Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor–stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.
Michael J. Kratochvil, Gernot Kaber, Sally Demirdjian, Pamela C. Cai, Elizabeth B. Burgener, Nadine Nagy, Graham L. Barlow, Medeea Popescu, Mark R. Nicolls, Michael G. Ozawa, Donald P. Regula, Ana E. Pacheco-Navarro, Samuel Yang, Vinicio A. de Jesus Perez, Harry Karmouty-Quintana, Andrew M. Peters, Bihong Zhao, Maximilian L. Buja, Pamela Y. Johnson, Robert B. Vernon, Thomas N. Wight, Stanford COVID-19 Biobank Study Group, Carlos E. Milla, Angela J. Rogers, Andrew J. Spakowitz, Sarah C. Heilshorn, Paul L. Bollyky
Immunosuppressed patients with inflammatory bowel disease (IBD) generate lower amounts of SARS-CoV-2 spike antibodies after mRNA vaccination than healthy controls. We assessed SARS-CoV-2 spike S1 receptor binding domain–specific (S1-RBD–specific) B lymphocytes to identify the underlying cellular defects. Patients with IBD produced fewer anti–S1-RBD antibody–secreting B cells than controls after the first mRNA vaccination and lower amounts of total and neutralizing antibodies after the second. S1-RBD–specific memory B cells were generated to the same degree in IBD and control groups and were numerically stable for 5 months. However, the memory B cells in patients with IBD had a lower S1-RBD–binding capacity than those in controls, which is indicative of a defect in antibody affinity maturation. Administration of a third shot to patients with IBD elevated serum antibodies and generated memory B cells with a normal antigen-binding capacity. These results show that patients with IBD have defects in the formation of antibody-secreting B cells and affinity-matured memory B cells that are corrected by a third vaccination.
Kathryn A. Pape, Thamotharampillai Dileepan, William E. Matchett, Charles Ellwood, Samuel Stresemann, Amanda J. Kabage, Daria Kozysa, Clayton Evert, Michael Matson, Sharon Lopez, Peter D. Krueger, Carolyn T. Graiziger, Byron P. Vaughn, Eugenia Shmidt, Joshua Rhein, Timothy W. Schacker, Tyler D. Bold, Ryan A. Langlois, Alexander Khoruts, Marc K. Jenkins
Long COVID, a type of Post-Acute Sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 could be exacerbated by microbial translocation (from gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation – measured as β-glucan, a fungal cell wall polysaccharide – in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from negative controls. This higher NF-κB signaling was abrogated by Piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.
Leila B. Giron, Michael J. Peluso, Jianyi Ding, Grace Kenny, Netanel F. Zilberstein, Jane Koshy, Kai Ying Hong, Heather Rasmussen, Gregory E. Miller, Faraz Bishehsari, Robert A. Balk, James N. Moy, Rebecca Hoh, Scott Lu, Aaron R. Goldman, Hsin-Yao Tang, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, J. Daniel Kelly, Haimanot Wasse, Jeffrey N. Martin, Qin Liu, Ali Keshavarzian, Alan Landay, Steven G. Deeks, Timothy J. Henrich, Mohamed Abdel-Mohsen
Vaccine-elicited SARS-CoV-2 antibody responses are an established correlate of protection against viral infection in humans and non-human primates. However, it is less clear that vaccine-induced immunity is able to limit infection-elicited inflammation in the lower respiratory tract. To assess this, we collected bronchoalveolar lavage fluid samples post-SARS-CoV-2 strain USA-WA1/2020 challenge from rhesus macaques vaccinated with mRNA-1273 in a dose-reduction study. Single-cell transcriptomic profiling revealed a broad cellular landscape 48 hours post-challenge with distinct inflammatory signatures that correlated with viral RNA burden in the lower respiratory tract. These inflammatory signatures included phagocyte-restricted expression of chemokines such as CXCL10 (IP10) and CCL3 (MIP-1A) and the broad expression of interferon-induced genes such as MX1, ISG15, and IFIT1. Induction of these inflammatory profiles was suppressed by prior mRNA-1273 vaccination in a dose-dependent manner, and negatively correlated with pre-challenge serum and lung antibody titers against SARS-CoV-2 spike. These observations were replicated and validated in a second independent macaque challenge study using the B.1.351/beta-variant of SARS-CoV-2. These data support a model wherein vaccine-elicited antibody responses restrict viral replication following SARS-CoV-2 exposure, including limiting viral dissemination to the lower respiratory tract and infection-mediated inflammation and pathogenesis.
Adam T. Waickman, Kaitlin Victor, Krista Newell, Tao Li, Heather Friberg, Kathryn E. Foulds, Mario Roederer, Diane L. Bolton, Jeffrey R. Currier, Robert Seder
Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines (from December 2020 through August 2021) were matched with 30 naturally infected women (from March 2020 through January 2021) by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type Spike, these nAbs were less effective against the Delta and Mu Spike variants. Vaccination during the third trimester induced higher cord nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure.
