Infectious Disease

Infectious Disease Publications

Zabaleta N, Dai W, Bhatt U, Hérate C, Maisonnasse P, Chichester JA, Sanmiguel J, Estelien R, Michalson KT, Diop C, Maciorowski D, Dereuddre-Bosquet N, Cavarelli M, Gallouët A-S, Naninck T, Kahlaoui N, Lemaitre J, Qi W, Hudspeth E, Cucalon A, Dyer CD, Pampena BM, Knox JJ, LaRocque RC, Charles RC, Li D, Kim M, Sheridan A, Storm N, Johnson RI, Feldman J, Hauser BM, Contreras V, Marlin R, Tsong Fang RH, Chapon C, van der Werf S, Zinn E, Ryan A, Kobayashi DT, Chauhan R, McGlynn M, Ryan ET, Schmidt AG, Price B, Honko A, Griffiths A, Yaghmour S, Hodge R, Betts MR, Freeman MW, Wilson JM, Le Grand R, Vandenberghe LH. An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates. Cell Host Microbe 2021;29(9):1437-1453.e8.Abstract
The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.
Nathan A, Rossin EJ, Kaseke C, Park RJ, Khatri A, Koundakjian D, Urbach JM, Singh NK, Bashirova A, Tano-Menka R, Senjobe F, Waring MT, Piechocka-Trocha A, Garcia-Beltran WF, Iafrate JA, Naranbhai V, Carrington M, Walker BD, Gaiha GD. Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses. Cell 2021;184(17):4401-4413.e10.Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8+ T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8+ T cell reactivity in convalescent individuals but reduced recognition in recipients of mRNA-based vaccines. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T-cell-based vaccine against emerging variants and SARS-like coronaviruses.
Ung L, Chodosh J. Urgent unmet needs in the care of bacterial keratitis: An evidence-based synthesis. Ocul Surf 2021;Abstract
Bacterial corneal infections, or bacterial keratitis (BK), are ophthalmic emergencies that frequently lead to irreversible visual impairment. Though increasingly recognized as a major cause of global blindness, modern paradigms of evidence-based care in BK have remained at a diagnostic and therapeutic impasse for over half a century. Current standards of management - based on the collection of corneal cultures and the application of broad-spectrum topical antibiotics - are beset by important yet widely underrecognized limitations, including approximately 30% of all patients who will develop moderate to severe vision loss in the affected eye. Though recent advances have involved a more clearly defined role for adjunctive topical corticosteroids, and novel therapies such as corneal crosslinking, overall progress to improve patient and population-based outcomes remains incommensurate to the chronic morbidity caused by this disease. Recognizing that the care of BK is guided by the clinical axiom, "time equals vision", this chapter offers an evidence-based synthesis for the clinical management of these infections, underscoring critical unmet needs in disease prevention, diagnosis, and treatment.
Kaseke C, Park RJ, Singh NK, Koundakjian D, Bashirova A, Garcia Beltran WF, Takou Mbah OC, Ma J, Senjobe F, Urbach JM, Nathan A, Rossin EJ, Tano-Menka R, Khatri A, Piechocka-Trocha A, Waring MT, Birnbaum ME, Baker BM, Carrington M, Walker BD, Gaiha GD. HLA class-I-peptide stability mediates CD8+ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV. Cell Rep 2021;36(2):109378.Abstract
Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.
