Search

Your search keyword '"Busman-Sahay, Kathleen"' showing total 45 results
Start Over Author "Busman-Sahay, Kathleen" Search Limiters Available in Library Collection
45 results on '"Busman-Sahay, Kathleen"'

1. In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation

Author

Jensen, Björn-Erik Ole, Knops, Elena, Cords, Leon, Lübke, Nadine, Salgado, Maria, Busman-Sahay, Kathleen, Estes, Jacob D., Huyveneers, Laura E. P., Perdomo-Celis, Federico, Wittner, Melanie, Gálvez, Cristina, Mummert, Christiane, Passaes, Caroline, Eberhard, Johanna M., Münk, Carsten, Hauber, Ilona, Hauber, Joachim, Heger, Eva, De Clercq, Jozefien, Vandekerckhove, Linos, Bergmann, Silke, Dunay, Gábor A., Klein, Florian, Häussinger, Dieter, Fischer, Johannes C., Nachtkamp, Kathrin, Timm, Joerg, Kaiser, Rolf, Harrer, Thomas, Luedde, Tom, Nijhuis, Monique, Sáez-Cirión, Asier, Schulze zur Wiesch, Julian, Wensing, Annemarie M. J., Martinez-Picado, Javier, and Kobbe, Guido

Published
2023
Full Text
View/download PDF

2. Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques

Author

Wu, Helen L., Busman-Sahay, Kathleen, Weber, Whitney C., Waytashek, Courtney M., Boyle, Carla D., Bateman, Katherine B., Reed, Jason S., Hwang, Joseph M., Shriver-Munsch, Christine, Swanson, Tonya, Northrup, Mina, Armantrout, Kimberly, Price, Heidi, Robertson-LeVay, Mitch, Uttke, Samantha, Kumar, Mithra R., Fray, Emily J., Taylor-Brill, Sol, Bondoc, Stephen, Agnor, Rebecca, Junell, Stephanie L., Legasse, Alfred W., Moats, Cassandra, Bochart, Rachele M., Sciurba, Joseph, Bimber, Benjamin N., Sullivan, Michelle N., Dozier, Brandy, MacAllister, Rhonda P., Hobbs, Theodore R., Martin, Lauren D., Panoskaltsis-Mortari, Angela, Colgin, Lois M.A., Siliciano, Robert F., Siliciano, Janet D., Estes, Jacob D., Smedley, Jeremy V., Axthelm, Michael K., Meyers, Gabrielle, Maziarz, Richard T., Burwitz, Benjamin J., Stanton, Jeffrey J., and Sacha, Jonah B.

Published
2023
Full Text
View/download PDF

3. HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells

Author

Wang, Yetao, Lifshitz, Lawrence, Gellatly, Kyle, Vinton, Carol L, Busman-Sahay, Kathleen, McCauley, Sean, Vangala, Pranitha, Kim, Kyusik, Derr, Alan, Jaiswal, Smita, Kucukural, Alper, McDonel, Patrick, Hunt, Peter W, Greenough, Thomas, Houghton, JeanMarie, Somsouk, Ma, Estes, Jacob D, Brenchley, Jason M, Garber, Manuel, Deeks, Steven G, and Luban, Jeremy

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Sexually Transmitted Infections, Infectious Diseases, Clinical Research, HIV/AIDS, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Infection, Good Health and Well Being, Cytokines, Gene Expression Regulation, HIV Infections, HIV-1, Homeostasis, Humans, Immunity, Innate, Immunologic Memory, In Vitro Techniques, Inflammation, Killer Cells, Natural, Lymphocytes, T Cell Transcription Factor 1, Wnt Signaling Pathway, Biochemistry and cell biology
Abstract

Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.

Published
2020

4. Impact of alemtuzumab-mediated lymphocyte depletion on SIV reservoir establishment and persistence.

Author

Varco-Merth, Benjamin, Chaunzwa, Morgan, Duell, Derick M., Marenco, Alejandra, Goodwin, William, Dannay, Rachel, Nekorchuk, Michael, Shao, Danica, Busman-Sahay, Kathleen, Fennessey, Christine M., Silipino, Lorna, Hull, Michael, Bosche, William J., Fast, Randy, Oswald, Kelli, Shoemaker, Rebecca, Bochart, Rachele, MacAllister, Rhonda, Labriola, Caralyn S., and Smedley, Jeremy V.

Subjects
T cells, RHESUS monkeys, LYMPHOID tissue, BLOOD cells, HIV-positive persons, ALEMTUZUMAB
Abstract

