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 primary 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?
1. Lopez CB. Defective Viral Genomes: Critical Danger Signals of Viral Infections. J Virol. 2014;88(16):8720-3.
2. 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.
3. 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.
4. 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.
5. 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.
6. Yount JS, Moran TM, and Lopez CB. Cytokine-independent upregulation of MDA5 in viral infection. J Virol. 2007;81(13):7316-9.
7. 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 the 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?
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
* For up to date information on our research go to www.lopezlab.org
* For up to date publications go to www.lopezlab.org
Nogusa S, Thapa RJ, Dillon CP, Oguin III TH, Ingram JP, Kosoff R, Sharma S, Sturm O, Verbist K, Slifker MJ, Gough P, Bertin P, Kaiser WJ, Mocarski ES, López CB, Thomas PG, Oberst A, Green DR, and Balachandran S. (2016). RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis to protect against influenza A virus. Cell Host & Microbes pii: S1931-3128(16)30207-4. doi: 10.1016/j.chom.2016.05.011. [Epub ahead of print] PMID: 27321907.
Sun Y, and López CB. (2016) Respiratory syncytial virus infection in mice and detection of viral genomes in the lung using RT-qPCR. Bio-protocol 6(10): e1819. http://www.bio-protocol.org/e1819.
Sun Y, and López CB. (2016) Preparation of respiratory syncytial virus stocks and purification of defective viral particles. Bio-protocol 6(10): e1820. http://www.bio-protocol.org/e1820.
Penkala I, Wang J, Syrett CM, López CB, and Anguera MC. (2016) LNCRHOXF1: a long noncoding RNA from the X-chromosome that suppresses viral response genes during development of the early human placenta. Mol. Cell. Biol. pii: MCB.01098-15. [Epub ahead of print].
Xue J, Chambers BS, Hensley SE and López CB. (2016) Propagation and characterization of influenza virus stocks that are not loaded with defective viral genomes and hemagglutinin mutations. Front. Microbiol. 7:326 doi: 10.3389/fmicb.2016.0032.
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. (2015). Identification of a Natural Viral RNA Motif that Facilitates Viral Recognition by RIG-I-Like Receptors. mBio 6(5):e01265-15. doi:10.1128/mBio.01265-15
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. 11(9): e1005122. doi:10.1371/journal.ppat.1005122
Benitez AA, Panis M, Xue J, Shim JV, Varble A, Frick AL, López CB, Sachs D, and tenOever BR. (2015) In vivo RNAi screening identifies MDA5 as a contributor to the cellular defense against influenza A virus. Cell Reports, published online on 11 June, 2015 doi:10.1016/j.celrep.2015.05.032.
López CB. (2014) Defective viral genomes: critical danger signals of viral infections (Review). Gem, J.Virol., published ahead of print 28 May 2014 , doi:10.1128/JVI.00556-14.
Kim WK, Jain D, Sánchez MD, Koziol-White C, Matthews K, Ge M, Haczku A, Panettieri RA, Frieman MB, and López CB. (2014) Deficiency of Melanoma Differentiation-associated protein 5 results in Exacerbated Chronic Post-Viral Lung Inflammation. Am. J. Respir. Crit. Care Med. 189(4):437-48. doi: 10.1164/rccm.201307-1338OC. PMID: 24417465.
Tapia K, Kim WK, Sun Y, Mercado-López X, Dunay E, Wise M, Adu M, and López CB. (2013) Defective Viral Genomes Arising In Vivo Provide Critical Danger Signals for the Triggering of Lung Antiviral Immunity. PLOS Pathog 9(10): e1003703. doi:10.1371/journal.ppat.1003703. * Featured Article. *Co-first authors.
Mercado-López M, Cotter CR, Kim WK, Muñoz L, Sun Y, Tapia K, and López CB. (2013) Highly Immunostimulatory RNA Derived from a Sendai Virus Defective Viral Genome. Vaccine. 2013 Oct 4. pii: S0264-410X(13)01294-2. doi: 10.1016/j.vaccine.2013.09.040. [Epub ahead of print] PMID: 2409987.
Hermesh T, Moran TM, Jain. D, and López CB. (2012) Granulocyte colony-stimulating factor protects mice during respiratory virus infections. PLOS One 7(5): e37334. doi:10.1371/journal.pone.0037334. PMID: 22615983 PMCID: PMC3353936.