Song A, Deshmukh R, Lin H, Ang M, Mehta JS, Chodosh J, Said DG, Dua HS, Ting DSJ. Post-keratoplasty Infectious Keratitis: Epidemiology, Risk Factors, Management, and Outcomes. Front Med (Lausanne) 2021;8:707242.Abstract
Post-keratoplasty infectious keratitis (PKIK) represents a unique clinical entity that often poses significant diagnostic and therapeutic challenges. It carries a high risk of serious complications such as graft rejection and failure, and less commonly endophthalmitis. Topical corticosteroids are often required to reduce the risk of graft rejection but their use in PKIK may act as a double-edged sword, particularly in fungal infection. The increased uptake in lamellar keratoplasty in the recent years has also led to complications such as graft-host interface infectious keratitis (IIK), which is particularly difficult to manage. The reported incidence of PKIK differs considerably across different countries, with a higher incidence observed in developing countries (9.2-11.9%) than developed countries (0.02-7.9%). Common risk factors for PKIK include the use of topical corticosteroids, suture-related problems, ocular surface diseases and previous corneal infection. PKIK after penetrating keratoplasty or (deep) anterior lamellar keratoplasty is most commonly caused by ocular surface commensals, particularly Gramme-positive bacteria, whereas PKIK after endothelial keratoplasty is usually caused by Candida spp. Empirical broad-spectrum antimicrobial treatment is the mainstay of treatment for both PKIK, though surgical interventions are required in medically refractory cases (during the acute phase) and those affected by visually significant scarring (during the late phase). In this paper, we aim to provide a comprehensive overview on PKIK, encompassing the epidemiology, risk factors, causes, management and outcomes, and to propose a treatment algorithm for systematically managing this challenging condition.
Ou J, Zhou Z, Dai R, Zhang J, Zhao S, Wu X, Lan W, Ren Y, Cui L, Lan Q, Lu L, Seto D, Chodosh J, Wu J, Zhang G, Zhang Q. V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity. J Virol 2021;95(16):e0061721.Abstract
The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.
Ung L, Chodosh J. Foundational concepts in the biology of bacterial keratitis. Exp Eye Res 2021;:108647.Abstract
Bacterial infections of the cornea, or bacterial keratitis (BK), are notorious for causing rapidly fulminant disease and permanent vision loss, even among treated patients. In the last sixty years, dramatic upward trajectories in the frequency of BK have been observed internationally, driven in large part by the commercialization of hydrogel contact lenses in the late 1960s. Despite this worsening burden of disease, current evidence-based therapies for BK - including broad-spectrum topical antibiotics and, if indicated, topical corticosteroids - fail to salvage vision in a substantial proportion of affected patients. Amid growing concerns of rapidly diminishing antibiotic utility, there has been renewed interest in urgently needed novel treatments that may improve clinical outcomes on an individual and public health level. Bridging the translational gap in the care of BK requires the identification of new therapeutic targets and rational treatment design, but neither of these aims can be achieved without understanding the complex biological processes that determine how bacterial corneal infections arise, progress, and resolve. In this chapter, we synthesize the current wealth of human and animal experimental data that now inform our understanding of basic BK pathophysiology, in context with modern concepts in ocular immunology and microbiology. By identifying the key molecular determinants of clinical disease, we explore how novel treatments can be developed and translated into routine patient care.
Than T, Morettin CE, Harthan JS, Hartwick ATE, Huecker JB, Johnson SD, Migneco MK, Shorter E, Whiteside M, Margolis MS, Olson CK, Alferez CS, van Zyl T, Rodic-Polic B, Storch GA, Gordon MO. Efficacy of a Single Administration of 5% Povidone-Iodine in the Treatment of Adenoviral Conjunctivitis. Am J Ophthalmol 2021;Abstract
PURPOSE: To evaluate the safety and efficacy of a single, in-office administration of 5% povidone-iodine (PVP-I) compared to artificial tears (AT) for adenoviral conjunctivitis (Ad-Cs). DESIGN: Double-masked pilot randomized trial METHODS: Patients presenting with presumed adenoviral conjunctivitis were screened at 9 U.S. clinics. INCLUSION CRITERIA: ≥ 18 years of age, symptoms ≤ 4 days and a positive AdenoPlus® test. EXCLUSION CRITERIA: thyroid disease, iodine allergy, recent ocular surgery, and ocular findings inconsistent with early-stage Ad-Cs. Randomization was to a single administration of 5% PVP-I or AT in one eye and examinations on days 1-2, 4, 7, 14 and 21 with conjunctival swabs taken each visit for quantitative polymerase chain reaction. Primary outcome was percent reduction from peak viral load. Secondary outcomes were improvement in clinical signs and symptoms. RESULTS: Of 56 patients randomized, 28 had detectable viral titers at baseline. Day 4 post-treatment, viral titers in the 5% PVP-I and AT groups were 2.5% ± 2.7% and 14.4% ± 10.5% of peak respectively (p=0.020). Severity of participant-reported tearing, lid swelling and redness as well as clinician-graded mucoid discharge, bulbar redness and bulbar edema were lower in the 5% PVP-I group than AT group on Day 4 (p< 0.05). After Day 4, viral titers, severity of signs and symptoms decreased markedly in both groups and no differences between groups were detected. CONCLUSIONS: Pilot data suggest a single, in-office administration of 5% PVP-I could reduce viral load and hasten improvement of clinical signs and symptoms in patients with Ad-Cs.