Persistence of the rebound-competent viral reservoir (RCVR) within the CD4+ T cell compartment of people living with HIV remains a major barrier to HIV cure. Here, we determined the effects of the pan-lymphocyte-depleting monoclonal antibody (mAb) alemtuzumab on the RCVR in SIVmac239-infected rhesus macaques (RM) receiving antiretroviral therapy (ART). Alemtuzumab administered during chronic ART or at the time of ART initiation induced >95% depletion of circulating CD4+ T cells in peripheral blood and substantial CD4+ T cell depletion in lymph nodes. However, treatment was followed by proliferation and reconstitution of CD4+ T cells in blood, and despite ongoing ART, levels of cell-associated SIV DNA in blood and lymphoid tissues were not substantially different between alemtuzumab-treated and control RM after immune cell reconstitution, irrespective of the time of alemtuzumab treatment. Upon ART cessation, 19 of 22 alemtuzumab-treated RM and 13 of 13 controls rebounded in <28 days with no difference in the time to rebound between treatment groups. Time to rebound and reactivation rate was associated with plasma viral loads (pVLs) at time of ART initiation, suggesting lymphocyte depletion had no durable impact on the RCVR. However, 3 alemtuzumab-treated RM that had lowest levels of pre-ART viremia, failed to rebound after ART withdrawal, in contrast to controls with similar levels of SIV replication. These observations suggest that alemtuzumab therapy has little to no ability to reduce well-established RCVRs but may facilitate RCVR destabilization when pre-ART virus levels are particularly low. Author summary: A major challenge to curing HIV is the presence of cells with rebound-competent viral reservoirs (RCVR) capable of re-establishing systemic infection when ART is interrupted. CD4+ T cells harboring RCVR persist for life due to homeostatic mechanisms that allow them to proliferate and expand during ART. In this study, we explored whether pan-lymphocyte depletion with a licensed CD52-depleting monoclonal antibody called alemtuzumab, can eliminate or reduce RCVR in SIV-infected rhesus macaques (RM) when administered either at the time of ART initiation or during chronic ART administration. While alemtuzumab induced massive depletion of lymphocytes in blood, including >95% depletion of CD4+ T cells, there were no measurable effects of alemtuzumab on cell-associated viral loads during ART or SIV rebound dynamics following ART interruption in most RM. Three alemtuzumab-treated RM failed to manifest rebound viremia during extended follow up after ART withdrawal. However, these animals had the lowest levels of pre-ART SIV replication, suggesting that alemtuzumab may have been effective in RM with early and presumably smaller RCVR. Overall, our study highlights the current limitations of lymphocyte depletion strategies in facilitating the permanent disruption of RCVR, particularly once the RCVR is established above levels that induce consistent post-ART viremia. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

5. Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Author

Tostanoski, Lisa H., Wegmann, Frank, Martinot, Amanda J., Loos, Carolin, McMahan, Katherine, Mercado, Noe B., Yu, Jingyou, Chan, Chi N., Bondoc, Stephen, Starke, Carly E., Nekorchuk, Michael, Busman-Sahay, Kathleen, Piedra-Mora, Cesar, Wrijil, Linda M., Ducat, Sarah, Custers, Jerome, Atyeo, Caroline, Fischinger, Stephanie, Burke, John S., Feldman, Jared, Hauser, Blake M., Caradonna, Timothy M., Bondzie, Esther A., Dagotto, Gabriel, Gebre, Makda S., Jacob-Dolan, Catherine, Lin, Zijin, Mahrokhian, Shant H., Nampanya, Felix, Nityanandam, Ramya, Pessaint, Laurent, Porto, Maciel, Ali, Vaneesha, Benetiene, Dalia, Tevi, Komlan, Andersen, Hanne, Lewis, Mark G., Schmidt, Aaron G., Lauffenburger, Douglas A., Alter, Galit, Estes, Jacob D., Schuitemaker, Hanneke, Zahn, Roland, and Barouch, Dan H.

Published
2020
Full Text
View/download PDF

6. CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption

Author

Harper, Justin, Gordon, Shari, Chan, Chi Ngai, Wang, Hong, Lindemuth, Emily, Galardi, Cristin, Falcinelli, Shane D., Raines, Samuel L. M., Read, Jenna L., Nguyen, Kevin, McGary, Colleen S, Nekorchuk, Michael, Busman-Sahay, Kathleen, Schawalder, James, King, Colin, Pino, Maria, Micci, Luca, Cervasi, Barbara, Jean, Sherrie, Sanderson, Andrew, Johns, Brian, Koblansky, A. Alicia, Amrine-Madsen, Heather, Lifson, Jeffrey, Margolis, David M., Silvestri, Guido, Bar, Katharine J., Favre, David, Estes, Jacob D., and Paiardini, Mirko

Published
2020
Full Text
View/download PDF

7. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Author

McBrien, Julia Bergild, Mavigner, Maud, Franchitti, Lavinia, Smith, S. Abigail, White, Erick, Tharp, Gregory K., Walum, Hasse, Busman-Sahay, Kathleen, Aguilera-Sandoval, Christian R., Thayer, William O., Spagnuolo, Rae Ann, Kovarova, Martina, Wahl, Angela, Cervasi, Barbara, Margolis, David M., Vanderford, Thomas H., Carnathan, Diane G., Paiardini, Mirko, Lifson, Jeffrey D., Lee, John H., Safrit, Jeffrey T., Bosinger, Steven E., Estes, Jacob D., Derdeyn, Cynthia A., Garcia, J. Victor, Kulpa, Deanna A., Chahroudi, Ann, and Silvestri, Guido

Published
2020
Full Text
View/download PDF

8. Rapamycin limits [CD4.sup.+] T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy

Author

Varco-Merth, Benjamin D., Brantley, William, Marenco, Alejandra, Duell, Derick D., Fachko, Devin N., Richardson, Brian, Busman-Sahay, Kathleen, Shao, Danica, Flores, Walter, Engelman, Kathleen, Fukazawa, Yoshinori, Wong, Scott W., Skalsky, Rebecca L., Smedley, Jeremy, Axthelm, Michael K., Lifson, Jeffrey D., Estes, Jacob D., Edlefsen, Paul T., Picker, Louis J., Cameron, Cheryl M.A., Henrich, Timothy J., and Okoye, Afam A.

