Browsing by Author "Li, Jonathan Z"

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    An enhanced isothermal amplification assay for viral detection.
    (Nature communications, 2020-11) Qian, Jason; Boswell, Sarah A; Chidley, Christopher; Lu, Zhi-Xiang; Pettit, Mary E; Gaudio, Benjamin L; Fajnzylber, Jesse M; Ingram, Ryan T; Ward, Rebecca H; Li, Jonathan Z; Springer, Michael
    Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.
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    Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.
    (Annals of internal medicine, 2021-08) Kuriakose, Safia; Singh, Kanal; Pau, Alice K; Daar, Eric; Gandhi, Rajesh; Tebas, Pablo; Evans, Laura; Gulick, Roy M; Lane, H Clifford; Masur, Henry; NIH COVID-19 Treatment Guidelines Panel; Aberg, Judith A; Adimora, Adaora A; Baker, Jason; Kreuziger, Lisa Baumann; Bedimo, Roger; Belperio, Pamela S; Cantrill, Stephen V; Coopersmith, Craig M; Davis, Susan L; Dzierba, Amy L; Gallagher, John J; Glidden, David V; Grund, Birgit; Hardy, Erica J; Hinkson, Carl; Hughes, Brenna L; Johnson, Steven; Keller, Marla J; Kim, Arthur Y; Lennox, Jeffrey L; Levy, Mitchell M; Li, Jonathan Z; Martin, Greg S; Naggie, Susanna; Pavia, Andrew T; Seam, Nitin; Simpson, Steven Q; Swindells, Susan; Tien, Phyllis; Waghmare, Alpana A; Wilson, Kevin C; Yazdany, Jinoos; Zachariah, Philip; Campbell, Danielle M; Harrison, Carly; Burgess, Timothy; Francis, Joseph; Sheikh, Virginia; Uyeki, Timothy M; Walker, Robert; Brooks, John T; Ortiz, Laura Bosque; Davey, Richard T; Doepel, Laurie K; Eisinger, Robert W; Han, Alison; Higgs, Elizabeth S; Nason, Martha C; Crew, Page; Lerner, Andrea M; Lund, Claire; Worthington, Christopher
    The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.
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    Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy.
    (The Journal of infectious diseases, 2017-07) Henrich, Timothy J; Hobbs, Kristen S; Hanhauser, Emily; Scully, Eileen; Hogan, Louise E; Robles, Yvonne P; Leadabrand, Kaitlyn S; Marty, Francisco M; Palmer, Christine D; Jost, Stephanie; Körner, Christian; Li, Jonathan Z; Gandhi, Rajesh T; Hamdan, Ayad; Abramson, Jeremy; LaCasce, Ann S; Kuritzkes, Daniel R

    Background

    Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses.

    Methods

    We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors.

    Results

    Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy.

    Conclusions

    Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy.
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    Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.
    (Science translational medicine, 2021-10) Bordt, Evan A; Shook, Lydia L; Atyeo, Caroline; Pullen, Krista M; De Guzman, Rose M; Meinsohn, Marie-Charlotte; Chauvin, Maeva; Fischinger, Stephanie; Yockey, Laura J; James, Kaitlyn; Lima, Rosiane; Yonker, Lael M; Fasano, Alessio; Brigida, Sara; Bebell, Lisa M; Roberts, Drucilla J; Pépin, David; Huh, Jun R; Bilbo, Staci D; Li, Jonathan Z; Kaimal, Anjali; Schust, Danny J; Gray, Kathryn J; Lauffenburger, Douglas; Alter, Galit; Edlow, Andrea G
    There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
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    Placental Expression of ACE2 and TMPRSS2 in Maternal Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Are Placental Defenses Mediated by Fetal Sex?
    (The Journal of infectious diseases, 2021-12) Shook, Lydia L; Bordt, Evan A; Meinsohn, Marie-Charlotte; Pepin, David; De Guzman, Rose M; Brigida, Sara; Yockey, Laura J; James, Kaitlyn E; Sullivan, Mackenzie W; Bebell, Lisa M; Roberts, Drucilla J; Kaimal, Anjali J; Li, Jonathan Z; Schust, Danny; Gray, Kathryn J; Edlow, Andrea G

    Background

    Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection.

    Methods

    Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA).

    Results

    Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .34) exposed to maternal SARS-CoV-2.

    Conclusions

    Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection, which may have implications for offspring vulnerability to placental infection.