Our laboratory focuses on the study of the innate immune response to well-adapted respiratory viruses. We are particularly interested in understanding the early events of the virus-host interaction that determine the quality of the antiviral response and the clinical outcome of the infection. 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:
a. Identification and characterization of viral features and host molecular mechanisms that determine the onset and quality of the antiviral immune response.
We have described a critical role for defective viral genomes (DVGs), which were until recently considered an epiphenomenon of in vitro virus replication, as primary stimuli for the activation of the antiviral response, both in vitro and in vivo. DVGs are generated by a large number of animal and plant viruses, but their role during the virus-host cycle remained speculative. We recently demonstrated that DVGs arise naturally during mouse infection with SeV or with mouse-adapted influenza virus and provide primary danger signals for the initiation of the antiviral response in the lung. We are interested in identifying viral features that confer the potent immunostimulatory activity to DVGs and to harness these motifs for the development of novel adjuvants. We are also interested in characterizing the host pathways involved in the response to DVGs in order to identify potential targets for antiviral therapy. Moreover, we are investigating the role of DVGs in determining the antiviral response during respiratory infections in the human lung in order to establish the role of DVGs in respiratory virus pathogenesis in humans.
Systemic regulation of the lung antiviral response.
b. Characterization of host mechanisms that regulate the antiviral immune response ensuring clearance of the virus while minimizing damage of the host tissue.
Upon viral recognition and sensing of the infecting virus, infected cells produce cytokines and chemokines that promote the recruitment and activation of immune cells. We reported 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. Cells instructed in the bone marrow by type I IFNs produced in the lung and transported to the bone marrow through the blood become resistant to virus infection and respond more efficiently to viral cues when recruited to the lung, therefore enhancing the innate immune response and facilitating the clearance of the virus. We are currently interested in characterizing other mediators of the lung-bone marrow axis and in determining their role during the initial anti-viral response. In particular, we are investigating the regulatory function of innate immune cells that massively infiltrate the lung during infection and that contribute to virus clearance while protecting the tissue for excessive damage.
Micah Gilbert (Undergraduate Student); Emily Dunay (Undergraduate Student); Yan Sun PhD (Postdoc); Jennifer Grier PhD (postdoc); Jie Xu PhD (postdoc); Deepika Jain PhD (Lab Manager); Jia Xue (Student, Visiting Scholar).
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Kim WK, Jain D, Sánchez MD, Koziol-White CJ, Matthews K, Ge MQ, Haczku A, Panettieri RA Jr, Frieman MB, López CB. Deficiency of MDA5 Results in Exacerbated Chronic Post-Viral Lung Inflammation. Am J Respir Crit Care Med. in press: , 2014.Mercado-López X, Cotter CR, Kim WK, Muñoz L, Tapia K, and López CB. Highly Immunostimulatory RNA Derived from a Sendai Virus Defective Viral Genome. Vaccine 31(48): 5713-21, 2013.Tapia K, Kim WK, Sun Y, Mercado-López X, Dunay E, Wise M, Adu M, and López CB Defective Viral Genomes Arising In Vivo Provide Critical Danger Signals for the Triggering of Lung Antiviral Immunity. PLoS Pathogens 9(10): , 2013.Hermesh T, Moran TM, Jain. D, and López CB. Granulocyte colony-stimulating factor protects mice during respiratory virus infections. PLoS One 7(5):e37334: , 2012.López CB and Hermesh T Systemic Responses During Local Viral Infections: Type I IFNs Sound the Alarm Curr.Opi. Immunol. : , 2011.Hu Jianzhong, Nudelman German, Shimoni Yishai, Kumar Madhu, Ding Yaomei, López Carolina, Hayot Fernand, Wetmur James G, Sealfon Stuart C Role of cell-to-cell variability in activating a positive feedback antiviral response in human dendritic cells. PloS one 6: e16614, 2011.Leung Lawrence W, Park Man-Seong, Martinez Osvaldo, Valmas Charalampos, López Carolina B, Basler Christopher F Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells. Immunology and cell biology : , 2011.Hermesh T, Moltedo B, López CB and Moran TM Buying Time—The Immune System Determinants of the Incubation Period to Respiratory Viruses Viruses 2: 2541, 2010.Hermesh Tamar, Moltedo Bruno, Moran Thomas M, López Carolina B Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell host & microbe 7: 343-53, 2010.Yount Jacob S, Moltedo Bruno, Yang Yu-Ying, Charron Guillaume, Moran Thomas M, López Carolina B, Hang Howard C Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Nature chemical biology 6: 610-4, 2010.