Subjects
Rhesus monkey -- Drug therapy, Antiviral agents -- Testing, T cell proliferation -- Research, Rapamycin -- Testing, HIV infection -- Drug therapy -- Models, Health care industry
Abstract

Proliferation of latently infected [CD4.sup.+] T cells with replication- competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating [CD4.sup.+] memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of [CD4.sup.+] TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir., Introduction The advent of antiretroviral therapy (ART) has dramatically improved the life expectancy of people with HIV (PWH) infection. However, current ART regimens act by blocking de novo infection of [...]

Published
2022
Full Text
View/download PDF

9. Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

Author

Harper, Justin, Ribeiro, Susan P., Chan, Chi Ngai, Aid, Malika, Deleage, Claire, Micci, Luca, Pino, Maria, Cervasi, Barbara, Raghunathan, Gopalan, Rimmer, Eric, Ayanoglu, Gulesi, Wu, Guoxin, Shenvi, Neeta, Barnard, Richard J.O., Del Prete, Gregory Q., Busman-Sahay, Kathleen, Silvestri, Guido, Kulpa, Deanna A., Bosinger, Steven E., Easley, Kirk A., Howell, Bonnie J., Gorman, Dan, Hazuda, Daria J., Estes, Jacob D., Sekaly, Rafick-Pierre, and Paiardini, Mirko

Subjects
Immunological research, Immune response -- Research, Viremia -- Measurement, Interleukin-10 -- Health aspects, Health care industry
Abstract

Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN [CD4.sup.+] memory subsets, including Tfh cells, and predicted the frequency of [CD4.sup.+] Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory [CD4.sup.+] T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair [CD4.sup.+] T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV., Introduction While the optimization of antiretroviral therapy (ART) has prevented AIDS and reduced HIV-related morbidities and mortality for the majority of people living with HIV (PLWH), a therapeutic regimen capable [...]

Published
2022
Full Text
View/download PDF

12. Correction: Mitigation of endemic GI-tract pathogen-mediated inflammation through development of multimodal treatment regimen and its impact on SIV acquisition in rhesus macaques

Author

Bochart, Rachele M., primary, Busman-Sahay, Kathleen, additional, Bondoc, Stephen, additional, Morrow, David W., additional, Ortiz, Alexandra M., additional, Fennessey, Christine M., additional, Fischer, Miranda B., additional, Shiel, Oriene, additional, Swanson, Tonya, additional, Shriver-Munsch, Christine M., additional, Crank, Hugh B., additional, Armantrout, Kimberly M., additional, Barber-Axthelm, Aaron M., additional, Langner, Charlotte, additional, Moats, Cassandra R., additional, Labriola, Caralyn S., additional, MacAllister, Rhonda, additional, Axthelm, Michael K., additional, Brenchley, Jason M., additional, Keele, Brandon F., additional, Estes, Jacob D., additional, Hansen, Scott G., additional, and Smedley, Jeremy V., additional

Published
2023
Full Text
View/download PDF

13. Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques

Author

Byrnes, Sarah J., primary, Busman-Sahay, Kathleen, additional, Angelovich, Thomas A., additional, Younger, Skyler, additional, Taylor-Brill, Sol, additional, Nekorchuk, Michael, additional, Bondoc, Stephen, additional, Dannay, Rachel, additional, Terry, Margaret, additional, Cochrane, Catherine R., additional, Jenkins, Trisha A., additional, Roche, Michael, additional, Deleage, Claire, additional, Bosinger, Steven E., additional, Paiardini, Mirko, additional, Brew, Bruce J., additional, Estes, Jacob D., additional, and Churchill, Melissa J., additional

Published
2023
Full Text
View/download PDF

14. T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

Author

Okoye, Afam A., Duell, Derick D., Fukazawa, Yoshinori, Varco-Merth, Benjamin, Marenco, Alejandra, Behrens, Hannah, Chaunzwa, Morgan, Selseth, Andrea N., Gilbride, Roxanne M., Shao, Jason, Edlefsen, Paul T., Geleziunas, Romas, Pinkevych, Mykola, Davenport, Miles P., Busman-Sahay, Kathleen, Nekorchuk, Michael, Park, Haesun, Smedley, Jeremy, Axthelm, Michael K., Estes, Jacob D., Hansen, Scott G., Keele, Brandon F., Lifson, Jeffery D., and Picker, Louis J.

