Biology subjects

Tseng, A. E.

Publications and source records attributed to Tseng, A. E..

5 recordsLinked to original sources

bioRxiv2025

A Mouse Model of SARS-CoV-2-Driven Acute Maladaptive Responses and Chronic Systemic Diseases

Our understanding of SARS-CoV-2 acute and post-acute pathogenesis is hindered by the lack of adequate small animal models. We present RAB/6N, a mouse model prone to severe disease after exposure to SARS-CoV-2 clinical isolates, with lethal cases showing no widespread brain infection typical of the widely used K18-hACE2 mouse model. Lung viral replication in RAB/6N mice remains steady for several days before a decline in viral titers. Delayed initiation of infection clearance is marked by increased lung T-cell extravasation and type-2 immune responses, leading to maladaptive lung consolidation. While systemic antiviral cytokine responses only correlate with SARS-CoV-2 brain infection in K18-hACE2 mice, they are concomitant with pulmonary immune dynamics in infected RAB/6N mice. Convalescent RAB/6N mice display systemic inflammation and decreased antibody titers against SARS-CoV-2 spike RBD, persistent viral RNA and prolonged lymphoid infiltration in the lungs. These animals also exhibit signatures of multi-organ dysfunction, cognitive impairment, cardiac inflammation, hyper- immunoglobulin production, and various autoimmune disorders, illuminating the molecular correlates of various pathologies associated with post-acute sequelae of COVID-19 (PASC). RAB/6N mice pave the way for dissecting the molecular drivers underlying SARS-CoV-2-induced acute maladaptive responses and subsequent post-acute systemic diseases. This preclinical platform also opens opportunities for the exploration of therapeutic interventions against systemic PASC and for anticipating the emergence of PASC-associated comorbidities. One-sentence summaryWe generated a hACE2-transgenic mouse model that develops maladaptive lung immune responses upon acute SARS-CoV-2 infection, leading to fatal outcomes or post-acute systemic disease syndromes in convalescent animals.

microbiology↗

bioRxiv2025

Sub-phenotypes of pneumonia defined by pulmonary histopathological features

Establishing sub-phenotypes of pneumonia based on distinct host processes will be a step towards using host-directed therapies (to complement microbe-directed therapies) more rationally and precisely. Although pneumonia is a pulmonary pathophysiology, histological changes within the lungs have not been leveraged for sub-phenotyping. We addressed this by scoring 18 histopathology features (e.g., type 2 cell hyperplasia or necrosis) across rapid autopsy lung samples from 276 elderly subjects with pneumonia. Machine learning algorithms segregated subjects into seven different sub-phenotypes of pneumonia with distinct histopathology signatures. Quantitative immunofluorescence demonstrated associations of macrophages, neutrophils, T cells, and B cells with select histology features and pulmonary pathology sub-phenotypes. Mouse models revealed corollary sub-phenotypes, although some histology features observed in human lungs were never observed in mice. By illuminating this spectrum of histopathologies and discriminating discrete sub-phenotypes of pneumonia, a foundational framework emerges for developing and using host-directed therapies for subsets of pneumonia patients.

immunology↗

bioRxiv2024

Resolution of SARS-CoV-2 infection in human lung tissues is driven by extravascular CD163+ monocytes

While human autopsy samples have provided insights into pulmonary immune mechanisms associated with severe viral respiratory diseases, the mechanisms that contribute to a clinically favorable resolution of viral respiratory infections remain unclear due to the lack of proper experimental systems. Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues. Viral infection is rapidly cleared from fLX following a peak of viral replication, histopathological manifestations of lung disease and loss of AT2 program, as reported in human COVID-19 patients. Infection resolution is associated with the activation of a limited number of hematopoietic subsets, including inflammatory monocytes and non-canonical double-negative T-cells with cytotoxic functions, which are highly enriched in viral RNA and dissipate upon infection resolution. Activation of specific human fibroblast and endothelial subsets also elicit robust antiviral and monocyte chemotaxis signatures, respectively. Notably, systemic depletion of human CD4+ cells, but not CD3+ cells, abrogates infection resolution in fLX and induces persistent infection, supporting evidence that peripheral CD4+ monocytes are important contributors to SARS-CoV-2 infection resolution in lung tissues. Collectively, our findings unravel a comprehensive picture of the immunological events defining effective resolution of SARS-CoV-2 infection in human lung tissues, revealing markedly divergent immunological trajectories between resolving and fatal COVID-19 cases.

immunology↗

bioRxiv2023

Aberrant macrophage activation and failed regeneration of pulmonary epithelium promote tuberculosis progression uniquely in lung tissue

Pulmonary tuberculosis (PTB) represents 85% of the disease burden caused by Mycobacterium tuberculosis (Mtb) and promotes aerosol transmission infecting about a quarter of people globally. Most Mtb infections are effectively limited within primary granulomatous lesions. Containment failures lead to hematogenous spread and the formation of post-primary destructive PTB lesions. Factors that favor Mtb survival and replication in the lungs after hematogenous spread despite systemic immunity represent appealing targets for host-directed TB therapies, but are currently unknown. We developed a novel mouse model that mimics progression of chronic post-primary PTB in humans: wherein PTB lesions form after hematogenous spread from a remote primary lesion in immunocompetent but TB-susceptible B6.Sst1S mice. The B6.Sst1S mice developed PTB lesions featuring granulomatous pneumonia, bronchogenic expansion and broncho-occlusion closely resembling post-primary PTB in humans. Using spatial transcriptomic and fluorescent multiplexed immunochemistry, we demonstrated the expansion of myeloid cell populations with the appearance of alternatively activated macrophages, dissolution of initial lymphoid follicles, and accumulation of de-differentiated lung epithelial cells in the advanced PTB lesions. To determine whether lung parenchymal cells or lung oxygenation were necessary for the pulmonary TB progression, we implanted lung and spleen fragments subcutaneously to serve as potential targets for hematogenous spread. The lung (but not spleen) implants displayed characteristic organized granulomas with necrosis and Mtb replication demonstrating that deleterious interactions of aberrantly activated macrophages with the inflammation-injured lung resident cells, and possibly hypoxia, not oxygenation, are critical determinants of PTB progression in immunocompetent hosts. Necrotic TB lesions also developed in subcutaneous implants of human lung tissue in mice with human immune system after respiratory infection. These animal models may serve to further dissect the lung-specific mechanisms of host susceptibility to virulent Mtb and for testing therapeutic interventions targeting these mechanisms.

immunology↗

bioRxiv2022

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

immunology↗