Singh RB, Liu L, Yung A, Anchouche S, Mittal SK, Blanco T, Dohlman TH, Yin J, Dana R. Ocular redness - II: Progress in development of therapeutics for the management of conjunctival hyperemia. Ocul Surf 2021;21:66-77.Abstract
Conjunctival hyperemia is one of the most common causes for visits to primary care physicians, optometrists, ophthalmologists, and emergency rooms. Despite its high incidence, the treatment options for patients with conjunctival hyperemia are restricted to over-the-counter drugs that provide symptomatic relief due to short duration of action, tachyphylaxis and rebound redness. As our understanding of the immunopathological pathways causing conjunctival hyperemia expands, newer therapeutic targets are being discovered. These insights have also contributed to the development of animal models for mimicking the pathogenic changes in microvasculature causing hyperemia. Furthermore, this progress has catalyzed the development of novel therapeutics that provide efficacious, long-term relief from conjunctival hyperemia with minimal adverse effects.
Keffeler EC, Iyer VS, Parthasarathy S, Ramsey MM, Gorman MJ, Barke TL, Varahan S, Olson S, Gilmore MS, Abdullahi ZH, Hancock EN, Hancock LE. Influence of the Alternative Sigma Factor RpoN on Global Gene Expression and Carbon Catabolism in Enterococcus faecalis V583. mBio 2021;12(3)Abstract
The alternative sigma factor σ54 has been shown to regulate the expression of a wide array of virulence-associated genes, as well as central metabolism, in bacterial pathogens. In Gram-positive organisms, the σ54 is commonly associated with carbon metabolism. In this study, we show that the Enterococcus faecalis alternative sigma factor σ54 (RpoN) and its cognate enhancer binding protein MptR are essential for mannose utilization and are primary contributors to glucose uptake through the Mpt phosphotransferase system. To gain further insight into how RpoN contributes to global transcriptional changes, we performed microarray transcriptional analysis of strain V583 and an isogenic rpoN mutant grown in a chemically defined medium with glucose as the sole carbon source. Transcripts of 340 genes were differentially affected in the rpoN mutant; the predicted functions of these genes mainly related to nutrient acquisition. These differentially expressed genes included those with predicted catabolite-responsive element (cre) sites, consistent with loss of repression by the major carbon catabolite repressor CcpA. To determine if the inability to efficiently metabolize glucose/mannose affected infection outcome, we utilized two distinct infection models. We found that the rpoN mutant is significantly attenuated in both rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI). Here, we examined a ccpA mutant in the CAUTI model and showed that the absence of carbon catabolite control also significantly attenuates bacterial tissue burden in this model. Our data highlight the contribution of central carbon metabolism to growth of E. faecalis at various sites of infection.IMPORTANCE Hospital-acquired infections account for 2 billion dollars annually in increased health care expenses and cause more than 100,000 deaths in the United States alone. Enterococci are the second leading cause of hospital-acquired infections. They form biofilms at surgical sites and are often associated with infections of the urinary tract following catheterization. Nutrient uptake and growth are key factors that influence their ability to cause disease. Our research identified a large set of genes that illuminate nutrient uptake pathways in enterococci. Perturbation of the metabolic circuit reduces virulence in a rabbit endocarditis model, as well as in catheter-associated urinary tract infection in mice. Targeting metabolic pathways that are important in infection may lead to new treatments against multidrug-resistant enterococcal infections.