Subjects
CD8 lymphocytes -- Health aspects, Antiviral agents -- Patient outcomes, Health care industry
Abstract

To define the contribution of [CD8.sup.+] T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term [CD8.sup.+] T cell depletion using a rhesusized anti-CD8|5 monoclonal antibody on barcoded SIVmac239 dynamics on stable ART and after ART cessation in rhesus macaques (RMs). Among the RMs with full [CD8.sup.+] T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV [RNA.sup.+] cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and DNA in blood and tissue relative to control-treated RMs during ART. Upon ART cessation, both [CD8.sup.+] T cell-depleted and control RMs rebounded in fewer than 12 days, with no difference in the time to viral rebound or in either the number or growth rate of rebounding SIVmac239M barcode clonotypes. However, effectively [CD8.sup.+] T cell-depleted RMs showed a stable, approximately 2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent antiviral [CD8.sup.+] T cell responses can develop during ART-suppressed SIV infection, these responses effectively intercept post-ART SIV rebound only after systemic viral replication, too late to limit reactivation frequency or the early spread of reactivating SIV reservoirs., Introduction [CD8.sup.+] T cells are crucial components of the adaptive immune response against HIV and SIV, and most examples of stringent, long-term, spontaneous and vaccine-associated immune control of these infections [...]

Published
2021
Full Text
View/download PDF

15. Author Correction: Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Author

McBrien, Julia Bergild, Mavigner, Maud, Franchitti, Lavinia, Smith, S. Abigail, White, Erick, Tharp, Gregory K., Walum, Hasse, Busman-Sahay, Kathleen, Aguilera-Sandoval, Christian R., Thayer, William O., Spagnuolo, Rae Ann, Kovarova, Martina, Wahl, Angela, Cervasi, Barbara, Margolis, David M., Vanderford, Thomas H., Carnathan, Diane G., Paiardini, Mirko, Lifson, Jeffrey D., Lee, John H., Safrit, Jeffrey T., Bosinger, Steven E., Estes, Jacob D., Derdeyn, Cynthia A., Garcia, J. Victor, Kulpa, Deanna A., Chahroudi, Ann, and Silvestri, Guido

Published
2020
Full Text
View/download PDF

18. Quantitative Imaging Analysis of the Spatial Relationship between Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus RNA, and Fibrosis in the Spleens of Nonhuman Primates

Author

Devanathan, Aaron S., primary, White, Nicole R., additional, Desyaterik, Yury, additional, De la Cruz, Gabriela, additional, Nekorchuk, Michael, additional, Terry, Margaret, additional, Busman-Sahay, Kathleen, additional, Adamson, Lourdes, additional, Luciw, Paul, additional, Fedoriw, Yuri, additional, Estes, Jacob D., additional, Rosen, Elias P., additional, and Kashuba, Angela D. M., additional

Published
2022
Full Text
View/download PDF

19. Combined protein and nucleic acid imaging reveals virus-dependent B cell and macrophage immunosuppression of tissue microenvironments

Author

Jiang, Sizun, primary, Chan, Chi Ngai, additional, Rovira-Clavé, Xavier, additional, Chen, Han, additional, Bai, Yunhao, additional, Zhu, Bokai, additional, McCaffrey, Erin, additional, Greenwald, Noah F., additional, Liu, Candace, additional, Barlow, Graham L., additional, Weirather, Jason L., additional, Oliveria, John Paul, additional, Nakayama, Tsuguhisa, additional, Lee, Ivan T., additional, Matter, Matthias S., additional, Carlisle, Anne E., additional, Philips, Darci, additional, Vazquez, Gustavo, additional, Mukherjee, Nilanjan, additional, Busman-Sahay, Kathleen, additional, Nekorchuk, Michael, additional, Terry, Margaret, additional, Younger, Skyler, additional, Bosse, Marc, additional, Demeter, Janos, additional, Rodig, Scott J., additional, Tzankov, Alexandar, additional, Goltsev, Yury, additional, McIlwain, David Robert, additional, Angelo, Michael, additional, Estes, Jacob D., additional, and Nolan, Garry P., additional

Published
2022
Full Text
View/download PDF

20. Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques

Author

Aid, Malika, primary, Vidal, Samuel J., additional, Piedra-Mora, Cesar, additional, Ducat, Sarah, additional, Chan, Chi N., additional, Bondoc, Stephen, additional, Colarusso, Alessandro, additional, Starke, Carly E., additional, Nekorchuk, Michael, additional, Busman-Sahay, Kathleen, additional, Estes, Jacob D., additional, Martinot, Amanda J., additional, and Barouch, Dan H., additional

Published
2022
Full Text
View/download PDF

21. Quantitative Imaging Analysis of the Spatial Relationship between Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus RNA, and Collagen in the Mesenteric Lymph Nodes of Nonhuman Primates

Author

Scholz, Erin M. B., primary, Mwangi, Joseph N., additional, De la Cruz, Gabriela, additional, Nekorchuk, Michael, additional, Chan, Chi Ngai, additional, Busman-Sahay, Kathleen, additional, Adamson, Lourdes, additional, Luciw, Paul, additional, Fedoriw, Yuri, additional, Estes, Jacob D., additional, Rosen, Elias P., additional, and Kashuba, Angela D. M., additional

Published
2021
Full Text
View/download PDF

22. Mitigation of endemic GI-tract pathogen-mediated inflammation through development of multimodal treatment regimen and its impact on SIV acquisition in rhesus macaques

