TfR1 to enter cells and how the iron metabolic pathway intersects with infection by these viruses. In addition, we are studying different host genes that confer resistance or susceptibility Junín virus, and whether polymorphisms in these genes in humans alter infection. These studies will help us identify host molecules involved in cell- and disease-tropism and help us to develop new anti-viral therapies.
Nouhou Ibrahim - Postdoc
Nicolas Sarute - Postdoc
Spyridon Stavrou - Postdoc
Yuki Nakaya - Postdoc
Cristhian Cadena - Post-bacc trainee
Nikita Agarwal - undergraduate
Alfi Abdullayev - undergraduate
Kristin Blouch - Lab Manager
back to top
Last updated: 04/30/2015
The Trustees of the University of Pennsylvania