Description of Research Expertise:
Mechanisms of HIV/SIV entry and target cell tropism, and their role in pathogenesis.
Monocyte/macrophage activation in HIV infection: mechanisms, role in pathogenesis, and modulation.
Microbiome and molecular microbiology of the human respiratory tract.
Key words: HIV, SIV, virus, tropism, signal transduction, gp120, viral envelope, macrophage, microbiome, lung microbiology.
Description of Research
Project 1. HIV/SIV entry. Our lab studies HIV and SIV infection, focusing on the mechanisms of entry into different target cells and how viral target cell tropism influences disease. HIV and SIV target T lymphocytes and macrophages, and within the T lymphocyte group several subsets of cell populations may be infected. Current work is focuses on how entry pathways including CCR5 and CXCR4, and in particularly non-cannonical entry coreceptors, are used in pathogenic (HIV-1, SIVmac infection of rhesus macaques) and non-pathogenic natural host (SIVsmm infection of sooty mangabeys), and how differential entry corecepto use and cell targeting may underlie outcome from infection.
Project 2. Monocyte/macrophage activation in HIV infection: mechanisms, role in pathogenesis and modulation. Immune activation, combined with viral replication, is an important driver of pathogenesis. In particular, neuropathogenesis (HIV dementia) is linked to monocyte activation in the systemic circulation and macrophage activation within the brain. Even in ART-treated subjects with viral suppression, activation persists and is associated with development of neurocognitive defecits. We are studying the features and mechanisms of persistent monocyte/macrophage immune activation, link to neuropathogenesis, and novel approches to combine with ART viral suppression that may modulate monocyte/macrophage activation.
Project 3. Human respiratory tract microbiome. The human lungs are normally thought to be sterile below the vocal cords. New molecular approaches now enable comprehensive analysis of bacterial, fungal and viral populations within particular niches. We are using high-stringency sampling, high-density sequencing, and novel bioinformatic approaches to determine the microbial inhabitants in the lower resiratory tract and upper respiratory tract in healthy people, and in disease states such as HIV infection, lung transplantation, and other lung diseases, and how microbial communities influence disease. We are also developing novel approaches to broad-range diagnostics for lung colonization and infection.
1. Define the distribution and use of alternative entry coreceptors on human, rhesus and mangabey lymphoid and monocytoid cell subsets.
2. Map viral determinants of SIV alterntative coreceptor utilization.
3. Test immune activation suppression of monocyte activation by HIV Env and LPS.
4. Transcriptional profiling of residual monocyte activation in ART-suppressed subjects.
5. Define the uncultured bacterial 16S sequences in lungs samples from patients with pneumonia
6. Determine fungal ITS sequences in lung samples.
Sarah Elliott (graduate student)
Nick Francella (graduate student)
Emily Charlson (graduate student)
Nadeene Riddick (graduate student)
Steven Bryan (Technician)
Yanjie Yi, PhD (Senior Research Investigator)
Anjana Yadav, PhD (Senior Research Investigator)
Farida Shaheen, PhD (Senior Research Investigator)
Ayannah Fitzgerald, BSN (Study Coordinator)
Wetzel, K.S., Bayer, A., Bello, E., Romero, D., Yi, Y., Bibollet-Ruche, F., Hahn, B.H., Silvestri, G., Peeters, M., Collman, R.G.: Loss of CXCR6 coreceptor usage characterizes pathogenic lentivirus infections PLoS Pathogens 14 (4): e1007003,2018.
Clarke, E.L., Lauder, A.P., Hofstaedter, C.E., Fitzgerald, A.S., Imai, I., Bierna, W., Bekawiecki, B., Majewska, H., Dubaniewicz, A., Litzky, L.A., Feldman, M.D., Bittinger, K., Rossman, M.D., Patterson, K.C., Bushman, F.D., Collman, R.G.: Microbial lineages in sarcoidosis: A metagenomic analysis tailored for low microbial content samples Am. J. Respiratory Crit. Care Med. 197 (2): 2018.