Harty RN, Schmitt AN, Bouamr F, López CB and Krummenacher C. (2011) Virus Budding/Host Interactions. Advances in Virology-Editorial. EPub doi:10.1155/2011/963192.
Neil RC, Tapia KA, Dandapani A, MacArthur BD, López C, Ma’ayan A. (2011). Stochastic model of virus and defective interfering particle spread across mammalian cells with immune response. Q-bio.PE, arXiv:1108.4901.
Cotter C, Kim WK, Nguyen M, Yount J, López CB, Blaho, and Moran TM. (2011) The Virion Host Shut-off (vhs) Protein of HSV-1 Blocks the Replication-Independent Activation of NF-κB in Dendritic Cells. J. Virol. Sept 21, EPub Ahead of Print. PMID: 2193765.
López CB and Hermesh T. (2011) Systemic Responses During Local Viral Infections: Type I IFNs Sound the Alarm (Review). Curr. Opin. Immunol 23(4):495-9. PMID: 21752617 PMCID: PMC3163724.
Zhang J, Zhang Y, Dutta D, Argaw AT, Bonnamain V, Seto J, Braun DA, Zameer A, Hayot F, López CB, Raine CS and John GR (2011) Pro- and Anti-apoptotic Actions of Stat1 versus Stat3 Underlie Neuroprotective and Immunoregulatory Functions of Interleukin-11. J. Immunol. 187:1129-1141. PMID: 21709156.
Leung LW, Park M, Martinez O, Valmas C, López CB, and Basler CF. (2011) The Ebolavirus VP35 Protein Suppresses Interferon Production from Conventional but not Plasmacytoid Dendritic Cells. Immunology and Cell Biology. EPub ahead of print. 25 Jan. PMID: 21263462.
Hu J, Nudelman G, Shimoni Y, Kumar M, Ding Y, López C, Hayot F, Wetmur JG, Sealfon SC. (2011) Role of Cell-to-Cell Variability in Activating a Positive Feedback Antiviral Response in Human Dendritic Cells. PLOS One. 2011 Feb 8;6(2):e16614.
2010 and before
Hermesh T, Moltedo B, López CB and Moran TM. (2010) Buying Time—The Immune System Determinants of the Incubation Period to Respiratory Viruses-Review. Viruses 2:2541-2558. PMID: 21994630 PMCID: PMC3185581.
Yount JS, Moltedo B, Yang Y, Charron G, Moran TM, López CB and Hang HH. (2010) Palmitoylome profiling reveals S-palmitoylation-dependent anti-viral activity of IFITM3. Nature Chem. Biol. 6:610-614. PMID: 20601941 *Evaluated in the Faculty of 1000 website.
Hermesh T, Moltedo B, Moran TM and López CB. (2010) Antiviral Instruction of Bone Marrow Leukocytes during Respiratory Viral Infections. Cell Host & Microbe.7:343-353. PMID: 20478536. PMCID: PMC2874206 * Featured Article and Previewed.
Cotter C, Nguyen ML, López CB, Blaho JA and Moran TM. (2010) Virion-Associated Vhs Protein Blocks the Activation of Human Dendritic Cells during a Productive HSV-1 Infection. PLOS One. 5:e8684. PMCID: PMC2823768.
Gurfein TB, Zhang Y, López CB, Argaw AT, Zameer A, Moran TM and John GR. Interleukin-11 Regulates Autoimmune Demyelination (2009). J Immunol. 183:4229-4240. PMID: 19734214.
Moltedo B, López CB, Pazos M, Becker MI, Hermesh T and Moran TM. (2009) Cutting Edge: stealth Influenza Virus Replication Precedes the Initiation of Adaptive Immunity. J Immunol. 183:3569-3573. PMID: 19717515.
Escribese MM, Kraus T, Rhee E, Fernandez-Sesma A, López CB and Moran TM. (2008) Estrogen Inhibits Dendritic Cell Maturation to dsRNA Viruses. Blood. 112:475-84. PMID: 18802009, PMCID: PMC2597128.
Yount JS, Gitlin L, Moran TM and López CB. (2008) MDA5 Participates in the Detection of Paramyxovirus Infection and is Essential for the Early Activation of DCs in Response to SeV DI Particles. J. Immunol. 180:4910-4919. PMID: 18354215.