Author

Bochart, Rachele M., primary, Busman-Sahay, Kathleen, additional, Bondoc, Stephen, additional, Morrow, David W., additional, Ortiz, Alexandra M., additional, Fennessey, Christine M., additional, Fischer, Miranda B., additional, Shiel, Oriene, additional, Swanson, Tonya, additional, Shriver-Munsch, Christine M., additional, Crank, Hugh B., additional, Armantrout, Kimberly M., additional, Barber-Axthelm, Aaron M., additional, Langner, Charlotte, additional, Moats, Cassandra R., additional, Labriola, Caralyn S., additional, MacAllister, Rhonda, additional, Axthelm, Michael K., additional, Brenchley, Jason M., additional, Keele, Brandon F., additional, Estes, Jacob D., additional, Hansen, Scott G., additional, and Smedley, Jeremy V., additional

Published
2021
Full Text
View/download PDF

23. CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

Author

Okoye, Afam A., primary, Duell, Derick D., additional, Fukazawa, Yoshinori, additional, Varco-Merth, Benjamin, additional, Marenco, Alejandra, additional, Behrens, Hannah, additional, Chaunzwa, Morgan, additional, Selseth, Andrea N., additional, Gilbride, Roxanne M., additional, Shao, Jason, additional, Edlefsen, Paul T., additional, Geleziunas, Romas, additional, Pinkevych, Mykola, additional, Davenport, Miles P., additional, Busman-Sahay, Kathleen, additional, Nekorchuk, Michael, additional, Park, Haesun, additional, Smedley, Jeremy, additional, Axthelm, Michael K., additional, Estes, Jacob D., additional, Hansen, Scott G., additional, Keele, Brandon F., additional, Lifson, Jeffery D., additional, and Picker, Louis J., additional

Published
2021
Full Text
View/download PDF

24. TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma

Author

Gern, Benjamin H., primary, Adams, Kristin N., additional, Plumlee, Courtney R., additional, Stoltzfus, Caleb R., additional, Shehata, Laila, additional, Moguche, Albanus O., additional, Busman-Sahay, Kathleen, additional, Hansen, Scott G., additional, Axthelm, Michael K., additional, Picker, Louis J., additional, Estes, Jacob D., additional, Urdahl, Kevin B., additional, and Gerner, Michael Y., additional

Published
2021
Full Text
View/download PDF

25. CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after ART interruption

Author

Harper, Justin, Gordon, Shari, Chan, Chi Ngai, Wang, Hong, Lindemuth, Emily, Galardi, Cristin, Falcinelli, Shane D., Raines, Samuel L.M., Read, Jenna L., Nguyen, Kevin, McGary, Colleen S, Nekorchuk, Michael, Busman-Sahay, Kathleen, Schawalder, James, King, Colin, Pino, Maria, Micci, Luca, Cervasi, Barbara, Jean, Sherrie, Sanderson, Andrew, Johns, Brian, Koblansky, A. Alicia, Amrine-Madsen, Heather, Lifson, Jeffrey, Margolis, David M., Silvestri, Guido, Bar, Katharine J, Favre, David, Estes, Jacob D., and Paiardini, Mirko

Subjects
Male, Programmed Cell Death 1 Receptor, Simian Acquired Immunodeficiency Syndrome, Antibodies, Monoclonal, Viral Load, Virus Replication, Macaca mulatta, Article, Anti-Retroviral Agents, Withholding Treatment, Animals, CTLA-4 Antigen, Simian Immunodeficiency Virus, Virus Activation, Viremia
Abstract

The primary HIV reservoir is composed of resting memory CD4(+) T-cells, which often express the immune checkpoint receptors PD-1 and CTLA-4 that limit T-cell activation via synergistic mechanisms. Using SIV-infected, long-term anti-retroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4, and dual CTLA-4/PD-1 immune checkpoint blockade (ICB) using monoclonal antibodies is well-tolerated with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T-cell cycling and differentiation; expanding effector-memory T-cells; and inducing robust viral reactivation in plasma and PBMCs. In lymph node, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased total and intact SIV-DNA in CD4(+) T-cells, and SIV-DNA and -RNA in B-cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8(+) T-cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that ICB regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

Published
2020

26. African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Author

Raehtz, Kevin D., Barrenäs, Fredrik, Xu, Cuiling, Busman-Sahay, Kathleen, Valentine, Audrey, Law, Lynn, Ma, Dongzhu, Policicchio, Benjamin B., Wijewardana, Viskam, Brocca-Cofano, Egidio, Trichel, Anita, Gale, Michael, Jr., Keele, Brandon F., Estes, Jacob D., Apetrei, Cristian, Pandrea, Ivona, Raehtz, Kevin D., Barrenäs, Fredrik, Xu, Cuiling, Busman-Sahay, Kathleen, Valentine, Audrey, Law, Lynn, Ma, Dongzhu, Policicchio, Benjamin B., Wijewardana, Viskam, Brocca-Cofano, Egidio, Trichel, Anita, Gale, Michael, Jr., Keele, Brandon F., Estes, Jacob D., Apetrei, Cristian, and Pandrea, Ivona

