Research profile - Dr. Carolina B. López

Dr. Carolina B. López is an Assistant Professor in the Department of Pathobiology. She received a B.S. (1992), a M.Sc., and a professional title of Biochemist (1995) from the Pontificia Universidad Católica de Chile, Santiago, Chile. During this period Dr. López studied the immune response to Litre, the Chilean version of poison ivy. After migrating to the US she worked as a Research Assistant at New York University and completed her Ph.D. in Biomedical Sciences (2002) at The Mount Sinai School of Medicine in NY. She continued at Mount Sinai as a post-doctoral fellow and was promoted to non-tenure track Assistant Professor in 2005.

She joined the Department of Pathobiology at Penn Vet in September, 2010. Dr. López’s research centers on understanding the processes that lead to the generation of the immune response against viruses. In particular, her group studies early events following virus-host interaction that determine the successful transition from the less specific initial innate immune response to the more specific and persistent adaptive immune response.

Are defective viral genomes the ultimate trigger for anti-viral immunity?

Following infection, pathogen-induced stimulation of dendritic cells promotes their migration from the tissues to the draining lymph nodes, enhances the production of pro-inflammatory molecules, and permits effective antigen presentation to T cells, thereby inducing the transition from a fast but unspecific immune response to a long-term protective and specific adaptive immune response. Identification and characterization of viral elements capable of triggering dendritic cell maturation will not only provide essential insight into the requisites for triggering effective immunity during infection, but may also identify potential novel adjuvant molecules to be used in vaccination.

While investigating the viral components required for the efficient triggering of dendritic cell maturation, Dr. López’s group discovered that defective interfering viral genomes (DIVGs) that are generated during the normal replication of viruses are potent stimuli for the activation of dendritic cells. DIVGs for a large number of animal and plant viruses have been characterized in vitro, but the mechanism for their generation as well as their role during the virus life cycle remain speculative. Dr. López reported that DIVGs activate dendritic cells through a unique mechanism that is different from that utilized by standard viruses and, moreover, is capable of overcoming the viral-encoded antagonist of immune activation found in mature viruses [1, 2].

Her group is now using a reverse genetics system that allows for the recovery of mutant DIVGs to characterize the viral motifs responsible for the potent stimulatory activity of DIVGs. The goal of this project is to identify a minimal stimulatory motif from DIVGs to be eventually harnessed as an adjuvant for vaccination. In addition, Dr. López’s group is investigating the generation and role of DIVGs during the course of natural viral infection to test the hypothesis that DIVGs are critical for triggering the anti-viral response in vivo.

What is the cellular machinery involved in the detection and response to viruses?

Anti-viral responses are initiated following recognition of “danger” signals by the infected host. Viral molecular motifs denoting danger are normally present in the virus genome and are exposed during viral replication within the host cell. A number of cellular sensors of viral genomic motifs have been identified, including members of the Toll-like receptor and RIG-I-like helicase families. These sensors localize to different cellular compartments and are partially redundant in their specificity. The signaling initiated by the binding of pathogen-specific molecular motifs to the sensors is critical for the initiation of the immune response. However, despite the presence of high levels of viral danger signals, pathogenic viruses replicate to high titers in the host.

In studies designed to understand how pathogenic viruses evade the host immune response, Dr. López and collaborators observed that it takes more than two days before the host response to influenza or parainfluenza virus infection can be detected in mice [3]. The delay in the onset of anti-viral immunity is presumably due to the presence of viral-encoded antagonists that counteract immune recognition by blocking detection and/or signaling by cellular sensors so that the virus can grow and spread successfully.

Dr. López’s group seeks to understand the cellular mechanisms that overcome viral antagonism of immune responses to pathogenic respiratory viruses, such as influenza, parainfluenza, and respiratory syncytial virus. The group is currently assessing the cellular response mediated by the viral sensors RIG-I and MDA5. Challenging the current paradigm, the group has shown that both proteins are involved in the response to parainfluenza virus [2] and they are currently investigating the specific role of each of these molecules in immune recognition and response to virus infection, as well as in overcoming viral immune antagonism. Dr. López is particularly interested in investigating cellular molecules that are involved in the efficient response to DIVGs.

Lung-Bone Marrow Axis: Essential role in anti-viral immunity.

Upon viral recognition and sensing of the infecting virus, infected cells produce cytokines and chemokines that promote the recruitment and activation of immune cells. Dr. López lab has shown that soon after a respiratory infection, molecules produced in the infected lung are transported through the blood to signal cells located in the distal bone marrow [4, 5]. Cells instructed in the bone marrow become resistant to virus infection and respond more efficiently to viral cues when recruited to the lung, thereby enhancing the innate immune response and facilitating the clearance of the virus. Dr. López group identified type I interferons as critical mediators of lung-bone marrow communication during viral infection [5, 4]. The group is currently interested in characterizing other mediators of the lung-bone marrow axis and in determining their role during the initial anti-viral response. In addition, they are investigating the specific effects of these signals in specific bone marrow cell populations.

Dr. López’s research is currently funded by the NIH/NIAID (R01AI083284 and R21AI083481). Her laboratory is located in the Hill Pavilion 337 and her office in Suite 318 Hill Pavilion.

References:

1. Yount, J.S., et al., A novel role for viral-defective interfering particles in enhancing dendritic cell maturation. J Immunol, 2006. 177(7): p. 4503-13.

2. Yount, J.S., et al., MDA5 Participates in the Detection of Paramyxovirus Infection and Is Essential for the Early Activation of Dendritic Cells in Response to Sendai Virus Defective Interfering Particles. J Immunol, 2008. 180(7): p. 4910-8.

3. Moltedo, B., et al., Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity. J Immunol, 2009. 183(6): p. 3569-73.

4. Hermesh, T., et al., Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe, 2010. 7(5): p. 343-53.

5. Lopez, C.B. and T. Hermesh, Systemic responses during local viral infections: type I IFNs sound the alarm. Current opinion in immunology, 2011. 23(4): p. 495-9.