Haque M, Lei F, Xiong X, Ren Y, Peng H-Y, Wang L, Kumar A, Das JK, Song J. Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells. Viruses 2021;13(5)Abstract
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.
Succar T, Beaver HA, Lee AG. Impact of COVID-19 Pandemic on Ophthalmology Medical Student Teaching: Educational Innovations, Challenges, and Future Directions. Surv Ophthalmol 2021;Abstract
Graduate medical education (GME) in ophthalmology has faced and overcome many challenges over the past years and 2020 has been a game-changing year. Although the severe acute respiratory syndrome coronavirus (SARS-CoV2) pandemic disrupted medical education globally, ophthalmic educators rapidly transformed their curricula to novel and effective virtual learning formats. Thus, while the COVID-19 outbreak has been one of the most significant challenges faced in the history of medical education, it has also provided an impetus to develop innovative teaching practices, bringing with it unprecedented success in allowing medical students to continue their education in ophthalmology despite these challenges. We review and appraise novel educational interventions implemented by various institutions in response to the COVID-19 pandemic, highlighting their effectiveness, challenges and proposing future directions beyond the pandemic. Many of these innovations will persist even after the end of the pandemic because they have proven that face-to-face learning is not required for all aspects of the ophthalmic GME curriculum. As ophthalmic educators harness the power of educational technology it is critical that their novel educational initiatives are incorporated into competency-based curricula with assessments mapped to the competencies. Future research should focus on evaluating the impact of this transformation to virtual learning environments on student performances as well as implementing longitudinal assessment strategies for clinical competence in workplace-based practice.
O'Hare M, Amarnani D, Whitmore HAB, An M, Marino C, Ramos L, Delgado-Tirado S, Hu X, Chmielewska N, Chandrahas A, Fitzek A, Heinrich F, Steurer S, Ondruschka B, Glatzel M, Krasemann S, Sepulveda-Falla D, Lagares D, Pedron J, Bushweller JH, Liu P, Arboleda-Velasquez JF, Kim LA. Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators. Am J Pathol 2021;191(7):1193-1208.Abstract
Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-β1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.
Muus C, Luecken MD, Eraslan G, Sikkema L, Waghray A, Heimberg G, Kobayashi Y, Vaishnav ED, Subramanian A, Smillie C, Jagadeesh KA, Duong ET, Fiskin E, Triglia ET, Ansari M, Cai P, Lin B, Buchanan J, Chen S, Shu J, Haber AL, Chung H, Montoro DT, Adams T, Aliee H, Allon SJ, Andrusivova Z, Angelidis I, Ashenberg O, Bassler K, Bécavin C, Benhar I, Bergenstråhle J, Bergenstråhle L, Bolt L, Braun E, Bui LT, Callori S, Chaffin M, Chichelnitskiy E, Chiou J, Conlon TM, Cuoco MS, Cuomo ASE, Deprez M, Duclos G, Fine D, Fischer DS, Ghazanfar S, Gillich A, Giotti B, Gould J, Guo M, Gutierrez AJ, Habermann AC, Harvey T, He P, Hou X, Hu L, Hu Y, Jaiswal A, Ji L, Jiang P, Kapellos TS, Kuo CS, Larsson L, Leney-Greene MA, Lim K, Litviňuková M, Ludwig LS, Lukassen S, Luo W, Maatz H, Madissoon E, Mamanova L, Manakongtreecheep K, Leroy S, Mayr CH, Mbano IM, McAdams AM, Nabhan AN, Nyquist SK, Penland L, Poirion OB, Poli S, Qi CC, Queen R, Reichart D, Rosas I, Schupp JC, Shea CV, Shi X, Sinha R, Sit RV, Slowikowski K, Slyper M, Smith NP, Sountoulidis A, Strunz M, Sullivan TB, Sun D, Talavera-López C, Tan P, Tantivit J, Travaglini KJ, Tucker NR, Vernon KA, Wadsworth MH, Waldman J, Wang X, Xu K, Yan W, Zhao W, Ziegler CGK, Ziegler CGK, Ziegler CGK. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med 2021;27(3):546-559.Abstract
Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2TMPRSS2 cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

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