Abstract

African nonhuman primates that are natural hosts to SIVs can provide us with unique insight into the pathogenesis of HIV disease due to their remarkable ability to avoid progression to AIDS, despite high levels of viral replication. A key question of SIV pathogenesis in natural hosts is whether the lack of disease progression is due to an exquisite ability to repair lesions occurring during the acute infection or to completely maintain the integrity of the mucosal barrier throughout the SIV infection. In pathogenic HIV/SIV infections of humans and macaques, the mucosal integrity is compromised during acute infection, leading to leakage of gut microbial byproducts and to the occurrence of chronic local and systemic inflammation, which plays a crucial role in driving progression to AIDS. Our study shows that the mucosal barrier integrity is never lost in African green monkeys, thereby avoiding the effects of chronic inflammation and disease progression. Unlike HIV infection, SIV infection is generally nonpathogenic in natural hosts, such as African green monkeys (AGMs), despite life-long high viral replication. Lack of disease progression was reportedly based on the ability of SIV-infected AGMs to prevent gut dysfunction, avoiding microbial translocation and the associated systemic immune activation and chronic inflammation. Yet, the maintenance of gut integrity has never been documented, and the mechanism(s) by which gut integrity is preserved are unknown. We sought to investigate the early events of SIV infection in AGMs, specifically examining the impact of SIVsab infection on the gut mucosa. Twenty-nine adult male AGMs were intrarectally infected with SIVsab92018 and serially sacrificed at well-defined stages of SIV infection, preramp-up (1-3 days post-infection (dpi)), ramp-up (4-6 dpi), peak viremia (9-12 dpi), and early chronic SIV infection (46-55 dpi), to assess the levels of immune activation, apoptosis, epithelial damage and microbial translocation in the G

Published
2020
Full Text
View/download PDF

27. Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Tostanoski, Lisa H., Wegmann, Frank, Martinot, Amanda J., Loos, Carolin, McMahan, Katherine, Mercado, Noe B., Yu, Jingyou, Chan, Chi N., Bondoc, Stephen, Starke, Carly E., Nekorchuk, Michael, Busman-Sahay, Kathleen, Piedra-Mora, Cesar, Wrijil, Linda M., Ducat, Sarah, Custers, Jerome, Atyeo, Caroline, Fischinger, Stephanie, Burke, John S., Feldman, Jared, Hauser, Blake M., Caradonna, Timothy M., Bondzie, Esther A., Dagotto, Gabriel, Gebre, Makda S., Jacob-Dolan, Catherine, Lin, Zijin, Mahrokhian, Shant H., Nampanya, Felix, Nityanandam, Ramya, Pessaint, Laurent, Porto, Maciel, Ali, Vaneesha, Benetiene, Dalia, Tevi, Komlan, Andersen, Hanne, Lewis, Mark G., Schmidt, Aaron G., Lauffenburger, Douglas A, Alter, Galit, Estes, Jacob D., Schuitemaker, Hanneke, Zahn, Roland, Barouch, Dan H., Massachusetts Institute of Technology. Department of Biological Engineering, Tostanoski, Lisa H., Wegmann, Frank, Martinot, Amanda J., Loos, Carolin, McMahan, Katherine, Mercado, Noe B., Yu, Jingyou, Chan, Chi N., Bondoc, Stephen, Starke, Carly E., Nekorchuk, Michael, Busman-Sahay, Kathleen, Piedra-Mora, Cesar, Wrijil, Linda M., Ducat, Sarah, Custers, Jerome, Atyeo, Caroline, Fischinger, Stephanie, Burke, John S., Feldman, Jared, Hauser, Blake M., Caradonna, Timothy M., Bondzie, Esther A., Dagotto, Gabriel, Gebre, Makda S., Jacob-Dolan, Catherine, Lin, Zijin, Mahrokhian, Shant H., Nampanya, Felix, Nityanandam, Ramya, Pessaint, Laurent, Porto, Maciel, Ali, Vaneesha, Benetiene, Dalia, Tevi, Komlan, Andersen, Hanne, Lewis, Mark G., Schmidt, Aaron G., Lauffenburger, Douglas A, Alter, Galit, Estes, Jacob D., Schuitemaker, Hanneke, Zahn, Roland, and Barouch, Dan H.

Abstract

Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters and nonhuman primates have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.

Published
2020

28. Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Author

Hoang, Timothy N., primary, Pino, Maria, additional, Boddapati, Arun K., additional, Viox, Elise G., additional, Starke, Carly E., additional, Upadhyay, Amit A., additional, Gumber, Sanjeev, additional, Nekorchuk, Michael, additional, Busman-Sahay, Kathleen, additional, Strongin, Zachary, additional, Harper, Justin L., additional, Tharp, Gregory K., additional, Pellegrini, Kathryn L., additional, Kirejczyk, Shannon, additional, Zandi, Keivan, additional, Tao, Sijia, additional, Horton, Tristan R., additional, Beagle, Elizabeth N., additional, Mahar, Ernestine A., additional, Lee, Michelle Y.H., additional, Cohen, Joyce, additional, Jean, Sherrie M., additional, Wood, Jennifer S., additional, Connor-Stroud, Fawn, additional, Stammen, Rachelle L., additional, Delmas, Olivia M., additional, Wang, Shelly, additional, Cooney, Kimberly A., additional, Sayegh, Michael N., additional, Wang, Lanfang, additional, Filev, Peter D., additional, Weiskopf, Daniela, additional, Silvestri, Guido, additional, Waggoner, Jesse, additional, Piantadosi, Anne, additional, Kasturi, Sudhir P., additional, Al-Shakhshir, Hilmi, additional, Ribeiro, Susan P., additional, Sekaly, Rafick P., additional, Levit, Rebecca D., additional, Estes, Jacob D., additional, Vanderford, Thomas H., additional, Schinazi, Raymond F., additional, Bosinger, Steven E., additional, and Paiardini, Mirko, additional

