James D. Brien, Ph.D.
Molecular Microbiology and Immunology
The role of immune control on the evolution and pathogenesis of arthropod-borne viruses in vivo.
RNA viruses exist in nature not as a single genomic sequence rather as an amalgam of related sequences referred to as a viral swarm or quasispecies. For viruses like WNV, DENV and CHIKV, which efficiently suppress immune response pathways, there is an increase in the potential virulence of a viral swarm. The functional consequences and capabilities of these viral swarms are only beginning to be understood. To understand how the immune system shapes virus sequence variation, and disease pathogenesis we utilize an animal model of WNV to understand how specific immune selective pressures are applied both locally and systemically to control infection and disease.
Identify evolutionarily conserved mechanisms of anti-viral restriction in insects and mammals.
The ability to distinguishing self from non-self is the central dogma behind an effective host response. Methylation at the 2'-O position of the 5' cap has recently been shown as one mechanism a cell uses to differentiate self from non-self mRNA in mammals. Interestingly, the host mRNA of insects is also methylated at the 2'-O position. I have shown that a WNV that lacks 2'-O methyltransferase activity (WNV-E218A) is markedly restricted in insect cells (Fig. 2). These results have lead us to hypothesize that novel evolutionarily conserved pathway(s) exists in insects and mammals that recognizes RNA lacking 2'-O methylation.
We have begun to identify the genes and pathways responsible for restricting infection of WNV-E218A in insect cells through multiple collaborations.
These results allow us to address the following questions:
- How do insects recognize the 5’ cap of arthropod borne flaviviruses?
- What are the mechanisms used by insects to restrict 2’O methylation deficient viruses?
- How do these pathways function to control viral pathogenesis in insects and mammals?
Study mechanisms of antibody mediated protection and enhancement of disease
With over 3.5 billion people at risk, and approximately 390 million human infections per year, Dengue virus (DENV) disease strains health care resources worldwide. In collaboration with Dr. Amelia Pinto (Assistant Professor, Saint Louis University), we developed a DENV disease mouse model using the Cre/Flox system that has resulted in the enhanced replication of primary DENV isolates in vivo. Administration of sub-neutralizing amounts of cross-reactive anti-DENV monoclonal antibodies prior to infection results in antibody-dependent enhancement (ADE) with many of the characteristics of severe DENV disease in humans. ADE in this mouse model is associated with plasma leakage, hypercytokinemia, liver injury, hemoconcentration, and thrombocytopenia.
Zika virus (ZIKV) has caused an unprecedented public health campaign, especially for an arbovirus infection that had not previously been known to cause severe disease. At the time of this time a total of 33 countries have reported autochthonous circulation of ZIKV with over two million people believed to have been infected. Most infections with ZIKV asymptomatic with around one in five cases resulting in a minor illness including symptoms such as fever and a rash. However, ZIKV infection in pregnant women has a suspected link with newborn microcephaly by mother-to-child transmission and in some cases Guillain–Barré syndrome.
ZIKV is currently co-circulating with DENV, CHKV and Yellow Fever virus (YF), and one hypothesis is that pre-exisitng cross-reactive antibody responses are increasing the severity of ZIKV disease. We have adapted our DENV mouse model to study the potential of pre-exisiting antibody responses to DENV and YF on the increase incidence of microcephaly and neurological diseases in ZIKV individuals.
With recent and dramatic changes to climate, travel, and population levels there has been an increase in the spread and incidence of emerging and re-emerging infectious diseases. My laboratory focuses on these diseases and their impact on human health, particularly the health of vulnerable populations. Arthropod-borne viruses account for 40% of all pathogenic viruses and are a major source of emerging and re-emerging infectious diseases. With over four billion people at risk of contracting at least one arthropod-borne viral pathogen, arboviruses including Dengue (DENV), Chikungunya (CHIKV), West Nile (WNV), and Zika (ZIKV) viruses have emerged as pathogens of global importance.
My laboratory seeks to improve our understanding of how the immune system recognizes and restricts re-emerging infectious diseases with the goal of designing treatments to reduce morbidity and mortality. We use animal models to investigate fundamental biological processes that control virus infection and identify the correlates of protection required for the development of vaccines and therapeutics. The benefit of focusing on re-emerging pathogens is that they provide a robust system for asking questions about immunity and disease as they have developed novel ways to exploit the host-pathogen imbalance.