Sherril-Mix, S., McCormick, K., Lauder, Al, Bailey, A., Zimmerman, L., Li, Y., Django, J.B.N., Bertolani, P., Colin, C., Hart, J.A. Hart, T.B., Georgiev, A.V., Zanz, C.M., Morgan, D. B., Atencia, R., Cox, D., Muller, M.N., Sommer, V., Piel, A., Stewart, F.A., Speede, S., Roman, J., Wu, G., Taylor, J., Bohm, R., Rose, H.M., Carlson, J., Mjungu, D., Schmidt, Pl, Gaughan, C., Bushman, J.I., Schmidt, E., Bittinger, K., Collman, R.G., Hahn, B.H., Bushman, F.D.: Allometry and ecology of the bilaterian gut microbiome mBio 9 (2): pii: e00319-18. doi: 10.1128/mBio.00319-18.,2018.
Abass, A., Diamond, J.M., Chehoud, C., Chang, B., Kotzin, J.J., Young, J.C., Imai, I., Haas, A.R., Cantu, E., Lederer, D.J., Meyer, K., Milewski, K., Orthoff, K.M., Shaked, A., Christie, J.D., Bushman, F.D., Collman, R.G.: The Perioperative Lung Transplant Virome: Torque Teno Viruses are Elevated in Donor Lungs and Show Divergent Dynamics In Primary Graft Dysfunction Am. J. Transplantation 17 (5): 1313-1324,2017.
Wetzel, K.S., Yi, Y., Elliott, S.T.C., Romero, D., Hahn, B.H., Muller-Trutwin, M., Apetrei, C., Pandrea, I., Collman, R.G.: CXCR6-mediated SIVagmSab entry into Sabaeus African Green Monkey lymphocytes implicates widespread use of non-CCR5 pathways in natural host infections J. Virology 91 (4): 2017.
Yadav, A., Betts, M.R., Collman, R.G.: Statin modulation of monocyte phenotype and function: implications for HIV-1 associated neurocognitive disorders J. Neurovirology 4 (1): 7,2016.
Kelly, B.J., Imai, I., Bittinger, K., Laughlin, A., Fuchs, B.D., Bushman, F.D., Collman, R.G.: Composition and dynamics of the respiratory tract microbiome in intubated patients Microbiome 11 (4): 7,2016.
Elliott, S.T.C., Wetzel, K.S., Francella, N., Bryan, S., Romero, D., Riddick, N.E., Shaheen, F., Vanderford, T., Derdeyn, C.A., Silvestri, G., Paiardini, M., Collman, R.G.: Dual-tropic CXCR6/CCR5 Simian Immunodeficiency Virus infection of Sooty Mangabey primary lymphocytes: Distinct coreceptor use in SIV natural versus pathogenic hosts J. Virology 89 (18): 9252-61,2015.
Young, J.C., Chehoud, C., Bittinger, K., Bailey, A., Diamond, J.M., Cantu, E., Abbas, A., Frye, L., Christie, J.D., Bushman, F.D., Collman, R.G.: Viral metagenomics reveals blooms of anelloviruses in the respiratory tract of lung transplant recipients Am. J. Transplantation 15 (1): 200-9,2015.
Beck, J.M., Schloss, P.D., Venkataraman, A., Twigg III, H., Jablonski, K.A., Bushman, F.D., Campbell, T.B., Charlson, E.S., Collman, R.G., Crothers, K., Curtis, J.L., Drews, K.L., Flores, S.L., Fontenot, A.P. Foulkes, M.P., Frank, I., Ghedin, E., Huang, L., Lynch, S.V., Morri, A., Palmer, B.E., Schmidt, T.M., Sodergren, E., Weinstock, G.M., Young, VB., for the Lung HIV Microbiome Project.: Multi-center Comparison of Lung and Oral Microbiomes of HIV-Infected and HIV-Uninfected Individuals. Am. J. Respiratory Crit. Care Med. 192 (11): 1335-44,2015.