Biology subjects

Allue Guardia, A.

Publications and source records attributed to Allue Guardia, A..

4 recordsLinked to original sources

bioRxiv2025

Targeting ROCK Signaling Mitigates Influenza Virus-Induced Fibrogenesis in Human Airway Organoids

Influenza A virus (IAV) pandemics continue to pose serious global health threats, particularly to immunocompromised individuals, children, and the elderly. IAV infections trigger inflammation and tissue damage, promoting lung fibrosis. Unraveling these mechanisms is key to preventing and treating viral-induced pulmonary fibrosis and its lasting impact on respiratory health. Despite available antivirals and vaccines, there is a lack of FDA-approved therapeutics for severe or prolonged IAV pathogenesis. We modeled infection with a recombinant highly pathogenic human A/Texas/37/2024 H5N1 (rHPh-TX H5N1) strain using human airway organoids (HAO) to investigate viral replication, innate immune response, infection-induced fibrogenesis, and therapeutic approaches. The rHPh-TX H5N1 replicated efficiently, triggering a potent interferon (IFN) response and pro-inflammatory cytokine expression in HAO. Prolonged infection led to increased fibroblast-like cells surrounding infected areas, characterized by increased alpha-smooth muscle actin (-SMA) expression and upregulation of transforming growth factor-beta (TGF-{beta}), which caused fibroblast activation and extracellular matrix remodeling. Fibrosis-associated markers (FN, COL1A, COL3A, MMP2, MMP9) were significantly higher than in HAO infected with a pandemic recombinant A/California/04/09 H1N1 (pH1N1). Notably, Rho-associated coiled-coil-forming protein kinase (ROCK) pathway inhibition reduced fibrogenesis, with ROCK1 inhibition proving more effective than ROCK2 inhibition. These findings highlight the potential of targeting ROCK signaling to mitigate IAV-induced lung fibrosis.

microbiology↗

bioRxiv2022

Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to a worldwide Coronavirus Disease 2019 (COVID-19) pandemic. Despite high efficacy of the authorized vaccines, protection against the surging variants of concern (VoC) was less robust. Live-attenuated vaccines (LAV) have been shown to elicit robust and long-term protection by induction of host innate and adaptive immune responses. We sought to develop a COVID-19 LAV by generating 3 double open reading frame (ORF)-deficient recombinant (r)SARS-CoV-2 simultaneously lacking two accessory open reading frame (ORF) proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). Here, we report that these double ORF-deficient rSARS-CoV-2 have slower replication kinetics and reduced fitness in cultured cells as compared to their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2 showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against different SARS-CoV-2 VoC, and also activated viral component-specific T-cell responses. Notably, the double ORF-deficient rSARS-CoV-2 were able to protect, as determined by inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2. Collectively, our results demonstrate the feasibility to implement these double ORF-deficient rSARS-CoV-2 as safe, stable, immunogenic and protective LAV for the prevention of SARS-CoV-2 infection and associated COVID-19 disease.

microbiology↗

bioRxiv2021

The aging lung mucosa: A proteomics study

The elderly population is at increased risk of acute and chronic respiratory infections and other pulmonary diseases, and it is estimated that this population will double in the next 30 years. Biochemical changes in the lung alveolar mucosa and lung cells alter local immune response as we age, creating opportunities for invading pathogens to establish successful infections. Indeed, the lungs of the elderly are a pro-inflammatory, pro-oxidative, dysregulated environment but this environment has remained understudied. We performed a comprehensive, quantitative proteomic profile of the lung mucosa in the elderly, developing insight into the molecular fingerprints, pathways, and regulatory networks that characterize the lung in old age. We identified neutrophils in the lungs of elderly individuals as possible contributors to dysregulated lung tissue environment. This study establishes a baseline for future investigations to develop strategies to mitigate susceptibility to respiratory infections in the elderly.

systems biology↗

bioRxiv2020

Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice

ABSTRACTVaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease currently lacks a validated small animal model. Here, we show that transgenic mice expressing human angiotensin converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2-transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2-transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 4. K18 hACE2-transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

microbiology↗