Our laboratory is interested in understanding the molecular basis of how viruses cause disease. Ongoing studies are focused on the role of Toll-Like Receptor pathways and the regulatory interplay of microRNAs in viral pathogenesis and host-defense in vivo. A second major long-term goal is to develop strategies to treat / inhibit viral infections. Our research focuses on human hepatitis C virus and coronaviruses.
Hepatitis C Virus
HCV is a member of the hepacivirus genus within the Flaviviridae family that infects an estimated 170-200 million individuals worldwide, and is the leading cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver transplantation. Viral replication persists in a majority of infected individuals. As a consequence of persistent viral replication in still not well defined cell and tissue reservoirs, re-infection of liver grafts after transplantation is very common and one of a broad clinical spectrum of extrahepatic complications and diseases (such as various autoimmune disorders, non-Hodgkin’s lymphoma, vasculitis, glomerulonephritis, lymphoproliferative disorders, and neuropathies) that are present in 75% of HCV-infected individuals.
During the last few years, the development of self-replicating HCV RNA replicons has revolutionized HCV research. However, only during the last year, an HCV replicon system that supports production of infectious HCV particles has been reported. These advances will allow the development of additional systems to study sustained viral replication in hepatocytes and in non-hepatocyte cultured cells, which are critically needed in order to perform the molecular characterization of extrahepatic replication of HCV and its role in the progression of chronic hepatitis C and other HCV-related diseases.
Figure 1: Detection by immunofluorescence of HCV core (A) and NS3 (B) proteins expressed in human hepatoma Huh7 cells infected with HCV particles produced in cell culture
Our work is currently directed at defining how coronaviruses infect cells, and how viral tropism influences disease. In addition, we are interested in understanding how coronaviruses induce acute self-limited, persistent, as well as fatal infections. Our research includes a number of approaches in cell culture systems as well as in infected animals. Murine coronavirus (mouse hepatitis virus, MHV) infection of the mouse provides a unique animal model in which both the virus and its natural host can be manipulated to elucidate mechanisms of disease. Using this animal model we try to understand the molecular basis of coronavirus-induced pathogenesis. We have also a long term interest in virus cross species transmission and evolution.
Coronaviruses form a group of enveloped, positive-sense, single-stranded polyadenylated RNA viruses that have the largest genome (~30 kb) among RNA viruses. Coronaviruses replicate in the cytoplasm of infected cells using a viral RNA-dependent RNA polymerase that is translated from the genomic RNA. Two major forces drive coronavirus evolution: recombination and mutation. Coronaviruses infect many species of animals including humans, and are considered as emerging pathogens. They target first respiratory and mucosal surfaces and then, depending of host, and virus strain, they may spread to other tissues (brain, eyes, liver, kidneys and spleen) and cause a range of pathologies (pneumonia, encephalitis, demyelination, hepatitis, enteritis, nephritis, among others). While the molecular determinants of coronaviruses’ pathogenesis remain poorly understood, there is evidence that both host and viral factors do play a role in coronavirus-induced disease. Among human coronaviruses, HCoV-229E and HCoV-OC43 cause about 30% of the common colds. A novel coronavirus has been recently identified as the causative agent of the severe acute respiratory syndrome (SARS). The molecular determinants that may account for the dramatic differences in pathogenesis between HCoV-229E and HCoV-OC43 and SARS-CoV are currently unknown. The origin of SARS remains undefined, although it has been suggested that SARS evolved from an animal host. One of our long term goals is to understand the basis of coronavirus cross species transmission and evolution.
Figure 2: Immunohistochemistry of liver (left) and brain (right) sections of C57BL/6 mice infected with recombinant MHV-A59 strain. Some strains of MHV, such as A59, infect both the liver and the central nervous system, inducing hepatitis, encephalitis and demyelination. We try to understand what viral and host factors are associated with disease outcome.
Figure 3: The coronavirus spike (S) protein mediates infection of receptor-bearing cells. Unlike many type I fusion glycoproteins, including those of other coronaviruses, the S protein of SARS is not cleaved in the virus-producing cell. The figure depicts MHV-JHM (left) strain-infected murine fibroblast L2 cells , and SARS-CoV-infected (right) Vero E6 cells.
Selected Publications (See all Sonia Navas-Martin's publications in PubMed.)
"MicroRNAs, Hepatitis C Virus, and HCV/HIV-1 Co-Infection: New Insights in Pathogenesis and Therapy"
Gupta A, Swaminathan G, Martín-García J, and S Navas-Martín
Viruses, 4(11), 2485-2513, 2012.
"A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages"
Swaminathan G, Rossi F, Sierra LJ, Gupta A, Navas-Martín S, and J Martín-García
PLoS Pathogens, 8: doi:10.1371/journal.ppat.1002937, 2012.
"Protective role of Toll like Receptor 3-induced type I interferon in murine coronavirus infection of macrophages"
Mazaleuskaya L, Veltrop R, Ikpeze N, Martin-Garcia J, and S Navas-Martín
Viruses, 4(5): 901-923, 2012.
"Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges"
Bouchard MJ, and S Navas-Martin
Cancer Letters, 305(2): 123-143, 2011.
"The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors"
F. Rossi, B. Querido, D. Nimmagadda, S. Cocklin, S. Navas-Martín, and J. Martín-García
Retrovirology, 5:89, 2008
"Replicase genes of murine coronavirus strains A59 and JHM are interchangeable: differences in pathogenesis map to the 3' one-third of the genome"
S. Navas-Martín, M. Brom, M.M. Chua, R. Watson, Z. Qiu, and S.R. Weiss
Journal of Virology, 81(2): 1022-1026, 2007
"Murine coronavirus evolution in vivo: functional compensation of a detrimental amino acid substitution in the receptor binding domain of the spike glycoprotein"
S. Navas-Martín and S. R. Weiss
Journal of Virology, 79: 7629-7640, 2005
"Coronavirus replication and pathogenesis: implications for the recent outbreak of SARS, and the challenge for vaccine development"
S. Navas-Martín and S. R. Weiss
Journal of Neurovirology, 10: 75-85, 2004
"The spike protein of murine coronavirus determines the ability of the virus to replicate in the liver and cause hepatitis"
S. Navas, S.H. Seo, M.M. Chua, J. Das Sarma, S.T. Hingley, E. Lavi, and S.R. Weiss
Journal of Virology, 75:2452-2457, 2001
"Genetic diversity and tissue compartmentalization of hepatitis C virus genome in blood mononuclear cells, liver and serum from chronic hepatitis C patients"
S. Navas, J. Martín, J.A. Quiroga, I. Castillo, and V. Carreño
Journal of Virology, 72: 1640-1646, 1998
"Concordance of hepatitis C virus typing methods based on RFLP analysis in 5' non-coding region, and NS4 serotyping, but not in core-PCR or a line probe assay"
S. Navas, I. Castillo, J. Martín, J.A. Quiroga, J. Bartolomé, and V. Carreño
Journal of Clinical Microbiology, 35: 317-321, 1997
"Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospective study"
S. Navas, O. Bosch, I. Castillo, and V. Carreño
Hepatology, 21: 279-284, 1995
"Plus and minus hepatitis C virus RNA strands in serum, liver and peripheral blood mononuclear cells in anti-HCV patients. Relation with the liver lesion"
S. Navas, I. Castillo, J. Bartolomé, E. Marriott, M. Herrero, and V. Carreño
Journal of Hepatology, 21: 182-186, 1994
"Detection of plus and minus HCV-RNA in normal liver of anti-HCV positive patients"
S. Navas, I. Castillo, and V. Carreño
Lancet, 341: 904-905, 1993