Published
2021
Full Text
View/download PDF

29. Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques

Author

Aid, Malika, primary, Busman-Sahay, Kathleen, additional, Vidal, Samuel J., additional, Maliga, Zoltan, additional, Bondoc, Stephen, additional, Starke, Carly, additional, Terry, Margaret, additional, Jacobson, Connor A., additional, Wrijil, Linda, additional, Ducat, Sarah, additional, Brook, Olga R., additional, Miller, Andrew D., additional, Porto, Maciel, additional, Pellegrini, Kathryn L., additional, Pino, Maria, additional, Hoang, Timothy N., additional, Chandrashekar, Abishek, additional, Patel, Shivani, additional, Stephenson, Kathryn, additional, Bosinger, Steven E., additional, Andersen, Hanne, additional, Lewis, Mark G., additional, Hecht, Jonathan L., additional, Sorger, Peter K., additional, Martinot, Amanda J., additional, Estes, Jacob D., additional, and Barouch, Dan H., additional

Published
2020
Full Text
View/download PDF

30. The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

Author

Webb, Gabriela M., primary, Molden, Jhomary, additional, Busman-Sahay, Kathleen, additional, Abdulhaqq, Shaheed, additional, Wu, Helen L., additional, Weber, Whitney C., additional, Bateman, Katherine B., additional, Reed, Jason S., additional, Northrup, Mina, additional, Maier, Nicholas, additional, Tanaka, Shiho, additional, Gao, Lina, additional, Davey, Brianna, additional, Carpenter, Benjamin L., additional, Axthelm, Michael K., additional, Stanton, Jeffrey J., additional, Smedley, Jeremy, additional, Greene, Justin M., additional, Safrit, Jeffrey T., additional, Estes, Jacob D., additional, Skinner, Pamela J., additional, and Sacha, Jonah B., additional

Published
2020
Full Text
View/download PDF

31. African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Author

Raehtz, Kevin D., primary, Barrenäs, Fredrik, additional, Xu, Cuiling, additional, Busman-Sahay, Kathleen, additional, Valentine, Audrey, additional, Law, Lynn, additional, Ma, Dongzhu, additional, Policicchio, Benjamin B., additional, Wijewardana, Viskam, additional, Brocca-Cofano, Egidio, additional, Trichel, Anita, additional, Gale, Michael, additional, Keele, Brandon F., additional, Estes, Jacob D., additional, Apetrei, Cristian, additional, and Pandrea, Ivona, additional

Published
2020
Full Text
View/download PDF

32. TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

Author

Schleimann, Mariane H., Kobbero, Maria-Louise, Vibholm, Line K., Kjaer, Kathrine, Giron, Leila B., Busman-Sahay, Kathleen, Chan, Chi Ngai, Nekorchuk, Michael, Schmidt, Manuel, Wittig, Burghardt, Damsgaard, Tine E., Ahlburg, Peter, Hellfritzsch, Michel B., Zuwala, Kaja, Rothemejer, Frederik H., Olesen, Rikke, Schommers, Phillipp, Klein, Florian, Dweep, Harsh, Kossenkov, Andrew, Nyengaard, Jens R., Estes, Jacob D., Abdel-Mohsen, Mohamed, Ostergaard, Lars, Tolstrup, Martin, Sogaard, Ole S., Denton, Paul W., Schleimann, Mariane H., Kobbero, Maria-Louise, Vibholm, Line K., Kjaer, Kathrine, Giron, Leila B., Busman-Sahay, Kathleen, Chan, Chi Ngai, Nekorchuk, Michael, Schmidt, Manuel, Wittig, Burghardt, Damsgaard, Tine E., Ahlburg, Peter, Hellfritzsch, Michel B., Zuwala, Kaja, Rothemejer, Frederik H., Olesen, Rikke, Schommers, Phillipp, Klein, Florian, Dweep, Harsh, Kossenkov, Andrew, Nyengaard, Jens R., Estes, Jacob D., Abdel-Mohsen, Mohamed, Ostergaard, Lars, Tolstrup, Martin, Sogaard, Ole S., and Denton, Paul W.

Abstract

Background: TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes. Methods: Participants receivedMGN1703 for 24weeks concurrentwith antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed. Findings: MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed. Interpretation: Our data present novel evidence that the TLR9 agonist MGN 1703 modulates human lymph node B cells in vivo. These findingswarrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. (C) 2019 The Authors. Published by Elsevier B.V.