Yount JS, Moran TM and López CB. (2007) Cytokine-Independent Upregulation of MDA5 in Viral Infection. J. Virol. 81:7316-7319. PMID: 17475649, PMCID: PMC1933291.
Yount JS, Kraus T, Horvath C, Moran TM and López CB. (2006) A Novel Role for Defective Interfering Particles in Enhancing Dendritic Cell Maturation. J. Immunol. 177:4503-4513. PMID: 16982887.
López CB, Yount JS, Hermesh T and Moran TM. (2006) Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I IFNs. J. Virol. 80:4538-4545. PMID: 16611914, PMCID: PMC1472017.
López CB, Yount JS and Moran TM. (2006) Minireview. TLR-independent Triggering of Dendritic Cell Maturation by Viruses. J. Virol. 80:3128-3134. PMID: 16505141, PMCID: PMC1440398.
Trumpfheller C, Finke JS, López CB, Moran TM, Moltedo B, Soares H, Huang Y, Schesinger S, Park CG, Nussenzweig MC, Granelli-Piperno A, Steinman RM. (2006) Intensified and Protective CD4+ T Cell Based Immunity at a Mucosal Surface Induced in Mice with Anti-dendritic Cell HIV gag Fusion Antibody Vaccine. J. Exp. Med. 203:607-617. PMCID: PMC2118242.
López CB, Moltedo B, Alexopoulou L, Bonifaz L, Flavell R and Moran T (2004). TLR-Independent Induction of Dendritic Cell Maturation and Immunity by Negative Stranded RNA Viruses. J. Immunol. 173:6882-6889. PMID: 15557183. *Evaluated in the Faculty of 1000 website.
Silva MA, López CB, Rivertin F, Oligny L, Menezes J and Seidman E (2004). Characterization and Distribution of Colonic Dendritic Cells in Paediatric Crohn’s Disease. Inf. Bowel Dis.10:504-512. PMID: 15472509.
López CB, Garcia-Sastre A, Williams BRG and Moran T (2003). The Type I Interferon Pathway, but Not the Secreted Interferon, Participates in the Maturation of Dendritic cells Induced by Negative Stranded RNA Viruses. J Inf. Dis., 187:1123-1136. PMID: 12660927.
López CB, Moran TM, Schulman JL, and Fernandez-Sesma A (2002) Antiviral Immunity and the Role of Dendritic Cells. Int. Rev. Immunol. 21:339-353. PMID: 12486818.
López CB, Fernandez-Sesma A, Schulman J and Moran T (2001) Myeloid Dendritic Cells Stimulate Both Th1 and Th2 Immune Responses depending on the Nature of the Antigen. J. Interf. Cytok. Res.21:763-773. PMID: 11576470.
López CB, Fernandez-Sesma A, Czelusniak S, Schulman J and Moran T (2000) A Mouse Model for immunization with Ex-Vivo Virus-Infected Dendritic Cells. Cell. Immunol. 206:107-115. PMID: 11161442.
López CB, Rao DT, Freiner H, Shapiro R, Marks J and Frey A (1998) Repression of Interleukin-2 mRNA Translation in Primary Human Breast Carcinoma Tumor Infiltrating Lymphocytes. Cell. Immunol. 190:141-155. PMID: 9878115.
López CB, Kalergis AM, Becker MI, Garbarino JA and De Ioannes AE (1998). CD8+ T Cells are the Effectors Cells of the Contact Dermatitis Induced by Urushiol in Mice and are Regulated by CD4+ T Cells. Int. Arch. Allergy and Immunol. 117:194-201. PMID: 9831807.
Kalergis AM, López CB, Díaz MI, Becker MI, Garbarino JA and De Ioannes AE (1997) Modulation by Clofibrate and Tetradecyl Glycidic Acid of the Contact Dermatitis Induced in Mice by an Urushiol Related Allergen 3-Pentadecyl (10-enyl) Cathecol. J. of Invest. Dermat. 108: 57-61. PMID: 8980288.
Book Chapters (Peer-Reviewed)
Moran T.M and López CB. (2009) Host Immune Response to Influenza Virus in “RNA Viruses: Host gene response to Infection” Decheng Yang, Editor. World Scientific Publishing, Vancouver, BC, Canada.