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.
Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity
to dengue virus.
Pantoja P, Pérez-Guzmán EX, Rodríguez IV, White LJ, González O, Serrano C, Giavedoni L, Hodara V, Cruz L, Arana T, Martínez MI, Hassert MA, Brien JD, Pinto AK, de Silva A, Sariol CA.
Nat Commun. 2017 Jun 23;8:15674. doi: 10.1038/ncomms15674. PMID: 28643775
Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection.
Pinto AK, Brien JD, Lam CY, Johnson S, Chiang C, Hiscott J, Sarathy VV, Barrett AD, Shresta S, Diamond MS.
MBio. 2015 Sep 15;6(5):e01316-15. doi: 10.1128/mBio.01316-15. PMID: 26374123
Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies
with Therapeutic Activity against Chikungunya Virus.
Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, Khomandiak S, Ashbrook AW, Kahle KM, Fong RH, Swayne S, Doranz BJ, McGee CE, Heise MT, Pal P, Brien JD, Austin SK, Diamond MS, Dermody TS, Crowe JE Jr.
Cell Host Microbe. 2015 Jul 8;18(1):86-95. PMID: 26159721
Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses
of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families.
Pinto AK, Williams GD, Szretter KJ, White JP, Proença-Módena JL, Liu G, Olejnik J, Brien JD, Ebihara H, Mühlberger E, Amarasinghe G, Diamond MS, Boon AC.
J Virol. 2015 Sep;89(18):9465-76. doi: 10.1128/JVI.00996-15. Epub 2015 Jul 8. PMID: 26157117
Propagation, quantification, detection, and storage of West Nile virus.
Brien JD, Lazear HM, Diamond MS.
Curr Protoc Microbiol. 2013 Nov 5;31:15D.3.1-15D.3.18. doi: 10.1002/9780471729259.mc15d03s31. PMID: 24510289
Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity.
Messaoudi I, Vomaske J, Totonchy T, Kreklywich CN, Haberthur K, Springgay L, Brien JD, Diamond MS, Defilippis VR, Streblow DN.
PLoS Negl Trop Dis. 2013 Jul 25;7(7):e2343. doi: 10.1371/journal.pntd.0002343. Print 2013. PMID: 23936572
Functional analysis of antibodies against dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection.
Sukupolvi-Petty S, Brien JD, Austin SK, Shrestha B, Swayne S, Kahle K, Doranz BJ, Johnson S, Pierson TC, Fremont DH, Diamond MS.
J Virol. 2013 Aug;87(16):8826-42. doi: 10.1128/JVI.01314-13. Epub 2013 Jun 19. PMID: 23785205
Protection by immunoglobulin dual-affinity retargeting antibodies against dengue virus.
Brien JD, Sukupolvi-Petty S, Williams KL, Lam CY, Schmid MA, Johnson S, Harris E, Diamond MS.
J Virol. 2013 Jul;87(13):7747-53. doi: 10.1128/JVI.00327-13. Epub 2013 May 8. PMID: 23658441
Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus.
Pal P, Dowd KA, Brien JD, Edeling MA, Gorlatov S, Johnson S, Lee I, Akahata W, Nabel GJ, Richter MK, Smit JM, Fremont DH, Pierson TC, Heise MT, Diamond MS.
PLoS Pathog. 2013;9(4):e1003312. doi: 10.1371/journal.ppat.1003312. Epub 2013 Apr 18. PMID: 23637602
Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging.
Cicin-Sain L, Brien JD, Uhrlaub JL, Drabig A, Marandu TF, Nikolich-Zugich J.
PLoS Pathog. 2012;8(8):e1002849. doi: 10.1371/journal.ppat.1002849. Epub 2012 Aug 16. PMID: 22916012
A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.
Pinto AK, Daffis S, Brien JD, Gainey MD, Yokoyama WM, Sheehan KC, Murphy KM, Schreiber RD, Diamond MS.
PLoS Pathog. 2011 Dec;7(12):e1002407. doi: 10.1371/journal.ppat.1002407. Epub 2011 Dec 1. PMID: 22144897
Interferon regulatory factor-1 (IRF-1) shapes both innate and CD8(+) T cell immune responses against West Nile virus infection.
Brien JD, Daffis S, Lazear HM, Cho H, Suthar MS, Gale M Jr, Diamond MS.
PLoS Pathog. 2011 Sep;7(9):e1002230. doi: 10.1371/journal.ppat.1002230. Epub 2011 Sep 1. PMID: 21909274
The interferon-inducible gene viperin restricts West Nile virus pathogenesis.
Szretter KJ, Brien JD, Thackray LB, Virgin HW, Cresswell P, Diamond MS.