Published
2019

33. TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

Author

Schleimann, Mariane H., primary, Kobberø, Maria-Louise, additional, Vibholm, Line K., additional, Kjær, Kathrine, additional, Giron, Leila B., additional, Busman-Sahay, Kathleen, additional, Chan, Chi Ngai, additional, Nekorchuk, Michael, additional, Schmidt, Manuel, additional, Wittig, Burghardt, additional, Damsgaard, Tine E., additional, Ahlburg, Peter, additional, Hellfritzsch, Michel B., additional, Zuwala, Kaja, additional, Rothemejer, Frederik H., additional, Olesen, Rikke, additional, Schommers, Phillipp, additional, Klein, Florian, additional, Dweep, Harsh, additional, Kossenkov, Andrew, additional, Nyengaard, Jens R., additional, Estes, Jacob D., additional, Abdel-Mohsen, Mohamed, additional, Østergaard, Lars, additional, Tolstrup, Martin, additional, Søgaard, Ole S., additional, and Denton, Paul W., additional

Published
2019
Full Text
View/download PDF

37. The Ia.2 Epitope Defines a Subset of Lipid Raft Resident MHC Class II Molecules Crucial to Effective Antigen Presentation1

Author

Busman-Sahay, Kathleen, Sargent, Elizabeth, Harton, Jonathan A., and Drake, James R.

Subjects
Antigen Presentation, B-Lymphocytes, Epitopes, Mice, Membrane Microdomains, T-Lymphocytes, Histocompatibility Antigens Class II, Animals, Humans, Cell Communication, Lymphocyte Activation, Article
Abstract

Previous work established that binding of the 11-5.2 anti-I-A(k) mAb, which recognizes the Ia.2 epitope on I-A(k) class II molecules, elicits MHC class II signaling, whereas binding of two other anti-I-A(k) mAbs that recognize the Ia.17 epitope fail to elicit signaling. Using a biochemical approach, we establish that the Ia.2 epitope recognized by the widely used 11-5.2 mAb defines a subset of cell surface I-A(k) molecules predominantly found within membrane lipid rafts. Functional studies demonstrate that the Ia.2-bearing subset of I-A(k) class II molecules is critically necessary for effective B cell-T cell interactions, especially at low Ag doses, a finding consistent with published studies on the role of raft-resident class II molecules in CD4 T cell activation. Interestingly, B cells expressing recombinant I-A(k) class II molecules possessing a β-chain-tethered hen egg lysosome peptide lack the Ia.2 epitope and fail to partition into lipid rafts. Moreover, cells expressing Ia.2(-) tethered peptide-class II molecules are severely impaired in their ability to present both tethered peptide or peptide derived from exogenous Ag to CD4 T cells. These results establish the Ia.2 epitope as defining a lipid raft-resident MHC class II conformer vital to the initiation of MHC class II-restricted B cell-T cell interactions.

Published
2011

41. Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

Author

Busman-Sahay, Kathleen, Drake, Lisa, Sitaram, Anand, Marks, Michael, Drake, James R, Busman-Sahay, Kathleen, Drake, Lisa, Sitaram, Anand, Marks, Michael, and Drake, James R

Abstract

Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system.

Published
2013

43. Cytokine crowdsourcing: multicellular production of TH17‐associated cytokines

Author

Busman‐Sahay, Kathleen O., Walrath, Travis, Huber, Samuel, and O’Connor, William

Abstract

Review of critical non‐TH17 sources of IL‐17A and associated cytokines during inflammation in mucosal tissues, with a focus on leukocytes of the gastrointestinal tract. In the 2 decades since its discovery, IL‐17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL‐17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL‐17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL‐17F, IL‐21, IL‐22, and IL‐26) or associated with other T cell lineages (e.g., IFN‐γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best‐understood cell types that secrete IL‐17A, they are frequently neither the earliest nor dominant producers. Indeed, non‐TH17 cell sources of IL‐17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17‐associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL‐17A and TH17‐associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non‐TH17 cell sources of IL‐17A and other TH17‐associated cytokines relevant to inflammatory events in mucosal tissues.

Published
2015
Full Text
View/download PDF

44. Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

Author

Hoang TN, Viox EG, Upadhyay AA, Strongin Z, Tharp GK, Pino M, Nchioua R, Hirschenberger M, Gagne M, Nguyen K, Harper JL, Marciano S, Boddapati AK, Pellegrini KL, Tisoncik-Go J, Whitmore LS, Karunakaran KA, Roy M, Kirejczyk S, Curran EH, Wallace C, Wood JS, Connor-Stroud F, Kasturi SP, Levit RD, Gale M Jr, Vanderford TH, Silvestri G, Busman-Sahay K, Estes JD, Vaccari M, Douek DC, Sparrer KMJ, Kirchhoff F, Johnson RP, Schreiber G, Bosinger SE, and Paiardini M

Abstract

Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-β pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.

Published
2022
Full Text
View/download PDF

45. Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

Author

Hoang TN, Pino M, Boddapati AK, Viox EG, Starke CE, Upadhyay AA, Gumber S, Busman-Sahay K, Strongin Z, Harper JL, Tharp GK, Pellegrini KL, Kirejczyk S, Zandi K, Tao S, Horton TR, Beagle EN, Mahar EA, Lee MY, Cohen J, Jean SM, Wood JS, Connor-Stroud F, Stammen RL, Delmas OM, Wang S, Cooney KA, Sayegh MN, Wang L, Weiskopf D, Filev PD, Waggoner J, Piantadosi A, Kasturi SP, Al-Shakhshir H, Ribeiro SP, Sekaly RP, Levit RD, Estes JD, Vanderford TH, Schinazi RF, Bosinger SE, and Paiardini M

Abstract

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

Published
2020
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results