New mouse model for inducible hACE2 expression enables to dissect SARS-CoV-2 pathology beyond the respiratory system

Mammalian Genome, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection is not limited to the respiratory tract as receptors, including angiotensin-converting enzyme 2 (ACE2), are expressed across many tissues. This study employed a new conditional mouse model, Rosa26creERT2/chACE2, which expresses human ACE2 (hACE2) multiple organs, investigate effects of SARS-CoV-2 beyond system. strain demonstrated susceptibility in dose and sex-dependent manner, showing that infected male mice exhibited more severe disease outcomes, significant weight loss, pronounced lung pathology dysfunction, increased mortality, compared females. In contrast intratracheal infection, intranasal virus administration facilitated viral spread brain, thereby underscoring nasal route's role pathogenesis neurological manifestations. Intranasal also led innate immune system activation administration, even though both routes activated adaptive response. model provides valuable tool individual tissues or use multisystemic approach, it advances possibilities for preclinical evaluation antiviral therapies vaccine strategies.

Language: Английский

---

SARS-CoV-2 infection primes cross-protective respiratory IgA in a MyD88- and MAVS-dependent manner

npj Vaccines, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 27, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is constantly evolving mutations in the Spike protein to evade humoral immunity. Respiratory tract antiviral IgA antibodies are superior circulating IgG preventing SARS-CoV-2 infection. However, role of innate immune signals required for induction mucosal against infection unknown. Here we show that hamsters recovered from ancestral cross-protected heterologous alpha, gamma, delta, and omicron BA.1 variants. Intranasal vaccination with an inactivated whole virus vaccine completely protects In addition, intranasal boost mice unadjuvanted induces robust levels anti-Spike a Furthermore, our findings suggest MyD88 MAVS play memory response following booster These provide useful basis development cross-protective vaccines

Language: Английский

---

CRISPR-Cas9 genetic screens reveal regulation of TMPRSS2 by the Elongin BC-VHL complex

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 7, 2025

Abstract The TMPRSS2 cell surface protease is used by a broad range of respiratory viruses to facilitate entry into target cells. Together with ACE2, represents key factor for SARS-CoV-2 infection, as mediates cleavage viral spike protein, enabling direct fusion the envelope host membrane. Since start COVID-19 pandemic, has gained attention therapeutic inhibitors which would inhibit but little known about regulation, particularly in types physiologically relevant infection. Here, we performed an unbiased genome-wide CRISPR-Cas9 library screen, together targeted at epigenetic modifiers and transcriptional regulators, identify cellular factors that modulate expression human colon epithelial We find endogenous regulated Elongin BC-VHL complex HIF transcription factors. Depletion B or treatment cells PHD resulted downregulation inhibition show still utilised Omicron variants colonic Our study enhances our understanding regulation

Language: Английский

---

Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19

Disease Models & Mechanisms, Journal Year: 2025, Volume and Issue: 18(9)

Published: April 8, 2025

ABSTRACT Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 deaths, it has become evident that COVID-19 is not solely pulmonary disease. Emerging evidence shown that, subset patients, certain symptoms − including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain – all indicate role vascular, neurological gastrointestinal (GI) pathology disease process. Many these processes persist long after been resolved, ‘long COVID’ or post-acute sequelae (PASC). The molecular mechanisms underlying systemic conditions associated remain incompletely defined. Appropriate animal models provide method understanding at system level through study progression, tissue pathology, immune response to pathogen behavioral responses. However, very few studies have addressed PASC whether existing hold promise for studying this challenging problem. Here, we review current literature on cardiovascular, GI pathobiology caused by along established manifestations their prospects use studies. Our aim guidance selection appropriate order recapitulate aspects enhance translatability mechanistic

Language: Английский

---

Exploring TMPRSS2 Drug Target to Combat Influenza and Coronavirus Infection

Scientifica, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Respiratory viral infections, including influenza and coronaviruses, present significant health risks worldwide. The recent COVID‐19 pandemic highlights the urgent need for novel effective antiviral agents. host cell protease, transmembrane serine protease 2 (TMPRSS2), facilitates pathogenesis by playing a critical role in invasion disease progression. This is coexpressed with receptors of angiotensin‐converting enzyme (ACE2) SARS‐CoV‐2 human respiratory tract plays activating proteins spreading. TMPRSS2 activates coronavirus spike (S) protein permits membrane fusion entry cleaving virus surface glycoproteins. It also hemagglutinin (HA) protein, an necessary spread virus. inhibitors can reduce propagation morbidity blocking into cells reducing spread, inflammation, severity. review examines replication pathogenicity. offers potential avenues to develop targeted antivirals inhibit function, suggesting possible focus on development. Ultimately, seeks contribute improving public outcomes related these infections.

Language: Английский

---