J Virol. 2011 Nov;85(22):11557-66. doi: 10.1128/JVI.05519-11. Epub 2011 Aug 31. PMID: 21880757
In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection.
de Alwis R, Beltramello M, Messer WB, Sukupolvi-Petty S, Wahala WM, Kraus A, Olivarez NP, Pham Q, Brien JD, Tsai WY, Wang WK, Halstead S, Kliks S, Diamond MS, Baric R, Lanzavecchia A, Sallusto F, de Silva AM.
PLoS Negl Trop Dis. 2011 Jun;5(6):e1188. doi: 10.1371/journal.pntd.0001188. Epub 2011 Jun 21. PMID: 21713020
Repeated in vivo stimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitis.
Uhrlaub JL, Brien JD, Widman DG, Mason PW, Nikolich-Zugich J.
J Immunol. 2011 Apr 1;186(7):3882-91. doi: 10.4049/jimmunol.1002799. Epub 2011 Feb 21. PMID: 21339368
Genotype-specific neutralization and protection by antibodies against dengue virus type 3.
Brien JD, Austin SK, Sukupolvi-Petty S, O'Brien KM, Johnson S, Fremont DH, Diamond MS.
J Virol. 2010 Oct;84(20):10630-43. doi: 10.1128/JVI.01190-10. Epub 2010 Aug 11. PMID: 20702644
Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2.
Sukupolvi-Petty S, Austin SK, Engle M, Brien JD, Dowd KA, Williams KL, Johnson S, Rico-Hesse R, Harris E, Pierson TC, Fremont DH, Diamond MS.
J Virol. 2010 Sep;84(18):9227-39. doi: 10.1128/JVI.01087-10. Epub 2010 Jun 30. PMID: 20592088
The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
Shrestha B, Brien JD, Sukupolvi-Petty S, Austin SK, Edeling MA, Kim T, O'Brien KM, Nelson CA, Johnson S, Fremont DH, Diamond MS.
PLoS Pathog. 2010 Apr 1;6(4):e1000823. doi: 10.1371/journal.ppat.1000823. PMID: 20369024
Inflation and long-term maintenance of CD8 T cells responding to a latent herpesvirus depend upon establishment of latency and presence of viral antigens.
Lang A, Brien JD, Nikolich-Zugich J.
J Immunol. 2009 Dec 15;183(12):8077-87. doi: 10.4049/jimmunol.0801117. PMID: 20007576
Key role of T cell defects in age-related vulnerability to West Nile virus.
Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Zugich J.
J Exp Med. 2009 Nov 23;206(12):2735-45. doi: 10.1084/jem.20090222. Epub 2009 Nov 9. PMID: 19901080
West nile virus capsid degradation of claudin proteins disrupts epithelial barrier function.
Medigeshi GR, Hirsch AJ, Brien JD, Uhrlaub JL, Mason PW, Wiley C, Nikolich-Zugich J, Nelson JA.
J Virol. 2009 Jun;83(12):6125-34. doi: 10.1128/JVI.02617-08. Epub 2009 Apr 15. PMID:19369347
West Nile virus-specific CD4 T cells exhibit direct antiviral cytokine secretion and cytotoxicity and are sufficient for antiviral protection.
Brien JD, Uhrlaub JL, Nikolich-Zugich J.
J Immunol. 2008 Dec 15;181(12):8568-75. PMID: 19050276
Cutting edge: TLR ligands increase TCR triggering by slowing peptide-MHC class I decay rates.
Rudd BD, Brien JD, Davenport MP, Nikolich-Zugich J.
J Immunol. 2008 Oct 15;181(8):5199-203. PMID: 18832671
Age-related dysregulation of CD8+ T cell memory specific for a persistent virus is independent of viral replication.
Lang A, Brien JD, Messaoudi I, Nikolich-Zugich J.
J Immunol. 2008 Apr 1;180(7):4848-57. PMID: 18354208
Protective capacity and epitope specificity of CD8(+) T cells responding to lethal West Nile virus infection.
Brien JD, Uhrlaub JL, Nikolich-Zugich J.
Eur J Immunol. 2007 Jul;37(7):1855-63. PMID: 17559175
Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18.
Raué HP, Brien JD, Hammarlund E, Slifka MK.
J Immunol. 2004 Dec 1;173(11):6873-81. PMID: 15557182
Antiviral T-cell-independent type 2 antibody responses induced in vivo in the absence of T and NK cells.
Szomolanyi-Tsuda E, Brien JD, Dorgan JE, Garcea RL, Woodland RT, Welsh RM.
Virology. 2001 Feb 15;280(2):160-8. PMID: 11162830
The role of CD40-CD154 interaction in antiviral T cell-independent IgG responses.
Szomolanyi-Tsuda E, Brien JD, Dorgan JE, Welsh RM, Garcea RL.
J Immunol. 2000 Jun 1;164(11):5877-82. PMID: 10820268