Yusuke Matsui, Lin Li, Mary Prahl, Arianna G. Cassidy, Nida Ozarslan, Yarden Golan, Veronica J. Gonzalez, Christine Y. Lin, Unurzul Jigmeddagva, Megan A. Chidboy, Mauricio Montano, Taha Y. Taha, Mir M. Khalid, Bharath Sreekumar, Jennifer M. Hayashi, Pei-Yi Chen, G. Renuka Kumar, Lakshmi Warrier, Alan H.B. Wu, Dongli Song, Priya Jegatheesan, Daljeet S. Rai, Balaji Govindaswami, Jordan M. Needens, Monica Rincon, Leslie Myatt, Ifeyinwa V. Asiodu, Valerie J. Flaherman, Yalda Afshar, Vanessa L. Jacoby, Amy P. Murtha, Joshua F. Robinson, Melanie Ott, Warner C. Greene, Stephanie L Gaw
The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC) containing a heavily mutated spike protein capable of escaping preexisting immunity identifies a continued need for interventional measures. Molnupiravir (MK-4482), an orally administered nucleoside analog, has demonstrated efficacy against earlier SARS-CoV-2 lineages and was recently approved for SARS-CoV-2 infections in high-risk adults. Here we assessed the efficacy of MK-4482 against the earlier Alpha, Beta and Delta VOCs and Omicron in the hamster COVID-19 model. Omicron replication and associated lung disease in vehicle treated hamsters was reduced compared to the earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of Alpha, Beta and Delta VOC infected hamsters. Importantly, MK-4482 profoundly inhibited virus replication in the upper and lower respiratory tract of hamsters infected with the Omicron VOC. Consistent with its mutagenic mechanism, MK-4482 treatment had a more pronounced inhibitory effect on infectious titers compared to viral RNA genome load. Histopathologic analysis showed that MK-4482 treatment caused a concomitant reduction in the level of lung disease and viral antigen load in infected hamsters across all VOCs examined. Together, our data indicate the potential of MK-4482 as an effective antiviral against known SARS-CoV-2 VOCs, especially Omicron, and likely future SARS-CoV-2 variants.
Kyle Rosenke, Atsushi Okumura, Matthew C. Lewis, Friederike Feldmann, Kimberly Meade-White, William F. Bohler, Amanda J. Griffin, Rebecca Rosenke, Carl Shaia, Michael A. Jarvis, Heinz Feldmann
BACKGROUND. Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses. METHODS. To test whether a short course of CSA was safe in COVID-19 patients, we treated 10 hospitalized, oxygen requiring, non-critically ill patients with CSA (starting dose of 9mg/kg/day). We evaluated patients for clinical response and adverse events and measured serum cytokines and chemokines associated with COVID-19 hyper-inflammation and conducted gene-expression analyses. RESULTS. Five subjects experienced adverse events, none were serious; transaminitis was most common. No subject required intensive care unit (ICU)-level care and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyper-inflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I interferon gene expression signatures and other transcriptional profiles associated with exacerbated hyper-inflammation in the peripheral blood cells of these patients. CONCLUSIONS. Short courses of CSA appear safe and feasible in COVID-19 patients requiring oxygen and may be a useful adjunct in resource-limited health care settings. TRIAL REGISTRATION. This trial was registered on ClinicalTrials.gov (IND#149997, ClinicalTrials.gov identifier: NCT04412785). FUNDING. This study was internally funded by the Center for Cellular Immunotherapies
Emily A. Blumberg, Julia Han Noll, Pablo Tebas, Joseph A. Fraietta, Ian Frank, Amy E. Marshall, Anne Chew, Elizabeth A. Veloso, Alison Carulli, Walter Rogal, Avery L. Gaymon, Aliza H. Schmidt, Tiffany Barnette, Renee Jurek, Rene Martins, Briana M. Hudson, Kalyan Chavda, Christina M. Bailey, Sarah E. Church, Hooman Noorchashm, Wei-Ting Hwang, Carl H. June, Elizabeth O. Hexner
BACKGROUND. Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). METHODS. This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. RESULTS. We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS. Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups. FUNDING. Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR) /COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (T.H.W. and A.C.G); CIHR FDN-143250 (T.H.W.), GA2- 177716 (V.C., A.C.G., T.H.W.), GA1-177703 (A.C.G.) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to A.C.G.).
Roya M. Dayam, Jaclyn C. Law, Rogier L. Goetgebuer, Gary Y.C. Chao, Kento T. Abe, Mitchell Sutton, Naomi Finkelstein, Joanne M. Stempak, Daniel Pereira, David Croitoru, Lily Acheampong, Saima Rizwan, Klaudia Rymaszewski, Raquel Milgrom, Darshini Ganatra, Nathalia V. Batista, Melanie Girard, Irene Lau, Ryan Law, Michelle W. Cheung, Bhavisha Rathod, Julia Kitaygorodsky, Reuben Samson, Queenie Hu, W. Rod Hardy, Nigil Haroon, Robert D. Inman, Vincent Piguet, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar injury shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of lethal COVID-19.
Michael Chait, Mine M. Yilmaz, Shanila Shakil, Amy W. Ku, Pranay Dogra, Thomas J. Connors, Peter A. Szabo, Joshua I. Gray, Steven B. Wells, Masaru Kubota, Rei Matsumoto, Maya M.L. Poon, Mark E. Snyder, Matthew R. Baldwin, Peter A. Sims, Anjali Saqi, Donna L. Farber, Stuart P. Weisberg
SARS-CoV-2 has resulted in over 450 million confirmed cases since 2019. Although several vaccines have been certified by World Health Organization and are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralisation by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 challenge in the K18-hACE2 mouse model. Our data demonstrates that intravenous BCG vaccination induces robust trained innate immune responses and provides protection against wild-type SARS-CoV-2 as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in the K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between intravenous BCG vaccination and protection against SARS-CoV-2 challenge.
Bao-Zhong Zhang, Huiping Shuai, Hua-rui Gong, Jing-Chu Hu, Bingpeng Yan, Terrence Tsz-Tai Yuen, Ye-Fan Hu, Chaemin Yoon, Xiao-Lei Wang, Yuxin Hou, Xuansheng Lin, Xiner Huang, Renhao Li, Yee Man Au-Yeung, Wenjun Li, Bingjie Hu, Yue Chai, Ming Yue, Jian-Piao Cai, Guang Sheng Ling, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Jasper Fuk-Woo Chan, Jian-Dong Huang, Hin Chu
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