Ongoing projects:   

                Our laboratory studies the events that ignite and regulate the host antiviral immune response resulting in viral clearance.  The overall goal of the laboratory is to identify viral and cellular factors that drive the development of effective antiviral immune responses able to control virus replication and dissemination. We are particularly interested in the immune responses to viruses that have developed efficient mechanisms to antagonize the immune system. We use a number of mouse models of respiratory infection including respiratory syncytial virus, influenza virus, and the mouse pathogen Sendai virus. We have strong virology and immunology components and use multiple in vitro and in vivo techniques to gather an inclusive mechanistic understanding of the processes that determine the successful development of antiviral immunity. We hope to gather knowledge that will lead to the development of better antiviral therapies and vaccines. We are interested in the following specific areas: 

Defective viral genomes as triggers of antiviral immunity

Virus replication generates multiple products in addition to full-length standard viruses. These products include a variety of slightly mutated versions of the virus (quasispecies) that enhance virus fitness, and a much less understood set of severely truncated genomic products collectively named defective viral genomes (DVGs) for their inability to replicate without a helper virus. Although most viruses generate a discrete population of DVGs, they have been considered irrelevant byproducts of virus replication and their biological role largely overlooked (1). DVGs were discovered in the 40s, and it was an active research field that was brought to a halt in the mid 80s when DVGs were considered in vitro artifacts of virus replication in tissue culture. Lack of appropriate technology further impaired their study in the context of infection. A handful of virologists studied viral particles containing DVGs by 2005, mainly using them as tools to understand virus replication, or as potential adjuvants for vaccination. However, with the aid of new technology, we have shown that DVGs serve as de facto danger signals for the triggering of immunity in infections with a number of respiratory viruses in mice and humans (2-5) and only cells with high numbers of DVGs show strong antiviral responses in vitro and in vivo (2, 3, 6, 7). Current projects in the lab aim at answering the following questions:


1. What is the molecular basis for the recognition of DVGs as danger signals that trigger immunity?

2. Are DVGs critical determinants of host survival and virus perpetuation?

3. Can we harness DVGs to better human health?


References:

1. Xu J, Mercado-López X, Grier J, Kim W, Chun L, Irvine EB, Del Toro Y, Kell A, Hur S, Gale M, Raj A, and López CB. Identification of a Natural Viral RNA Motif that Facilitates Viral Recognition by RIG-I-Like Receptors. mBio 2015 6(5):e01265-15.
2. Sun Y, Jain D, Koziol-White CJ, Genoyer E, Gilbert M, Tapia K, Panettieri RA, Hodinka RL, and López CB. Immunostimulatory Defective Viral Genomes Promote Strong Innate Antiviral Responses During Respiratory Syncytial Virus Infection in Mice and Humans (2015). PLOS Pathog. 2015 11(9): e1005122. 
3. Lopez CB. Defective Viral Genomes: Critical Danger Signals of Viral Infections. J Virol. 2014;88(16):8720-3. 
4. Tapia K, Kim WK, Sun Y, Mercado-Lopez X, Dunay E, Wise M, Adu M, and Lopez CB. Defective viral genomes arising in vivo provide critical danger signals for the triggering of lung antiviral immunity. PLoS Pathog. 2013;9(10):e1003703.
5. Mercado-Lopez X, Cotter CR, Kim WK, Sun Y, Munoz L, Tapia K, and Lopez CB. Highly immunostimulatory RNA derived from a Sendai virus defective viral genome. Vaccine. 2013;31(48):5713-21.
6. Yount JS, Gitlin L, Moran TM, and Lopez CB. 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):4910-8.
7. Yount JS, Moran TM, and Lopez CB. Cytokine-independent upregulation of MDA5 in viral infection. J Virol. 2007;81(13):7316-9. 
8. Yount JS, Kraus TA, Horvath CM, Moran TM, and Lopez CB. A novel role for viral-defective interfering particles in enhancing dendritic cell maturation. J Immunol. 2006;177(7):4503-13.
9. Lopez CB, Yount JS, Hermesh T, and Moran TM. Sendai virus infection induces efficient adaptive immunity independently of type I interferons. J Virol. 2006;80(9):4538-45.

Regulation of the lung antiviral response


Upon viral recognition and sensing of the infecting virus, infected cells produce cytokines and chemokines that promote the recruitment and activation of immune cells. This inflammatory response that is essential for viral clearance could result in lung damage and the development of disease. We study innate immune factors that determine clinical outcome during respiratory viral infections. Our work revealed that bone marrow leukocytes enhance their protective capacity in response to cytokines produced at the lung and transmitted through the blood. This distal instruction mechanism allows cells to escape virus antagonism once recruited to the lung revealing an adaptation to counter viruses that interfere with immune recognition (8-10). In addition, we reported a critical role of t
he viral sensor protein MDA5 in the detection of the respiratory viruses Sendai viral and influenza virus (11, 12). These data exposed an intriguing non-redundant role of intracellular viral sensing molecules during virus infection. Current projects in the lab aim at answering the following questions: 

1. How do different viral sensing molecules orchestrate the innate antiviral immune response in the lung?

2. What is the impact of antiviral molecules on disease outcome and long-term pulmonary disease?

3. What innate immune mechanisms protect the lung from acute and chronic post-viral disease?

References:

1. Hermesh T, Moran TM, Jain D, and Lopez CB. Granulocyte Colony-Stimulating Factor Protects Mice during Respiratory Virus Infections. PLoS One. 2012;7(5):e37334.
2. Lopez CB, and Hermesh T. Systemic responses during local viral infections: type I IFNs sound the alarm. Curr Opin Immunol. 2011;23(4):495-9.
3. Hermesh T, Moltedo B, Moran TM, and Lopez CB. Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe. 2010;7(5):343-53.
4. Benitez AA, Panis M, Xue J, Varble A, Shim JV, Frick AL, Lopez CB, Sachs D, and tenOever BR. In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus. Cell Rep. 2015;11(11):1714-26.
5. Kim WK, Jain D, Sanchez MD, Koziol-White CJ, Matthews K, Ge MQ, Haczku A, Panettieri RA, Jr., Frieman MB, and Lopez CB. Deficiency of Melanoma Differentiation-associated Protein 5 Results in Exacerbated Chronic Postviral Lung Inflammation. Am J Respir Crit Care Med. 2014;189(4):437-48.